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Michael J Rennie

University of Nottingham,
School of Graduate Entry Medicine and Health,
Derby Royal Hospital
Uttoxeter Rd
Derby DE22 3DT
michael.rennie@nottingham.ac.uk
+44(0)1332724603
mobile +44(0)7766662383
michael.rennie@nottingham.ac.uk
Date of Birth 28th July, 1946

School Royal Grammar School Newcastle upon Tyne. 1954-64 (Ochiltree Scholar)

Degrees and Honours: BSc Hons Biological Chemistry/Zoology, Hull 1968; MSc Neurochemistry by Thesis, Manchester 1970; PhD, Hormonal and Metabolic effects of Exercise University of Glasgow 1973. Fellow Royal Society of Edinburgh 1995. Fellow Higher Education Academy 2001.
Present positions: Professor of Clinical Physiology, School of Biomedical Sciences, University of Nottingham at School of Graduate Entry Medicine and Health Derby; also Associate Director Research and Development , South Derbyshire Acute Hospitals NHS Trust and Honorary Professor University of Dundee. Member of 2008 HEFCE Research Assessment Panel 46.

Previous Career
1970-74 Research Assistant, Department of Neurology, Glasgow
1974-76 MRC Travelling Fellow & Instructor, Washington University, St Louis, Mo., U.S.A.
1976-77 Muscular Dystrophy Association of America, Fellow and Instructor as above
1977-79 Lecturer in Human Metabolism, University College London Medical School.
1979-83 Wellcome Senior Lecturer, Department of Medicine, University College London Medical School.
1983-88 Professor of Physiology, Division of Molecular Physiology, University of Dundee. Active teacher, researcher and
administrator in RAE grade 5* Unit of Assessment 2002; appointed Symers Professor , September 1985
1991- 97 Head of Department of Anatomy & Physiology, University of Dundee.
1997-98 Head of Division of Biological Sciences , Faculty of Science

Editorial Brds: Past: Clinical Science; Eur J Appl Physiol;; Biochem J; J Parent & Ent Nutr.; Clin Nutr; Am J Physiol; Eur J Clin invest; J Physiol (Lond), Senior Distributing Editor and member of management Committee 2001-3. Editor, British Journal of Intensive Care. Editor-in -Chief of The Journal of Physiology from July 2010

Honours: Arvid Wretlind Lecturer of European Society of Parenteral and Enteral Nutrition, 1985. Rank Prize Funds Award, 1988. Fellow of the Royal Society of Edinburgh, (elected March 1995). Sir G Lindor Brown Prize Lecturer of The Physiological Society of Great Britain and Ireland, 2003-4

Grant funding: Over 30 y of continuous funding from UK research councils (MRC and BBSRC) , industry, medical charities , EC, US NIH.

Journal articles

2013
Bethan E Phillips, Kenneth Smith, Sarah Liptrot, Philip J Atherton, Krishna Varadhan, Michael J Rennie, Mike Larvin, Jonathan N Lund, John P Williams (2013)  Effect of colon cancer and surgical resection on skeletal muscle mitochondrial enzyme activity in colon cancer patients: a pilot study.   J Cachexia Sarcopenia Muscle 4: 1. 71-77 Mar  
Abstract: Colon cancer (CC) patients commonly suffer declines in muscle mass and aerobic function. We hypothesised that CC would be associated with reduced muscle mass and mitochondrial enzyme activity and that curative resection would exacerbate these changes.
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2012
Vinod Kumar, Philip J Atherton, Anna Selby, Debbie Rankin, John Williams, Kenneth Smith, Natalie Hiscock, Michael J Rennie (2012)  Muscle protein synthetic responses to exercise: effects of age, volume, and intensity.   J Gerontol A Biol Sci Med Sci 67: 11. 1170-1177 Nov  
Abstract: We explored the relationships between resistance exercise volume/intensity and muscle myofibrillar protein synthetic (MPS) responses in young and older men. In a crossover design, four groups of six young (24±6 years) and older (70±5 years) men performed two volumes of resistance exercise: either 40% one repetition maximum (1RM) (3 à 14, then 6 à 14 repetitions) or 75% 1RM (3 à 8, then 6 à 8 repetitions), such that at the same volume, work was identical between intensities. Muscle biopsies were taken 0, 1, 2, and 4hours after exercise to measure MPS via myofibrillar bound [1,2-(13)C(2)]leucine and indices of mammalian target of rapamycin signaling by immunoblotting. In younger men, doubling exercise volume produced limited added effects, whereas in older men, it resulted in greater MPS and p70S6 kinase (p70S6K(Thr389)) phosphorylation at both intensities, that is, MPS area under the curve: 75% (1à volume: 0.07±0.01 vs 2à volume: 0.14% ± 0.02% protein synthesized/4hours (p < .001). Doubling exercise volume is a valid strategy to maximize postexercise MPS in ageing.
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Bethan Phillips, John Williams, Philip Atherton, Kenneth Smith, Wulf Hildebrandt, Debbie Rankin, Paul Greenhaff, Ian Macdonald, Michael J Rennie (2012)  Resistance exercise training improves age-related declines in leg vascular conductance and rejuvenates acute leg blood flow responses to feeding and exercise.   J Appl Physiol 112: 3. 347-353 Feb  
Abstract: One manifestation of age-related declines in vascular function is reduced peripheral (limb) blood flow and vascular conduction at rest and in response to vasodilatory stimuli such as exercise and feeding. Since, even in older age, resistance exercise training (RET) represents an efficacious strategy for increasing muscle mass and function, we hypothesized that likewise RET would improve age-related declines in leg blood flow (LBF) and vascular conductance (LVC). We studied three mixed-sex age groups (young: 18-28 yr, n = 14; middle aged: 45-55 yr, n = 20; older: 65-75 yr, n = 17) before and after 20 wk of whole body RET in the postabsorptive state (BASAL) and after unilateral leg extensions (6 à 8 repetitions; 75% 1 repetition maximum) followed by intermittent mixed-nutrient liquid feeds (â¼6.5 kJ·kg(-1)·30 min(-1)), which allowed us to discern the acute effects of feeding (nonexercised leg; FED) and exercise plus feeding (exercised leg; FEDEX) on vascular function. We measured LBF using Doppler ultrasound and recorded mean arterial pressure (MAP) to calculate LVC. Our results reveal that although neither age nor RET influenced BASAL LBF, age-related declines in LBF responses to FED were eradicated by RET. Moreover, increases in LBF after FEDEX, which occurred only in young and middle-aged groups before RET (+73 ± 9%, and +90 ± 13%, P < 0.001, respectively), increased in all groups after RET (young +78 ± 10%, middle-aged +96 ± 15%, older +80 ± 19%, P < 0.001). Finally, RET robustly improved LVC under FASTED, FED, and FEDEX conditions in the older group. These data provide novel information that supports the premise that RET represents a valuable strategy to counter age-related impairments in LBF/LVC.
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2011
Gordon I Smith, Philip Atherton, Dominic N Reeds, B Selma Mohammed, Debbie Rankin, Michael J Rennie, Bettina Mittendorfer (2011)  Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women.   Clin Sci (Lond) 121: 6. 267-278 Sep  
Abstract: Increased dietary LCn-3PUFA (long-chain n-3 polyunsaturated fatty acid) intake stimulates muscle protein anabolism in individuals who experience muscle loss due to aging or cancer cachexia. However, it is not known whether LCn-3PUFAs elicit similar anabolic effects in healthy individuals. To answer this question, we evaluated the effect of 8 weeks of LCn-3PUFA supplementation (4 g of Lovaza®/day) in nine 25-45-year-old healthy subjects on the rate of muscle protein synthesis (by using stable isotope-labelled tracer techniques) and the activation (phosphorylation) of elements of the mTOR (mammalian target of rapamycin)/p70S6K (p70 S6 kinase) signalling pathway during basal post-absorptive conditions and during a hyperinsulinaemic-hyperaminoacidaemic clamp. We also measured the concentrations of protein, RNA and DNA in muscle to obtain indices of the protein synthetic capacity, translational efficiency and cell size. Neither the basal muscle protein fractional synthesis rate nor basal signalling element phosphorylation changed in response to LCn-3PUFA supplementation, but the anabolic response to insulin and amino acid infusion was greater after LCn-3PUFA [i.e. the muscle protein fractional synthesis rate during insulin and amino acid infusion increased from 0.062±0.004 to 0.083±0.007%/h and the phospho-mTOR (Ser2448) and phospho-p70S6K (Thr389) levels increased by â¼50%; all P<0.05]. In addition, the muscle protein concentration and the protein/DNA ratio (i.e. muscle cell size) were both greater (P<0.05) after LCn-3PUFA supplementation. We conclude that LCn-3PUFAs have anabolic properties in healthy young and middle-aged adults.
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Nicholas A Burd, Daniel W D West, Daniel R Moore, Philip J Atherton, Aaron W Staples, Todd Prior, Jason E Tang, Michael J Rennie, Steven K Baker, Stuart M Phillips (2011)  Enhanced amino acid sensitivity of myofibrillar protein synthesis persists for up to 24 h after resistance exercise in young men.   J Nutr 141: 4. 568-573 Apr  
Abstract: We aimed to determine whether an exercise-mediated enhancement of muscle protein synthesis to feeding persisted 24 h after resistance exercise. We also determined the impact of different exercise intensities (90% or 30% maximal strength) or contraction volume (work-matched or to failure) on the response at 24 h of recovery. Fifteen men (21 ± 1 y, BMI = 24.1 ± 0.8 kg · m(-2)) received a primed, constant infusion of l-[ring-(13)C(6)]phenylalanine to measure muscle protein synthesis after protein feeding at rest (FED; 15 g whey protein) and 24 h after resistance exercise (EX-FED). Participants performed unilateral leg exercises: 1) 4 sets at 90% of maximal strength to failure (90FAIL); 2) 30% work-matched to 90FAIL (30WM); or 3) 30% to failure (30FAIL). Regardless of condition, rates of mixed muscle protein and sarcoplasmic protein synthesis were similarly stimulated at FED and EX-FED. In contrast, protein ingestion stimulated rates of myofibrillar protein synthesis above fasting rates by 0.016 ± 0.002%/h and the response was enhanced 24 h after resistance exercise, but only in the 90FAIL and 30FAIL conditions, by 0.038 ± 0.012 and 0.041 ± 0.010, respectively. Phosphorylation of protein kinase B on Ser473 was greater than FED at EX-FED only in 90FAIL, whereas phosphorylation of mammalian target of rapamycin on Ser2448 was significantly increased at EX-FED above FED only in the 30FAIL condition. Our results suggest that resistance exercise performed until failure confers a sensitizing effect on human skeletal muscle for at least 24 h that is specific to the myofibrillar protein fraction.
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E A Wilkes, A L Selby, A T Cole, J G Freeman, M J Rennie, Z H Khan (2011)  Poor tolerability of thalidomide in end-stage oesophageal cancer.   Eur J Cancer Care (Engl) 20: 5. 593-600 Sep  
Abstract: Oesophageal cancer cachexia is a significant clinical problem, resulting in excessive morbidity and mortality. In a pilot study, 10 patients with cachexia due to advanced cancer of the oesophagus gained weight, including lean tissue, after 14-day treatment with thalidomide. Here, we present randomised placebo controlled trial data over a 6-week period to test the hypothesis that thalidomide is superior to placebo in terms of weight gain in patients with cachexia caused by oesophageal cancer. Thalidomide, 200 mg daily, or an identical placebo was given to patients with advanced oesophageal cancer. Total body weight and lean body mass were assessed in addition to drug tolerability and performance indices. Thirty-four patients were recruited. Of these, six given thalidomide and 16 given placebo completed the protocol; all withdrawals were due to adverse drug reactions or complications of disease. Thalidomide showed no benefit over placebo in participants who completed the protocol. These data suggest that thalidomide is poorly tolerated in patients with advanced cancer of the oesophagus and may not ameliorate the progression of cachexia. In the absence of hard supportive evidence, off-licence treatment with thalidomide should be used with great caution as an adjunct to nutritional support in patients with advanced cancer.
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René Koopman, Benjamin G Gleeson, Annemie P Gijsen, Bart Groen, Joan M G Senden, Michael J Rennie, Luc J C van Loon (2011)  Post-exercise protein synthesis rates are only marginally higher in type I compared with type II muscle fibres following resistance-type exercise.   Eur J Appl Physiol 111: 8. 1871-1878 Aug  
Abstract: We examined the effect of an acute bout of resistance exercise on fractional muscle protein synthesis rates in human type I and type II muscle fibres. After a standardised breakfast (31 ± 1 kJ kg(-1) body weight, consisting of 52 Energy% (En%) carbohydrate, 34 En% protein and 14 En% fat), 9 untrained men completed a lower-limb resistance exercise bout (8 sets of 10 repetitions leg press and leg extension at 70% 1RM). A primed, continuous infusion of L: -[ring-(13)C(6)]phenylalanine was combined with muscle biopsies collected from both legs immediately after exercise and after 6 h of post-exercise recovery. Single muscle fibres were dissected from freeze-dried biopsies and stained for ATPase activity with pre-incubation at a pH of 4.3. Type I and II fibres were separated under a light microscope and analysed for protein-bound L: -[ring-(13)C(6)]phenylalanine labelling. Baseline (post-exercise) L: -[ring-(13)C(6)]phenylalanine muscle tissue labelling, expressed as (â(13)C/(12)C), averaged -32.09 ± 0.28, -32.53 ± 0.10 and -32.02 ± 0.16 in the type I and II muscle fibres and mixed muscle, respectively (P = 0.14). During post-exercise recovery, muscle protein synthesis rates were marginally (8 ± 2%) higher in the type I than type II muscle fibres, at 0.100 ± 0.005 versus 0.094 ± 0.005%/h, respectively (P < 0.05), whereby rates of mixed muscle protein were 0.091 ± 0.005%/h. Muscle protein synthesis rates following resistance-type exercise are only marginally higher in type I compared with type II muscle fibres.
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Aaron W Staples, Nicholas A Burd, Daniel W D West, Katharine D Currie, Philip J Atherton, Daniel R Moore, Michael J Rennie, Maureen J Macdonald, Steven K Baker, Stuart M Phillips (2011)  Carbohydrate does not augment exercise-induced protein accretion versus protein alone.   Med Sci Sports Exerc 43: 7. 1154-1161 Jul  
Abstract: We tested the thesis that CHO and protein coingestion would augment muscle protein synthesis (MPS) and inhibit muscle protein breakdown (MPB) at rest and after resistance exercise.
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D R Moore, P J Atherton, M J Rennie, M A Tarnopolsky, S M Phillips (2011)  Resistance exercise enhances mTOR and MAPK signalling in human muscle over that seen at rest after bolus protein ingestion.   Acta Physiol (Oxf) 201: 3. 365-372 Mar  
Abstract: Aim:â Feeding protein after resistance exercise enhances the magnitude and duration of myofibrillar protein synthesis (MPS) over that induced by feeding alone. We hypothesized that the underlying mechanism for this would be a greater and prolonged phosphorylation of signalling involved in protein translation. Methods:â Seven healthy young males performed unilateral resistance exercise followed immediately by the ingestion of 25âg of whey protein to maximally stimulate MPS in a rested and exercised leg. Results:â Phosphorylation of p70 ribosomal protein S6 kinase (p70S6K) was elevated (Pâ<â0.05) above fasted at 1âh at rest whereas it was elevated at 1, 3 and 5âh after exercise with protein ingestion and displayed a similar post-exercise time course to that shown by MPS. Extracellular regulated kinase1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK) phosphorylation were unaltered after protein ingestion at rest but were elevated (Pâ<â0.05) above fasted early in recovery (1âh) and were greater for the exercised-fed leg than feeding alone (main effect; Pâ<â0.01). Eukaryotic elongation factor 2 (eEF2) phosphorylation was also less (main effect; Pâ<â0.05) in the exercised-fed leg than in the rested leg suggesting greater activity after exercise. Eukaryotic initiation 4E binding protein-1 (4EBP-1) phosphorylation was increased (Pâ<â0.05) above fasted to the same extent in both conditions. Conclusion:â Our data suggest that resistance exercise followed by protein feeding stimulates MPS over that induced by feeding alone in part by enhancing the phosphorylation of select proteins within the mammalian target of rapamycin (p70S6K, eEF2) and by activating proteins within the mitogen-activated protein kinase (ERK1/2, p90RSK) signalling.
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Gordon I Smith, Philip Atherton, Dominic N Reeds, B Selma Mohammed, Debbie Rankin, Michael J Rennie, Bettina Mittendorfer (2011)  Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial.   Am J Clin Nutr 93: 2. 402-412 Feb  
Abstract: Loss of muscle mass with aging is a major public health concern. Omega-3 (n-3) fatty acids stimulate protein anabolism in animals and might therefore be useful for the treatment of sarcopenia. However, the effect of omega-3 fatty acids on human protein metabolism is unknown.
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2010
Philip J Atherton, Timothy Etheridge, Peter W Watt, Daniel Wilkinson, Anna Selby, Debbie Rankin, Ken Smith, Michael J Rennie (2010)  Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling.   Am J Clin Nutr 92: 5. 1080-1088 Nov  
Abstract: We previously showed that human muscle protein synthesis (MPS) increased during infusion of amino acids (AAs) and peaked at â120 min before returning to baseline rates, despite elevated plasma AA concentrations.
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Nicholas A Burd, Daniel W D West, Aaron W Staples, Philip J Atherton, Jeff M Baker, Daniel R Moore, Andrew M Holwerda, Gianni Parise, Michael J Rennie, Steven K Baker, Stuart M Phillips (2010)  Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men.   PLoS One 5: 8. 08  
Abstract: We aimed to determine the effect of resistance exercise intensity (%1 repetition maximum-1RM) and volume on muscle protein synthesis, anabolic signaling, and myogenic gene expression.
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Kevin I Watt, Richard T Jaspers, Phillip Atherton, Ken Smith, Michael J Rennie, Aivaras Ratkevicius, Henning Wackerhage (2010)  SB431542 treatment promotes the hypertrophy of skeletal muscle fibers but decreases specific force.   Muscle Nerve 41: 5. 624-629 May  
Abstract: The small molecule inhibitor SB431542 inhibits activin type I receptors. The muscle growth-inhibitor myostatin binds to and signals via these receptors. The aim of this study was to test the hypothesis that SB431542 can inhibit myostatin-related Smad signaling and induce muscle growth in cultured C2C12 myotubes and increase growth and specific force in cultured Xenopus muscle fibers. The effect of SB431542 was assessed in vitro on C2C12 myotubes and ex vivo using mature Xenopus muscle fibers. SB431542 treatment reduced myostatin-induced C-terminal Smad2 phosphorylation and resulted in the formation of enlarged myotubes. However myogenin expression was unchanged, while p70 S6k phosphorylation at Thr389, total myosin heavy chain, and the rate of protein synthesis were all reduced. Mature Xenopus muscle fibers that were treated with SB431542 had a higher fiber cross-sectional area but decreased specific force production than control. SB431542 can initially antagonize myostatin signaling, but long-term unexpected signaling effects occur. Muscle fibers hypertrophy, but their specific force decreases compared to control.
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2009
Michael J Rennie (2009)  Anabolic resistance: the effects of aging, sexual dimorphism, and immobilization on human muscle protein turnover.   Appl Physiol Nutr Metab 34: 3. 377-381 Jun  
Abstract: In healthy active older persons, there is no derangement of muscle protein metabolism. However, there is a major deficit in the ability of older muscles to regulate their maintenance during feeding and exercise. The dose-response relationship between myofibrillar protein synthesis and the availability of essential amino acids (EAA) is shifted down and to the right, and giving extra amino acids is unable to overcome this. There is no sex difference in basal or fed muscle protein metabolism in the young, but postmenopausal women have a greater anabolic resistance than older men. Anabolic resistance is also shown by the decreased phosphorylation in the PKB-mTOR-eIF4BP1 pathway in response to increased EAA. The muscle synthetic system is refractory to EAA provision, irrespective of the availability of insulin, insulin-like growth factor 1, and growth hormone. However, insulin is a major regulator of muscle protein breakdown, and there is a blunting of the ability of older muscle to decrease proteolysis in response to low concentrations of insulin, such as those observed after a light breakfast. Providing more EAA seems not to be useful, and modern N-balance data confirm that the dietary protein requirements of older persons are not increased. The sigmoidal dose-response relationship between muscle protein synthesis and resistance exercise intensity is shifted downward and to the right in older men. Decreased physical activity itself, even in young subjects, can produce anabolic resistance of muscle protein synthesis, which cannot be overcome by increasing amino acid availability. Exercise may retune the amino acid and (or) insulin sensitivity of muscle in older people.
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Emilie A Wilkes, Anna L Selby, Philip J Atherton, Rekha Patel, Debbie Rankin, Ken Smith, Michael J Rennie (2009)  Blunting of insulin inhibition of proteolysis in legs of older subjects may contribute to age-related sarcopenia.   Am J Clin Nutr 90: 5. 1343-1350 Nov  
Abstract: BACKGROUND: Reduced postprandial muscle proteolysis is mainly due to increased insulin availability. Whether rates of proteolysis in response to low physiologic doses of insulin are affected by aging is unknown. OBJECTIVES: We tested the hypothesis that suppression of leg protein breakdown (LPB) by insulin is blunted in older subjects, together with blunted activation of Akt-protein kinase B (PKB). DESIGN: Groups of 8 young [mean (+/-SD) age: 24.5 +/- 1.8 y] and older (65.0 +/- 1.3 y) participants were studied during euglycemic (5 mmol/L), isoaminoacidemic (blood leucine approximately 120 micromol/L) clamp procedures at plasma insulin concentrations of approximately 5 and approximately 15 microIU/mL for 1.5 h. Leg amino acid balance, whole-leg protein turnover (as dilution of amino acid tracers), and muscle protein synthesis were measured with D(5)-phenylalanine and [1,2-(13)C(2)]leucine. The kinase activity of muscle Akt-PKB and the extent of phosphorylation of signaling proteins associated with the mTOR (mammalian target of rapamycin) pathway were measured before and after the clamp procedures. RESULTS: Basal LPB rates were not different between groups (66 +/- 11 compared with 51 +/- 10 nmol leucine x 100 mL leg(-1) x min(-1) and 30 +/- 5 compared with 24 +/- 4 nmol phenylalanine x 100 mL leg(-1) x min(-1) in young and older groups, respectively). However, although insulin at approximately 15 microIU/mL lowered LPB by 47% in the young subjects (P < 0.05) and abolished the negative leg amino acid balance, this caused only a 12% fall (P > 0.05) in the older group. Akt-PKB activity mirrored decreases in LPB. No differences were seen in muscle protein synthesis or associated anabolic signaling phosphoproteins. CONCLUSIONS: At moderate availability, the effect of insulin on LPB is diminished in older human beings, and this effect may be mediated through blunted Akt-PKB activation.
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Vinod Kumar, Philip Atherton, Kenneth Smith, Michael J Rennie (2009)  Human muscle protein synthesis and breakdown during and after exercise.   J Appl Physiol 106: 6. 2026-2039 Jun  
Abstract: Skeletal muscle demonstrates extraordinary mutability in its responses to exercise of different modes, intensity, and duration, which must involve alterations of muscle protein turnover, both acutely and chronically. Here, we bring together information on the alterations in the rates of synthesis and degradation of human muscle protein by different types of exercise and the influences of nutrition, age, and sexual dimorphism. Where possible, we summarize the likely changes in activity of signaling proteins associated with control of protein turnover. Exercise of both the resistance and nonresistance types appears to depress muscle protein synthesis (MPS), whereas muscle protein breakdown (MPB) probably remains unchanged during exercise. However, both MPS and MPB are elevated after exercise in the fasted state, when net muscle protein balance remains negative. Positive net balance is achieved only when amino acid availability is increased, thereby raising MPS markedly. However, postexercise-increased amino acid availability is less important for inhibiting MPB than insulin, the secretion of which is stimulated most by glucose availability, without itself stimulating MPS. Exercise training appears to increase basal muscle protein turnover, with differential responses of the myofibrillar and mitochondrial protein fractions to acute exercise in the trained state. Aging reduces the responses of myofibrillar protein and anabolic signaling to resistance exercise. There appear to be few, if any, differences in the response of young women and young men to acute exercise, although there are indications that, in older women, the responses may be blunted more than in older men.
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Gordon I Smith, Philip Atherton, Dominic N Reeds, B Selma Mohammed, Hadia Jaffery, Debbie Rankin, Michael J Rennie, Bettina Mittendorfer (2009)  No major sex differences in muscle protein synthesis rates in the postabsorptive state and during hyperinsulinemia-hyperaminoacidemia in middle-aged adults.   J Appl Physiol 107: 4. 1308-1315 Oct  
Abstract: Men have more muscle than women, but most studies evaluating sex differences in muscle protein metabolism have been unable to discern sexual dimorphism in basal muscle protein turnover rates in young and middle-aged adults. We hypothesized that the anabolic response to nutritional stimuli (i.e., amino acids and insulin) would be greater in young/middle-aged men than women. We therefore measured the rates of muscle protein synthesis (MPS) in 16 healthy individuals [8 men and 8 women, matched for age (mean +/- SE: 37.7 +/- 1.5 yr) and body mass index (25.2 +/- 0.7 kg/m2)] after an overnight fast (plasma insulin approximately 5 microU/ml and plasma phenylalanine approximately 60 microM) and during a hyperinsulinemic-hyperaminoacidemic-euglycemic clamp (plasma insulin approximately 28 microU/ml; plasma phenylalanine approximately 110 microM; plasma glucose approximately 5.4 mM). The rates of MPS were not different between men and women (ANOVA main effect for sex; P = 0.49). During the clamp, the rate of MPS increased by approximately 50% (P = 0.003) with no difference in the increases from basal values between men and women (+0.019 +/- 0.004 vs. +0.018 +/- 0.010%/h, respectively; P = 0.93). There were also no differences between men and women in the basal concentrations of muscle phosphorylated Akt(Ser473), Akt(Thr308), mTOR(Ser2448), and p70s6k(Thr389) or in the hyperinsulinemia-hyperaminoacidemia-induced increases in phosphorylation of those signaling elements (P > or = 0.25). We conclude that there are no major differences in the rate of MPS and its intracellular control during basal conditions and during hyperinsulinemia-hyperaminoacidema between young and middle-aged adult men and women.
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Michael J Rennie (2009)  Anabolic resistance in critically ill patients.   Crit Care Med 37: 10 Suppl. S398-S399 Oct  
Abstract: Most patients who are critically ill lose muscle as a result of an inability to maintain rates of protein synthesis above those of protein breakdown. In addition to the effects of a procatabolic hormonal and cytokine milieu, which accelerate protein breakdown, age and immobility also influence the ability of muscle to maintain itself. Although the basal rates of protein turnover are not altered with aging, age is associated with a smaller ability to capture blood-borne amino acids as protein, the results of a decreased capacity for protein synthesis (total RNA/DNA) and decreased sensitivity and capacity of signaling proteins to indicate the availability of amino acids. Furthermore, muscle of older individuals is resistant to the effects of insulin in decreasing muscle proteolysis. Both of these effects are part of "anabolic resistance"-the inability of muscle to maintain its protein mass by appropriate stimulation of muscle protein turnover and inhibition of protein breakdown. Overlain on the effects of age are the effects of immobility, which has some of the characteristics of anabolic resistance. Immobility per se causes a decrease in muscle protein synthesis with no apparent stimulation of muscle protein breakdown; furthermore, muscle of immobilized legs is unable to stimulate muscle protein synthesis to the same extent as that of nonimmobilized legs when amino acids are infused, even at high rates.
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P J Atherton, N J Szewczyk, A Selby, D Rankin, K Hillier, K Smith, M J Rennie, P T Loughna (2009)  Cyclic stretch reduces myofibrillar protein synthesis despite increases in FAK and anabolic signalling in L6 cells.   J Physiol 587: Pt 14. 3719-3727 Jul  
Abstract: Muscle protein synthesis is increased after exercise, but evidence is now accruing that during muscular activity it is suppressed. In life, muscles are subjected to shortening forces due to contraction, but may also be subject to stretching forces during lengthening. It would be biologically inefficient if contraction and stretch have different effects on muscle protein turnover, but little is known about the metabolic effects of stretch. To investigate this, we assessed myofibrillar and sarcoplasmic protein synthesis (MPS, SPS, respectively) by incorporation of [1-13C]proline (using gas chromatography-mass spectrometry) and anabolic signalling (by phospho-immunoblotting and kinase assays) in cultured L6 skeletal muscle cells during 30 min of cyclic stretch and over 30 min intervals for up to 120 min afterwards. SPS was unaffected, whereas MPS was suppressed by 40 +/- 0.03% during stretch, before returning to basal rates by 90-20 min afterwards. Paradoxically, stretch stimulated anabolic signalling with peak values after 2-30 min: e.g. focal adhesion kinase (FAK Tyr576/577; +28 +/- 6%), protein kinase B activity (Akt; +113 +/- 31%), p70S6K1 (ribosomal S6 kinase Thr389; 25 +/- 5%), 4E binding protein 1 (4EBP1 Thr37/46; 14 +/- 3%), eukaryotic elongation factor 2 (eEF2 Thr56; -47 +/- 4%), extracellular regulated protein kinase 1/2 (ERK1/2 Tyr202/204; +65% +/- 9%), eukaryotic initiation factor 2alpha (eIF2alpha Ser51; -20 +/- 5%, P < 0.05) and eukaryotic initiation factor 4E (eIF4E Ser209; +33 +/- 10%, P < 0.05). After stretch, except for Akt activity, stimulatory phosphorylations were sustained: e.g. FAK (+26 +/- 11%) for > or =30 min, eEF2 for > or =60 min (peak -45 +/- 4%), 4EBP1 for > or =90 min (+33 +/- 5%), and p70S6K1 remained elevated throughout (peak +64 +/- 7%). Adenosine monophosphate-activated protein kinase (AMPK) phosphorylation was unchanged throughout. We report for the first time that acute cyclic stretch specifically suppresses MPS, despite increases in activity/phosphorylation of elements thought to increase anabolism.
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M J Rennie, A Selby, P Atherton, K Smith, V Kumar, E L Glover, S M Philips (2009)  Facts, noise and wishful thinking: muscle protein turnover in aging and human disuse atrophy.   Scand J Med Sci Sports Jun  
Abstract: Surprisingly little is known about the mechanisms of muscle atrophy with aging and disuse in human beings, in contrast to rodents, from which much has been extrapolated to explain the human condition. However, this extrapolation is likely unwarranted because the time course, extent of wasting, muscle fiber involvement and alterations of muscle protein turnover are all quite different in rodent and human muscle. Furthermore, there is little evidence that static indices of protein turnover represent dynamic changes and may be misleading. With disuse there are reductions in the rate of muscle protein synthesis (MPS) large enough to explain the atrophic loss of muscle protein without a concomitant increase in proteolysis. In aging, there is no evidence that there are marked alterations in basal muscle protein turnover in healthy individuals but instead the ability to maintain muscle after feeding is compromised. This anabolic resistance is evident with physical inactivity, which exacerbates the inability to maintain muscle mass with aging. The main conclusion of this review is that in uncomplicated, non-inflammatory disuse atrophy, the facilitative change causing loss of muscle mass is a depression of MPS, exacerbated by anabolic resistance during feeding, with possible adaptive depressions, rather than increases, of muscle proteolysis.
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S M Phillips, E I Glover, M J Rennie (2009)  Alterations of protein turnover underlying disuse atrophy in human skeletal muscle.   J Appl Physiol 107: 3. 645-654 Sep  
Abstract: Unloading-induced atrophy is a relatively uncomplicated form of muscle loss, dependent almost solely on the loss of mechanical input, whereas in disease states associated with inflammation (cancer cachexia, AIDS, burns, sepsis, and uremia), there is a procatabolic hormonal and cytokine environment. It is therefore predictable that muscle loss mainly due to disuse alone would be governed by mechanisms somewhat differently from those in inflammatory states. We suggest that in vivo measurements made in human subjects using arterial-venous balance, tracer dilution, and tracer incorporation are dynamic and thus robust by comparison with static measurements of mRNA abundance and protein expression and/or phosphorylation in human muscle. In addition, measurements made with cultured cells or in animal models, all of which have often been used to infer alterations of protein turnover, appear to be different from results obtained in immobilized human muscle in vivo. In vivo measurements of human muscle protein turnover in disuse show that the primary variable that changes facilitating the loss of muscle mass is protein synthesis, which is reduced in both the postabsorptive and postprandial states; muscle proteolysis itself appears not to be elevated. The depressed postprandial protein synthetic response (a phenomenon we term "anabolic resistance") may even be accompanied by a diminished suppression of proteolysis. We therefore propose that most of the loss of muscle mass during disuse atrophy can be accounted for by a depression in the rate of protein synthesis. Thus the normal diurnal fasted-to-fed cycle of protein balance is disrupted and, by default, proteolysis becomes dominant but is not enhanced.
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John Andree Babraj, Kristy Mustard, Calum Sutherland, Mhari C Towler, Shaui Chen, Kenneth Smith, Kevin Green, Graham Leese, David Grahame Hardie, Michael J Rennie, Daniel James Cuthbertson (2009)  Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status.   Am J Physiol Endocrinol Metab 296: 5. E1042-E1048 May  
Abstract: We demonstrated previously that, in healthy young men, 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR) stimulates human muscle 2-deoxyglucose (2DG) uptake without detectable activation of muscle AMP-activated protein kinase (AMPK) but with extracellular-regulated kinase 1/2 (ERK1/2) activation. We tested whether AICAR stimulates muscle 2DG uptake in healthy older patients with or without type 2 diabetes (T2D). Six healthy young subjects (23 +/- 3 yr, BMI 25 +/- 2 kg/m(-2); means +/- SE), eight older subjects (59 +/- 4 yr, BMI 28 +/- 2 kg/m(-2)), and eight subjects with T2D (62 +/- 4 yr, BMI 27 +/- 2 kg/m(-2)) received a 6-h 2DG infusion (prime 10 mg/kg, 6 mg.kg(-1).h(-1)) and AICAR (10 or 20 mg.kg(-1).h(-1)) from 3 to 6 h. Quadriceps biopsies were taken at 0, 3, and 6 h. We determined 1) 2DG uptake, 2) total AMPKalpha activity, AMPK, acetyl-CoA carboxylase (ACC), and AS160 phosphorylation, and 3) ERK1/2 phosphorylation. Ten milligrams per kilogram per hour AICAR increased 2DG uptake by 2.9 +/- 0.7-fold in young men (P < 0.001), 1.8 +/- 0.2-fold in older men (P < 0.01), and 1.6 +/- 0.1-fold in men with T2D; 20 mg.kg(-1).h(-1) AICAR increases were 2.5 +/- 0.1-fold (older men, P < 0.001) and 2.2 +/- 0.2-fold (men with T2D, P < 0.001). At 3-h AMPK activity and AMPK, ACC and AS160 phosphorylation were unchanged, but ERK1/2 phosphorylation increased at both AICAR doses. The fold changes of ERK1/2 phosphorylation and 2DG uptake closely correlated (R(2) = 0.55, P = 0.003). AICAR stimulates muscle 2DG uptake in T2D to the same extent as in healthy age-matched controls, but there is an age-related reduction.
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Vinod Kumar, Anna Selby, Debbie Rankin, Rekha Patel, Philip Atherton, Wulf Hildebrandt, John Williams, Kenneth Smith, Olivier Seynnes, Natalie Hiscock, Michael J Rennie (2009)  Age-related differences in the dose-response relationship of muscle protein synthesis to resistance exercise in young and old men.   J Physiol 587: Pt 1. 211-217 Jan  
Abstract: We investigated how myofibrillar protein synthesis (MPS) and muscle anabolic signalling were affected by resistance exercise at 20-90% of 1 repetition maximum (1 RM) in two groups (25 each) of post-absorptive, healthy, young (24 +/- 6 years) and old (70 +/- 5 years) men with identical body mass indices (24 +/- 2 kg m(-2)). We hypothesized that, in response to exercise, anabolic signalling molecule phosphorylation and MPS would be modified in a dose-dependant fashion, but to a lesser extent in older men. Vastus lateralis muscle was sampled before, immediately after, and 1, 2 and 4 h post-exercise. MPS was measured by incorporation of [1,2-(13)C] leucine (gas chromatography-combustion-mass spectrometry using plasma [1,2-(13)C]alpha-ketoisocaparoate as surrogate precursor); the phosphorylation of p70 ribosomal S6 kinase (p70s6K) and eukaryotic initiation factor 4E binding protein 1 (4EBP1) was measured using Western analysis with anti-phosphoantibodies. In each group, there was a sigmoidal dose-response relationship between MPS at 1-2 h post-exercise and exercise intensity, which was blunted (P < 0.05) in the older men. At all intensities, MPS fell in both groups to near-basal values by 2-4 h post-exercise. The phosphorylation of p70s6K and 4EBP1 at 60-90% 1 RM was blunted in older men. At 1 h post-exercise at 60-90% 1 RM, p70s6K phosphorylation predicted the rate of MPS at 1-2 h post-exercise in the young but not in the old. The results suggest that in the post-absorptive state: (i) MPS is dose dependant on intensity rising to a plateau at 60-90% 1 RM; (ii) older men show anabolic resistance of signalling and MPS to resistance exercise.
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Philip J Atherton, Ken Smith, Timothy Etheridge, Debbie Rankin, Michael J Rennie (2009)  Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells.   Amino Acids Nov  
Abstract: The essential amino acids (EAA) activate anabolic signalling through mechanisms, which are unclear in detail but include increased signalling through the mammalian target of rapamycin complex 1 (mTORC1). Of all the EAA, the branched chain amino acid (BCAA) leucine has been suggested as the most potent in stimulating protein synthesis, although there have been no studies investigating the effects of each EAA on anabolic signalling pathways. We therefore undertook a systematic analysis of the effect of each EAA on mTORC1 signalling in C2C12 myotubes whereby cells were serum (4 h) and amino acid (1 h) starved before stimulation with 2 mM of each amino acid. Immunoblotting was used to detect phosphorylated forms of protein kinase B (Akt)/mTORC1 signalling enzymes. The phosphorylation of Akt was unchanged by incubation with EAA. Phosphorylation of mTOR and 4E binding protein-1 (4EBP1) were increased 1.67 +/- 0.1-fold and 2.5 +/- 0.1-fold, respectively, in response to leucine stimulation but not in response to any other EAA. The phosphorylation of ribosomal s6 kinase (p70S6K1) was increased by stimulation with all EAA with the exceptions of isoleucine and valine. However, the increase with leucine was significantly greater, 5.9 +/- 0.3-fold compared to 1.6-2.0-fold for the non-BCAA EAA. This pattern of activation was identical in ribosomal protein s6 (RPS6) with the additional effect of leucine being 3.8 +/- 0.3-fold versus 1.5-2.0-fold. Phosphorylation of eukaryotic initiation/elongation factors eIF2alpha and eEF2 were unaffected by EAA. We conclude that leucine is unique amongst the amino acids in its capacity to stimulate both mTOR and 4EBP1 phosphorylation and to enhance p70S6K1 signalling.
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Daniel W D West, Gregory W Kujbida, Daniel R Moore, Philip Atherton, Nicholas A Burd, Jan P Padzik, Michael De Lisio, Jason E Tang, Gianni Parise, Michael J Rennie, Steven K Baker, Stuart M Phillips (2009)  Resistance exercise-induced increases in putative anabolic hormones do not enhance muscle protein synthesis or intracellular signalling in young men.   J Physiol 587: Pt 21. 5239-5247 Nov  
Abstract: We aimed to determine whether exercise-induced elevations in systemic concentration of testosterone, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) enhanced post-exercise myofibrillar protein synthesis (MPS) and phosphorylation of signalling proteins important in regulating mRNA translation. Eight young men (20 +/- 1.1 years, BMI = 26 +/- 3.5 kg m(-2)) completed two exercise protocols designed to maintain basal hormone concentrations (low hormone, LH) or elicit increases in endogenous hormones (high hormone, HH). In the LH protocol, participants performed a bout of unilateral resistance exercise with the elbow flexors. The HH protocol consisted of the same elbow flexor exercise with the contralateral arm followed immediately by high-volume leg resistance exercise. Participants consumed 25 g of protein after arm exercise to maximize MPS. Muscle biopsies and blood samples were taken as appropriate. There were no changes in serum testosterone, GH or IGF-1 after the LH protocol, whereas there were marked elevations after HH (testosterone, P < 0.001; GH, P < 0.001; IGF-1, P < 0.05). Exercise stimulated a rise in MPS in the biceps brachii (rest = 0.040 +/- 0.007, LH = 0.071 +/- 0.008, HH = 0.064 +/- 0.014% h(-1); P < 0.05) with no effect of elevated hormones (P = 0.72). Phosphorylation of the 70 kDa S6 protein kinase (p70S6K) also increased post-exercise (P < 0.05) with no differences between conditions. We conclude that the transient increases in endogenous purportedly anabolic hormones do not enhance fed-state anabolic signalling or MPS following resistance exercise. Local mechanisms are likely to be of predominant importance for the post-exercise increase in MPS.
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2008
Louise Deldicque, Philip Atherton, Rekha Patel, Daniel Theisen, Henri Nielens, Michael J Rennie, Marc Francaux (2008)  Effects of resistance exercise with and without creatine supplementation on gene expression and cell signaling in human skeletal muscle.   J Appl Physiol 104: 2. 371-378 Feb  
Abstract: To test the hypothesis that creatine supplementation would enhance the anabolic responses of muscle cell signaling and gene expression to exercise, we studied nine subjects who received either creatine or a placebo (maltodextrin) for 5 days in a double-blind fashion before undergoing muscle biopsies: at rest, immediately after exercise (10 x 10 repetitions of one-leg extension at 80% 1 repetition maximum), and 24 and 72 h later (all in the morning after fasting overnight). Creatine supplementation decreased the phosphorylation state of protein kinase B (PKB) on Thr308 at rest by 60% (P < 0.05) and that of eukaryotic initiation factor 4E-binding protein on Thr37/46 (4E-BP1) by 30% 24 h postexercise (P < 0.05). Creatine increased mRNA for collagen 1 (alpha(1)), glucose transporter-4 (GLUT-4), and myosin heavy chain I at rest by 250%, 45%, and 80%, respectively, and myosin heavy chain IIA (MHCIIA) mRNA immediately after exercise by 70% (all P < 0.05). Immediately after exercise, and independent of creatine, mRNA for muscle atrophy F-box (MAFbx), MHCIIA, peroxisome proliferator-activated receptor gamma coactivator-1alpha, and interleukin-6 were upregulated (60-350%; P < 0.05); the phosphorylation state of p38 both in the sarcoplasm and nucleus were increased (12- and 25-fold, respectively; both P < 0.05). Concurrently, the phosphorylation states of PKB (Thr308) and 4E-BP1 (Thr37/46) were decreased by 50% and 75%, respectively (P < 0.05). Twenty-four hours postexercise, MAFbx, myostatin, and GLUT-4 mRNA expression decreased below preexercise values (-35 to -50%; P < 0.05); calpain 1 mRNA increased 70% 72 h postexercise (P < 0.05) and at no other time. In conclusion, 5 days of creatine supplementation do not enhance anabolic signaling but increase the expression of certain targeted genes.
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P L Greenhaff, L G Karagounis, N Peirce, E J Simpson, M Hazell, R Layfield, H Wackerhage, K Smith, P Atherton, A Selby, M J Rennie (2008)  Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle.   Am J Physiol Endocrinol Metab 295: 3. E595-E604 Sep  
Abstract: We determined the effects of intravenous infusion of amino acids (AA) at serum insulin of 5, 30, 72, and 167 mU/l on anabolic signaling, expression of ubiquitin-proteasome components, and protein turnover in muscles of healthy young men. Tripling AA availability at 5 mU/l insulin doubled incorporation of [1-(13)C]leucine [i.e., muscle protein synthesis (MPS), P < 0.01] without affecting the rate of leg protein breakdown (LPB; appearance of d(5)-phenylalanine). While keeping AA availability constant, increasing insulin to 30 mU/l halved LPB (P < 0.05) without further inhibition at higher doses, whereas rates of MPS were identical to that at 5 mU/l insulin. The phosphorylation of PKB Ser(473) and p70(S6k) Thr(389) increased concomitantly with insulin, but whereas raising insulin to 30 mU/l increased the phosphorylation of mTOR Ser(2448), 4E-BP1 Thr(37/46), or GSK3beta Ser(9) and decreased that of eEF2 Thr(56), higher insulin doses to 72 and 167 mU/l did not augment these latter responses. MAFbx and proteasome C2 subunit proteins declined as insulin increased, with MuRF-1 expression largely unchanged. Thus increasing AA and insulin availability causes changes in anabolic signaling and amounts of enzymes of the ubiquitin-proteasome pathway, which cannot be easily reconciled with observed effects on MPS or LPB.
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Sarah B Wilkinson, Stuart M Phillips, Philip J Atherton, Rekha Patel, Kevin E Yarasheski, Mark A Tarnopolsky, Michael J Rennie (2008)  Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle.   J Physiol 586: Pt 15. 3701-3717 Aug  
Abstract: Resistance (RE) and endurance (EE) exercise stimulate mixed skeletal muscle protein synthesis. The phenotypes induced by RE (myofibrillar protein accretion) and EE (mitochondrial expansion) training must result from differential stimulation of myofibrillar and mitochondrial protein synthesis. We measured the synthetic rates of myofibrillar and mitochondrial proteins and the activation of signalling proteins (Akt-mTOR-p70S6K) at rest and after an acute bout of RE or EE in the untrained state and after 10 weeks of RE or EE training in young healthy men. While untrained, RE stimulated both myofibrillar and mitochondrial protein synthesis, 67% and 69% (P < 0.02), respectively. After training, only myofibrillar protein synthesis increased with RE (36%, P = 0.05). EE stimulated mitochondrial protein synthesis in both the untrained, 154%, and trained, 105% (both P < 0.05), but not myofibrillar protein synthesis. Acute RE and EE increased the phosphorylation of proteins in the Akt-mTOR-p70S6K pathway with comparatively minor differences between two exercise stimuli. Phosphorylation of Akt-mTOR-p70S6K proteins was increased after 10 weeks of RE training but not by EE training. Chronic RE or EE training modifies the protein synthetic response of functional protein fractions, with a shift toward exercise phenotype-specific responses, without an obvious explanatory change in the phosphorylation of regulatory signalling pathway proteins.
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Elisa I Glover, Stuart M Phillips, Bryan R Oates, Jason E Tang, Mark A Tarnopolsky, Anna Selby, Kenneth Smith, Michael J Rennie (2008)  Immobilization induces anabolic resistance in human myofibrillar protein synthesis with low and high dose amino acid infusion.   J Physiol 586: Pt 24. 6049-6061 Dec  
Abstract: We tested the hypothesis that increasing blood amino acid (AA) availability would counter the physical inactivity-induced reduction in muscle protein synthesis. We determined how 14 days of unilateral knee immobilization affected quadriceps myofibrillar protein synthesis (MPS) in young healthy subjects (10 men, 2 women, 21 +/- 1 years; 80.2 +/- 4.0 kg, mean +/- S.E.M.) in the post-absorptive state and after infusing AA (10% Primene) at low or high doses (43 and 261 mg kg(-1) h(-1)). Muscle cross-sectional area (MRI) and peak isometric torque declined in the immobilized leg (-5.0 +/- 1.2% and -25 +/- 3%, respectively, both P < 0.005), but were unchanged (all P > 0.6) in the non-immobilized leg. Immobilization induced a 27% decline in the rate of post-absorptive MPS (immobilized, 0.027 +/- 0.003: non-immobilized, 0.037 +/- 0.003% h(-1); P < 0.001). Regardless of dose, AA infusion stimulated a greater rise in MPS in the non-immobilized legs; at 4 h MPS was greater by +54 +/- 12% with low dose and +68 +/- 17% with high dose AA infusion (both P < 0.001). There was some evidence of delayed responsiveness of phosphorylation of Akt to high doses of AA and p70S6k at both doses but no marked differences in that of mTOR, GSK3beta or eEF2. Phosphorylation of focal adhesion kinase (Tyr(576/577)) was reduced (P < 0.05) with immobilization. We observed no change in polyubiquitinated protein content after immobilization. We confirm that 14 days of immobilization reduces MPS in the post-absorptive state and this diminution is reduced but not abolished by increased provision of AA, even at high rates. The immobilization-induced decline in post-absorptive MPS with the 'anabolic resistance' to amino acids can account for much of immobilization-induced muscle atrophy.
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Louise Deldicque, Philip Atherton, Rekha Patel, Daniel Theisen, Henri Nielens, Michael J Rennie, Marc Francaux (2008)  Decrease in Akt/PKB signalling in human skeletal muscle by resistance exercise.   Eur J Appl Physiol 104: 1. 57-65 Sep  
Abstract: We analysed the effects of resistance exercise upon the phosphorylation state of proteins associated with adaptive processes from the Akt/PKB (protein kinase B) and the mitogen-activated protein kinase (MAPK) pathways. Nine healthy young men (21.7 +/- 0.55 year) performed 10 sets of 10 leg extensions at 80% of their 1-RM (repetition maximum). Muscle biopsies were taken from the vastus lateralis at rest, within the first 30 s after exercise and at 24 h post-exercise. Immediately post exercise, the phosphorylation states of Akt/PKB on Thr308 and Ser473 and 4E-BP1 on Thr37/46 (eukaryotic initiation factor 4E-binding protein 1) were decreased (-60 to -90%, P < 0.05). Conversely, the phosphorylation of p70(s6k) (p70 ribosomal S6 kinase) on Thr421/Ser424 was increased more than 20-fold (P < 0.05), and this was associated with a 10- to 50-fold increase in the phosphorylation of p38 and ERK1/2 (extracellular signal-regulated kinase) (P < 0.05). Twenty-four hours post-exercise the phosphorylation state of Akt/PKB on Thr308 was depressed, whereas the phosphorylation of p70(s6k) on Thr421/Ser424 and sarcoplasmic ERK1/2 were elevated. The present results indicate that high-intensity resistance exercise in the fasted state inhibits Akt/PKB and 4E-BP1 whilst concomitantly augmenting MAPK signalling and p70(s6k) on Thr421/Ser424.
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Gordon I Smith, Philip Atherton, Dennis T Villareal, Tiffany N Frimel, Debbie Rankin, Michael J Rennie, Bettina Mittendorfer (2008)  Differences in muscle protein synthesis and anabolic signaling in the postabsorptive state and in response to food in 65-80 year old men and women.   PLoS ONE 3: 3. 03  
Abstract: Women have less muscle than men but lose it more slowly during aging. To discover potential underlying mechanism(s) for this we evaluated the muscle protein synthesis process in postabsorptive conditions and during feeding in twenty-nine 65-80 year old men (n = 13) and women (n = 16). We discovered that the basal concentration of phosphorylated eEF2(Thr56) was approximately 40% less (P<0.05) and the basal rate of MPS was approximately 30% greater (P = 0.02) in women than in men; the basal concentrations of muscle phosphorylated Akt(Thr308), p70s6k(Thr389), eIF4E(Ser209), and eIF4E-BP1(Thr37/46) were not different between the sexes. Feeding increased (P<0.05) Akt(Thr308) and p70s6k(Thr389) phosphorylation to the same extent in men and women but increased (P<0.05) the phosphorylation of eIF4E(Ser209) and eIF4E-BP1(Thr37/46) in men only. Accordingly, feeding increased MPS in men (P<0.01) but not in women. The postabsorptive muscle mRNA concentrations for myoD and myostatin were not different between sexes; feeding doubled myoD mRNA (P<0.05) and halved that of myostatin (P<0.05) in both sexes. Thus, there is sexual dimorphism in MPS and its control in older adults; a greater basal rate of MPS, operating over most of the day may partially explain the slower loss of muscle in older women.
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G D Summers, C M Deighton, M J Rennie, A H Booth (2008)  Rheumatoid cachexia: a clinical perspective.   Rheumatology (Oxford) 47: 8. 1124-1131 Aug  
Abstract: Rheumatoid cachexia is under-recognized in clinical practice. The loss of lean body tissue, which characterizes cachexia, is often compensated for by gain in body fat-so called 'cachectic obesity'-so that 85% or more RA patients have a normal BMI. Severe cachexia with loss of weight leads to increased morbidity and premature mortality but loss of muscle bulk with a normal BMI also associates with poor clinical outcomes. Increasing BMI, even into the obese range, is associated with less joint damage and reduced mortality. Measurement of body composition using DXA and other techniques is feasible but the results must be interpreted with care. Newer techniques such as whole-body MRI will help define with more confidence the mass and distribution of fat and muscle and help elucidate the relationships between body composition and outcomes. Cachexia shows little response to diet alone but progressive resistance training and anti-TNF therapies show promise in tackling this potentially disabling extra-articular feature of RA.
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2007
Ken Smith, Michael J Rennie (2007)  New approaches and recent results concerning human-tissue collagen synthesis.   Curr Opin Clin Nutr Metab Care 10: 5. 582-590 Sep  
Abstract: PURPOSE OF REVIEW: Knowledge of the physiological regulation of human-tissue collagen metabolism in vivo is poor, due to the lack of appropriately robust methods. Recent application of stable isotope tracer techniques to measure human collagen synthesis has provided some insights into the role of nutrition and exercise on collagen turnover in the extracellular matrix of the musculoskeletal system. RECENT FINDINGS: Collagen turnover in the musculoskeletal system is faster than previously thought. Bone collagen synthesis is increased by feeding, whereas both muscle collagen and tendon are unresponsive. Exercise stimulates collagen synthesis in both muscle and tendon in an apparently coordinated manner. There are also sex differences and normal aging is associated with increased muscle collagen synthesis and reductions in bone collagen synthesis, particularly in mature bone collagen. SUMMARY: Collagen turnover appears to be faster than previously thought and is regulated by feeding and exercise, in a tissue-specific manner. Further application of these approaches, coupled with measures of gene and protein expression, to measure the acute regulation of collagen, will lead to a better understanding of the physiology and pathophysiology of human collagen turnover. This is particularly important for developing new therapies to improve bone health and minimize tissue fibrosis.
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M D de Boer, C N Maganaris, O R Seynnes, M J Rennie, M V Narici (2007)  Time course of muscular, neural and tendinous adaptations to 23-day unilateral lower-limb suspension in young men.   Scand J Med Sci Sports 17: 5. Oct  
Abstract: Muscles and tendons are highly adaptive to changes in chronic loading, though little is known about the adaptative time course. We tested the hypothesis that, in response to unilateral lower limb suspension (ULLS), the magnitude of tendon mechanical adaptations would match or exceed those of skeletal muscle. Seventeen men, (1.79+/-0.05 m, 76.6+/-10.3 kg, 22.3+/-3.8 years underwent ULLS for 23 days (n=9) or acted as controls (n=8). Knee extensors (KE) torque, voluntary activation (VA), cross-sectional area (CSA) (by magnetic resonance imaging), vastus lateralis fascicle length (Lf) and pennation angle (vartheta), patellar tendon stiffness and Young's modulus (by ultrasonography) were measured before, during and at the end of ULLS. After 14 and 23 days, (i) KE torque decreased by 14.8+/-5.5% and 21.0+/-7.1%, respectively (P<0.001); (ii) VA did not change; (iii) KE CSA decreased by 5.2+/-0.7% (P<0.001) and 10.0+/-2.0% (P<0.001); Lf decreased by 5.9% (NS) and 7.7% (P<0.05) and vartheta by 3.2% (P<0.05) and, (iv) tendon stiffness and modulus decreased by 9.8+/-8.2% (P<0.05) and 9.2+/-8.2% (P<0.05) at 14 days, and by 29.3+/-11.5% (P<0.005) and 30.1+/-11.9% (P<0.01) at 23 days, with no changes in the controls. Hence, ULLS induces rapid losses of KE muscle size, architecture and function, but not in neural drive. Significant deterioration in tendon mechanical properties also occurs within 2 weeks, exacerbating in the third week of ULLS. Rehabilitation to limit muscle and tendon deterioration should probably start within 2 weeks of unloading.
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Daniel J Cuthbertson, John A Babraj, Kirsteen J W Mustard, Mhairi C Towler, Kevin A Green, Henning Wackerhage, Graeme P Leese, Keith Baar, Michaela Thomason-Hughes, Calum Sutherland, D Grahame Hardie, Michael J Rennie (2007)  5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men.   Diabetes 56: 8. 2078-2084 Aug  
Abstract: Activation of AMP-activated protein kinase (AMPK) in rodent muscle by exercise, metformin, 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR), and adiponectin increases glucose uptake. The aim of this study was to determine whether AICAR stimulates muscle glucose uptake in humans. We studied 29 healthy men (aged 26 +/- 8 years, BMI 25 +/- 4 kg/m(2) [mean +/- SD]). Rates of muscle 2-deoxyglucose (2DG) uptake were determined by measuring accumulation of total muscle 2DG (2DG and 2DG-6-phosphate) during a primed, continuous 2DG infusion. The effects of AICAR and exercise on muscle AMPK activity/phosphorylation and 2DG uptake were determined. Whole-body glucose disposal was compared before and during AICAR with the euglycemic-hyperinsulinemic clamp. Muscle 2DG uptake was linear over 9 h (R(2) = 0.88 +/- 0.09). After 3 h, 2DG uptake increased 2.1 +/- 0.8- and 4.7 +/- 1.7-fold in response to AICAR or bicycle exercise, respectively. AMPK alpha(1) and alpha(2) activity or AMPK phosphorylation was unchanged after 20 min or 3 h of AICAR, but AMPK phosphorylation significantly increased immediately and 3 h after bicycle exercise. AICAR significantly increased phosphorylation of extracellular signal-regulated kinase 1/2, but phosphorylation of beta-acetyl-CoA carboxylase, glycogen synthase, and protein kinase B or insulin receptor substrate-1 level was unchanged. Mean whole-body glucose disposal increased by 7% with AICAR from 9.3 +/- 0.6 to 10 +/- 0.6 mg x kg(-1) x min(-1) (P < 0.05). In healthy people, AICAR acutely stimulates muscle 2DG uptake with a minor effect on whole-body glucose disposal.
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Beyer, Simonsen, Bülow, Lorenzen, Jensen, Larsen, Rasmussen, Rennie, Kjær (2007)  Old women with a recent fall history show improved muscle strength and function sustained for six months after finishing training.   Aging Clin Exp Res 19: 4. 300-309 Aug  
Abstract: BACKGROUND AND AIMS: Restricted physical activity as a consequence of chronic disease or injury is a predictor of functional decline. The aim of this study was to test the hypothesis that a 6- month multidimensional training program would have sustained beneficial effects upon the physiological, functional and psychological condition of old women with a recent history of falls. METHODS: Participants were 65 home-dwelling women (70-90 years) identified from hospital records as having had an accidental fall. After assessment of muscle strength, balance performance, walking speed, balance confidence, and physical activity level, the participants were randomly assigned to a control group (n=33) or a training group (n=32), who performed a multidimensional training program including moderate resistance exercise and balance exercise twice weekly for 6 months. Measurements were repeated after 6 and 12 months. RESULTS: Six months of multidimensional training resulted in significant improvements and between-group differences in isometric knee extension strength (p<0.05), trunk extension/ flexion strength (p<0.001), habitual/maximal walking speed (p<0.001) and balance performance (p<0.001). At follow-up, 6 months after intervention, these improvements were preserved in the training group and there was also a significant between- group difference with regard to balance confidence. No between-group differences were found concerning number of falls or physical activity level during the one-year study period. CONCLUSIONS: A multi-dimensional training program produced significant improvements in physiological and functional risk factors for falls and disability in women aged 70-90 years with a recent history of falls.
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Benjamin F Miller, Mette Hansen, Jens L Olesen, Peter Schwarz, John A Babraj, Kenneth Smith, Michael J Rennie, Michael Kjaer (2007)  Tendon collagen synthesis at rest and after exercise in women.   J Appl Physiol 102: 2. 541-546 Feb  
Abstract: In general, there is a higher incidence of musculoskeletal injuries during physical activity in women than in men. We hypothesized that in women rates of tendon collagen synthesis would be lower than in men at rest and after exercise, especially in the later luteal phase when estrogen and progesterone concentrations are higher than the early follicular phase. We studied tendon collagen fractional synthesis rate (FSR) in 15 young, healthy female subjects in either the early follicular (n = 8) or the late luteal phase (n = 7) 72 h after an acute bout of one-legged exercise (60 min kicking at 67% workload maximum) (72 h) and compared the results with those previously obtained for men. Samples were taken from the patellar tendon in both the exercised and rested legs to determine collagen FSR by the incorporation of [15N]proline into tendon collagen hydroxyproline. There was no effect of menstrual phase on tendon collagen synthesis either at rest or after exercise. However, there was a significant difference between women and men at rest (women = 0.025 +/- 0.002%/h, men = 0.045 +/- 0.008%/h; P < 0.05) and 72 h after exercise (women = 0.027 +/- 0.005%/h; men = 0.058 +/- 0.008%/h). Furthermore, rest and 72-h tendon collagen synthesis were not different in women, whereas in men tendon collagen synthesis remained significantly elevated 72 h after exercise. It is concluded that both in the resting state and after exercise, tendon collagen FSR is lower in women than in men, which may contribute to a lower rate of tissue repair after exercise.
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Matthew C Kostek, Yi-Wen Chen, Daniel J Cuthbertson, Rongye Shi, Mark J Fedele, Karyn A Esser, Michael J Rennie (2007)  Gene expression responses over 24 h to lengthening and shortening contractions in human muscle: major changes in CSRP3, MUSTN1, SIX1, and FBXO32.   Physiol Genomics 31: 1. 42-52 Sep  
Abstract: Resistance training using lengthening (eccentric) contractions induces greater increases in muscle size than shortening (concentric) contractions, but the underlying molecular mechanisms are not clear. Using temporal expression profiling, we compared changes in gene expression within 24 h of an acute bout of each type of contractions conducted simultaneously in the quadriceps of different legs. Five healthy young men performed shortening contractions with one leg while the contralateral leg performed lengthening contractions. Biopsies were taken from both legs before exercise and 3, 6, and 24 h afterwards, in the fed state. Expression profiling (n = 3) was performed using a custom-made Affymetrix MuscleChip containing probe sets of approximately 3,300 known genes and expressed sequence tags expressed in skeletal muscle. We identified 51 transcripts differentially regulated between the two exercise modes. Using unsupervised hierarchical clustering, we identified four distinct clusters, three of which corresponded to unique functional categories (protein synthesis, stress response/early growth, and sarcolemmal structure). Using quantitative RT-PCR (n = 5), we verified expression changes (lengthening/shortening) in SIX1 (3 h, -1.9-fold, P < 0.001), CSRP3 (6 h, 2.9-fold, P < 0.05), and MUSTN1 (24 h, 4.3-fold, P < 0.05). We examined whether FBXO32/atrogin-1/MAFbx, a known regulator of protein breakdown and of muscle atrophy was differentially expressed: the gene was downregulated after lengthening contractions (3 h, 2.7-fold, P < 0.05; 6 h, 3.3-fold, P < 0.05; 24 h, 2.3-fold, P < 0.05). The results suggested that lengthening and shortening contractions activated distinct molecular pathways as early as 3 h postexercise. The molecular differences might contribute to mechanisms underlying the physiological adaptations seen with training using the two modes of exercise.
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Anne Marie Winther Petersen, Faidon Magkos, Philip Atherton, Anna Selby, Kenneth Smith, Michael J Rennie, Bente Klarlund Pedersen, Bettina Mittendorfer (2007)  Smoking impairs muscle protein synthesis and increases the expression of myostatin and MAFbx in muscle.   Am J Physiol Endocrinol Metab 293: 3. E843-E848 Sep  
Abstract: Smoking causes multiple organ dysfunction. The effect of smoking on skeletal muscle protein metabolism is unknown. We hypothesized that the rate of skeletal muscle protein synthesis is depressed in smokers compared with non-smokers. We studied eight smokers (> or =20 cigarettes/day for > or =20 years) and eight non-smokers matched for sex (4 men and 4 women per group), age (65 +/- 3 and 63 +/- 3 yr, respectively; means +/- SEM) and body mass index (25.9 +/- 0.9 and 25.1 +/- 1.2 kg/m(2), respectively). Each subject underwent an intravenous infusion of stable isotope-labeled leucine in conjunction with blood and muscle tissue sampling to measure the mixed muscle protein fractional synthesis rate (FSR) and whole body leucine rate of appearance (Ra) in plasma (an index of whole body proteolysis), the expression of genes involved in the regulation of muscle mass (myostatin, a muscle growth inhibitor, and MAFBx and MuRF-1, which encode E3 ubiquitin ligases in the proteasome proteolytic pathway) and that for the inflammatory cytokine TNF-alpha in muscle, and the concentration of inflammatory markers in plasma (C-reactive protein, TNF-alpha, interleukin-6) which are associated with muscle wasting in other conditions. There were no differences between nonsmokers and smokers in plasma leucine concentration, leucine rate of appearance, and plasma concentrations of inflammatory markers, or TNF-alpha mRNA in muscle, but muscle protein FSR was much less (0.037 +/- 0.005 vs. 0.059 +/- 0.005%/h, respectively, P = 0.004), and myostatin and MAFBx (but not MuRF-1) expression were much greater (by approximately 33 and 45%, respectivley, P < 0.05) in the muscle of smokers than of nonsmokers. We conclude that smoking impairs the muscle protein synthesis process and increases the expression of genes associated with impaired muscle maintenance; smoking therefore likely increases the risk of sarcopenia.
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Maarten D de Boer, Constantinos N Maganaris, Olivier R Seynnes, Michael J Rennie, Marco V Narici (2007)  Time course of muscular, neural and tendinous adaptations to 23 day unilateral lower-limb suspension in young men.   J Physiol 583: Pt 3. 1079-1091 Sep  
Abstract: Muscles and tendons are highly adaptive to changes in chronic loading, though little is known about the adaptative time course. We tested the hypothesis that, in response to unilateral lower limb suspension (ULLS), the magnitude of tendon mechanical adaptations would match or exceed those of skeletal muscle. Seventeen men (1.79 +/- 0.05 m, 76.6 +/- 10.3 kg, 22.3 +/- 3.8 years) underwent ULLS for 23 days (n = 9) or acted as controls (n = 8). Knee extensor (KE) torque, voluntary activation (VA), cross-sectional area (CSA) (by magnetic resonance imaging), vastus lateralis fascicle length (L(f)) and pennation angle (), patellar tendon stiffness and Young's modulus (by ultrasonography) were measured before, during and at the end of ULLS. After 14 and 23 days (i) KE torque decreased by 14.8 +/- 5.5% (P < 0.001) and 21.0 +/- 7.1% (P < 0.001), respectively; (ii) VA did not change; (iii) KE CSA decreased by 5.2 +/- 0.7% (P < 0.001) and 10.0 +/- 2.0% (P < 0.001), respectively; L(f) decreased by 5.9% (n.s.) and 7.7% (P < 0.05), respectively, and by 3.2% (P < 0.05) and 7.6% (P < 0.01); (iv) tendon stiffness decreased by 9.8 +/- 8.2% (P < 0.05) and 29.3 +/- 11.5% (P < 0.005), respectively, and Young's modulus by 9.2 +/- 8.2% (P < 0.05) and 30.1 +/- 11.9% (P < 0.01), respectively, with no changes in the controls. Hence, ULLS induces rapid losses of KE muscle size, architecture and function, but not in neural drive. Significant deterioration in tendon mechanical properties also occurs within 2 weeks, exacerbating in the third week of ULLS. Rehabilitation to limit muscle and tendon deterioration should probably start within 2 weeks of unloading.
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M J Rennie (2007)  Exercise- and nutrient-controlled mechanisms involved in maintenance of the musculoskeletal mass.   Biochem Soc Trans 35: Pt 5. 1302-1305 Nov  
Abstract: The mechanisms of maintenance of the protein mass of muscle and associated connective tissue and bone are becoming more accessible as a result of the use of a combination of well-established techniques for measurement of protein turnover and measurement of protein expression and phosphorylation state of signalling molecules involved in anabolic and catabolic responses. Amino acids, hormones and physical activity appear to be the major short-term physiological regulators of muscle mass, mainly through their actions on protein synthesis and breakdown, on a time scale of minutes to hours, with duration of changes in gene expression up to weeks. Amino acids are the main components in the diet regulating protein turnover, having marked effects in stimulating muscle protein synthesis and with almost no effect on muscle protein breakdown. Branched-chain amino acids, and in particular leucine, simulate protein synthesis via signalling pathways involving mTOR (mammalian target of rapamycin) in a dose-response manner. Insulin has little effect on protein synthesis in human muscle, but it has a marked inhibitory effect on protein breakdown. The amino acid simulation of anabolism is not dependent on the presence of insulin, IGF-1 (insulin-like growth factor-1) or growth hormone. Exercise not only stimulates protein synthesis in muscle, but also in tendon; and disuse atrophy is accompanied by marked decreases of both muscle and tendon collagen protein synthesis. Bone collagen synthesis appears to be nutritionally regulated by the availability of amino acids, but not lipid or glucose.
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Maarten D de Boer, Anna Selby, Philip Atherton, Ken Smith, Olivier R Seynnes, Constantinos N Maganaris, Nicola Maffulli, Tomas Movin, Marco V Narici, Michael J Rennie (2007)  The temporal responses of protein synthesis, gene expression and cell signalling in human quadriceps muscle and patellar tendon to disuse.   J Physiol 585: Pt 1. 241-251 Nov  
Abstract: We hypothesized that rates of myofibrillar and patellar tendon collagen synthesis would fall over time during disuse, the changes being accompanied in muscle by decreases in focal adhesion kinase (FAK) phosphorylation and in gene expression for proteolytic enzymes. We studied nine men (22 +/- 4 years, BMI 24 +/- 3 kg m(-2) (means +/- s.d.) who underwent unilateral lower leg suspension for 23 days; five were studied between 0 and 10 days and four between 10 and 21 days. Muscle and tendon biopsies were taken in the postabsorptive state at days 0, 10 and 21 for measurement of protein synthesis, gene expression and protein phosphorylation. Muscle cross-sectional area decreased by 5.2% at 14 days and 10.0% (both P < 0.001), at 23 days, i.e. 0.5% day(-1), whereas tendon dimensions were constant. Rates of myofibrillar protein synthesis fell (P < 0.01) from 0.047% h(-1) at day 0 to 0.022% h(-1) at 10 days without further changes. Tendon collagen synthetic rates also fell (P < 0.01), from 0.052 to 0.023% h(-1) at 10 days and then to 0.010% h(-1) at 21 days. FAK phosphorylation decreased 30% (P < 0.01) at 10 days. No changes occurred in the amounts/phosphorylation of PKB-P70s6k-mTOR pathway components. Expression of mRNA for MuRF-1 increased approximately 3-fold at 10 days without changes in MAFbx or tripeptidyl peptidase II mRNA, but all decreased between 10 and 21 days. Thus, both myofibrillar and tendon protein synthetic rates show progressive decreases during 21 days of disuse; in muscle, this is accompanied by decreased phosphorylation of FAK, with no marked increases in genes for proteolytic enzymes.
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2006
Viraine Weerasooriya, Michael J Rennie, Shri Anant, David H Alpers, Bruce W Patterson, Samuel Klein (2006)  Dietary fiber decreases colonic epithelial cell proliferation and protein synthetic rates in human subjects.   Am J Physiol Endocrinol Metab 290: 6. E1104-E1108 Jun  
Abstract: Although it has been proposed that high fiber consumption can prevent proliferative diseases of the colon, the clinical data to support this hypothesis have been inconsistent. To provide a more robust measure of the effects of fiber on colonic mucosal growth than previous studies, we evaluated both cell proliferation and colonic mucosal protein synthesis in nine healthy volunteers after they consumed a typical Western diet (<20 g fiber/day) or a Western diet supplemented with wheat bran (24 g/day) in a randomized crossover design. Biopsies taken from the sigmoid colon were used to assess mucosal proliferation by determining proliferating cell nuclear antigen (PCNA) in crypt cells and to assess mucosal protein synthetic rate using stable isotopically labeled leucine infusion. Fiber supplementation produced a 12% decrease in labeling index (%crypt cells stained with PCNA) (P < 0.001) and an 11% decrease in mucosal protein fractional synthetic rate (FSR; P < 0.05). Moreover, mucosal protein FSR correlated directly with labeling index (r2= 0.22, P < 0.05). These data demonstrate that increased wheat bran consumption decreases colonic mucosal proliferation and support the potential importance of dietary fiber in preventing proliferative diseases of the colon.
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Benjamin F Miller, Mette Hansen, Jens L Olesen, Allan Flyvbjerg, Peter Schwarz, John A Babraj, Kenneth Smith, Michael J Rennie, Michael Kjaer (2006)  No effect of menstrual cycle on myofibrillar and connective tissue protein synthesis in contracting skeletal muscle.   Am J Physiol Endocrinol Metab 290: 1. E163-E168 Jan  
Abstract: We tested the hypothesis that acute exercise would stimulate synthesis of myofibrillar protein and intramuscular collagen in women and that the phase of the menstrual cycle at which the exercise took place would influence the extent of the change. Fifteen young, healthy female subjects were studied in the follicular (FP, n=8) or the luteal phase (LP, n=7, n=1 out of phase) 24 h after an acute bout of one-legged exercise (60 min of kicking at 67% W(max)), samples being taken from the vastus lateralis in both the exercised and resting legs. Rates of synthesis of myofibrillar and muscle collagen proteins were measured by incorporation of [(13)C]leucine. Myofibrillar protein synthesis (means+/-SD; rest FP: 0.053+/-0.009%/h, LP: 0.055+/-0.013%/h) was increased at 24-h postexercise (FP: 0.131+/-0.018%/h, P<0.05, LP: 0.134+/-0.018%/h, P< 0.05) with no differences between phases. Similarly, muscle collagen synthesis (rest FP: 0.024+/- 0.017%/h, LP: 0.021+/- 0.006%/h) was elevated at 24-h postexercise (FP: 0.073+/- 0.016%/h, P<0.05, LP: 0.072+/- 0.015%/h, P<0.05), but the responses did not differ between menstrual phases. Therefore, there is no effect of menstrual cycle phase, at rest or in response to an acute bout of exercise, on myofibrillar protein synthesis and muscle collagen synthesis in women.
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Jörn Rittweger, Keith Winwood, Olivier Seynnes, Maarten de Boer, Desirée Wilks, Rosalind Lea, Michael Rennie, Marco Narici (2006)  Bone loss from the human distal tibia epiphysis during 24 days of unilateral lower limb suspension.   J Physiol 577: Pt 1. 331-337 Nov  
Abstract: Bone loss during immobilization is well documented. Currently, the only means of studying this in human beings is bed rest, which is resource intensive and inconvenient for the subjects. Unilateral lower limb suspension (ULLS) has been suggested as an alternative, but has not previously been demonstrated to cause bone loss. The main aim of our study was to test the hypothesis that ULLS would cause bone loss determined by peripheral quantitative computed tomography (pQCT). We investigated eight young healthy volunteers (19.1 +/- 0.7 years; body mass index, 22.4 +/- 2.6 kg m(-2)), who underwent ULLS for 24 days; their right foot was suspended with a strap attached to the shoulder so the knee angle was 10 deg and they wore a left shoe with a 7.5 cm sole to allow clearance of the right foot and used bilateral crutches to perambulate. Bone scans were obtained by pQCT from the distal epiphyses and from the diaphyses of the tibia in each leg twice before suspension, at days 7, 14 and 21 of the ULLS, and at days 4, 9, 35 and 90 of recovery. After 21 days of ULLS, bone mineral content of the peripheral portion of the epiphysis of the suspended tibia was reduced by 0.89 +/- 0.48% (from 280.9 +/- 34.5 to 278.4 +/- 34.2 mg mm(-1), P < 0.001) but no changes were observed in its central portion or in the unsuspended tibia. In the peripheral epiphyseal portion, significant bone loss (by 0.32 +/- 0.54%, P = 0.045) occurred as early as day 7 of ULLS. We have demonstrated, for the first time, that in humans bone is lost during ULLS at rates comparable to those seen with bed rest, without alteration in limb fluid volumes thus validating the technique and raising important questions about the mechanisms involved.
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Michael J Rennie, Julien Bohé, Ken Smith, Henning Wackerhage, Paul Greenhaff (2006)  Branched-chain amino acids as fuels and anabolic signals in human muscle.   J Nutr 136: 1 Suppl. 264S-268S Jan  
Abstract: During exercise, there is an increase in amino acid (AA) oxidation accompanied by a depression in whole-body protein synthesis and an increase in protein breakdown. Leucine oxidation increases in proportion to energy expenditure, but the total contribution of BCAA to fuel provision during exercise is minor and insufficient to increase dietary protein requirements. When investigating the effects of AA on the control of muscle protein synthesis (MPS), we showed that increased availability of mixed AAs caused a rise in human MPS to about the same extent as complete meals. Leucine alone (and to some extent other essential, but not nonessential, AAs) can stimulate MPS for a short period, suggesting that leucine acts as a signal as well as a substrate. MPS stimulation by infused AAs shows tachyphylaxis, returning to basal rates after 2 h, possibly explaining why chronically elevated leucine delivery does not elevate MPS clinically. Increased availability of essential amino acids (EAAs) results in dose-related responses of MPS, but, in elderly subjects, there is blunted sensitivity and responsiveness associated with decreased total RNA and mRNA for signaling proteins and signaling activity. Increases of MPS due to EAAs are associated with elevation of signaling activity in the mammalian target of rapamycin (mTOR)/p70 ribosomal subunit S6 kinase eukaryotic initiation factor 4 binding protein 1 pathway, without requiring rises of plasma insulin availability above 10 microU/mL. However, at insulin of <5 microU/mL, AAs appear to stimulate MPS without increasing mTOR signaling. Further increasing availability of insulin to postprandial values increases signaling activity, but has no further effect on MPS.
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Julien Bohé, Michael J Rennie (2006)  Muscle protein metabolism during hemodialysis.   J Ren Nutr 16: 1. 3-16 Jan  
Abstract: Despite improvement in many aspects of the care of maintenance hemodialysis (HD) patients, protein-calorie malnutrition, which is characterized by an insidious loss of somatic protein, is common and is a major risk factor for increased morbidity and mortality. We present here an overview of the current knowledge on protein metabolism in uremic patients with the expectation of providing insights into the mechanisms involved in HD-associated catabolism and outlining the rationale underlying intradialytic nutrition. We concentrate on the discussion of muscle protein metabolism because muscle is the predominant site of protein storage, and its integrity is mandatory for the maintenance of a good quality of life.
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Henning Wackerhage, Michael J Rennie (2006)  How nutrition and exercise maintain the human musculoskeletal mass.   J Anat 208: 4. 451-458 Apr  
Abstract: In this article we review some of our recent work concerning the effects of nutrition and exercise on protein synthesis and signal transduction in human musculoskeletal tissues. A great deal of new information is being generated by the application of recently refined techniques for measuring protein turnover. The field remains one that is largely descriptive but increasingly we are beginning to discern mechanisms underlying lean tissue maintenance, growth and wasting especially as multidisciplinary tools are applied to its study. Several types of exercise and nutrition are potent stimuli for protein synthesis in skeletal muscle. By contrast, collagen in the extracellular matrix in muscle and tendon appears to be mechanically but not nutritionally sensitive. The rates of collagen turnover in a variety of tissues are sufficiently high to account for a sizeable proportion of whole body protein turnover. One of the most recent surprises is the high turnover rate of human bone collagen and its anabolic response to feeding. As our understanding of the normal physiology of these processes advances, we become better able to construct testable hypotheses concerning the effects of ageing and disease on the musculoskeletal mass. Current evidence suggests that one of the major problems with loss of muscle during ageing is an inability of the tissue to respond adequately to increased availability of nutrients.
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2005
B Mittendorfer, J L Andersen, P Plomgaard, B Saltin, J A Babraj, K Smith, M J Rennie (2005)  Protein synthesis rates in human muscles: neither anatomical location nor fibre-type composition are major determinants.   J Physiol 563: Pt 1. 203-211 Feb  
Abstract: In many animals the rate of protein synthesis is higher in slow-twitch, oxidative than fast-twitch, glycolytic muscles. To discover if muscles in the human body also show such differences, we measured [13C]leucine incorporation into proteins of anatomically distinct muscles of markedly different fibre-type composition (vastus lateralis, triceps, soleus) after an overnight fast and during infusion of a mixed amino acid solution (75 mg amino acids kg(-1) h(-1)) in nine healthy, young men. Type-1 fibres contributed 83 +/- 4% (mean +/-s.e.m.) of total fibres in soleus, 59 +/- 3% in vastus lateralis and 22 +/- 2% in triceps. The basal myofibrillar and sarcoplasmic protein fractional synthetic rates (FSR, % h(-1)) were 0.034 +/- 0.001 and 0.064 +/- 0.001 (soleus), 0.031 +/- 0.001 and 0.060 +/- 0.001 (vastus), and 0.027 +/- 0.001 and 0.055 +/- 0.001 (triceps). During amino acid infusion, myofibrillar protein FSR increased to 3-fold, and sarcoplasmic to 2-fold basal values (P < 0.001). The differences between muscles, although significant statistically (triceps versus soleus and vastus lateralis, P < 0.05), were within approximately 15%, biologically probably insignificant. The rates of collagen synthesis were not affected by amino acid infusion and varied by < 5% between muscles and experimental conditions.
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Daniel Cuthbertson, Kenneth Smith, John Babraj, Graham Leese, Tom Waddell, Philip Atherton, Henning Wackerhage, Peter M Taylor, Michael J Rennie (2005)  Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle.   FASEB J 19: 3. 422-424 Mar  
Abstract: The nature of the deficit underlying age-related muscle wasting remains controversial. To test whether it could be due to a poor anabolic response to dietary amino acids, we measured the rates of myofibrillar and sarcoplasmic muscle protein synthesis (MPS) in 44 healthy young and old men, of similar body build, after ingesting different amounts of essential amino acids (EAA). Basal rates of MPS were indistinguishable, but the elderly showed less anabolic sensitivity and responsiveness of MPS to EAA, possibly due to decreased intramuscular expression, and activation (phosphorylation) after EAA, of amino acid sensing/signaling proteins (mammalian target of rapamycin, mTOR; p70 S6 kinase, or p70(S6k); eukaryotic initiation factor [eIF]4BP-1; and eIF2B). The effects were independent of insulin signaling since plasma insulin was clamped at basal values. Associated with the anabolic deficits were marked increases in NFkappaB, the inflammation-associated transcription factor. These results demonstrate first, EAA stimulate MPS independently of increased insulin availability; second, in the elderly, a deficit in MPS in the basal state is unlikely; and third, the decreased sensitivity and responsiveness of MPS to EAA, associated with decrements in the expression and activation of components of anabolic signaling pathways, are probably major contributors to the failure of muscle maintenance in the elderly. Countermeasures to maximize muscle maintenance should target these deficits.
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J A Babraj, D J R Cuthbertson, K Smith, H Langberg, B Miller, M R Krogsgaard, M Kjaer, M J Rennie (2005)  Collagen synthesis in human musculoskeletal tissues and skin.   Am J Physiol Endocrinol Metab 289: 5. E864-E869 Nov  
Abstract: We have developed a direct method for the measurement of human musculoskeletal collagen synthesis on the basis of the incorporation of stable isotope-labeled proline or leucine into protein and have used it to measure the rate of synthesis of collagen in tendon, ligament, muscle, and skin. In postabsorptive, healthy young men (28 +/- 6 yr) synthetic rates for tendon, ligament, muscle, and skin collagen were 0.046 +/- 0.005, 0.040 +/- 0.006, 0.016 +/- 0.002, and 0.037 +/- 0.003%/h, respectively (means +/- SD). In postabsorptive, healthy elderly men (70 +/- 6 yr) the rate of skeletal muscle collagen synthesis is greater than in the young (0.023 +/- 0.002%/h, P < 0.05 vs. young). The rates of synthesis of tendon and ligament collagen are similar to those of mixed skeletal muscle protein in the postabsorptive state, whereas the rate for muscle collagen synthesis is much lower in both young and elderly men. After nutrient provision, collagen synthesis was unaltered in tendon and skeletal muscle, remaining at postabsorptive values (young: tendon, 0.045 +/- 0.008%/h; muscle, 0.016 +/- 0.003%/h; elderly: muscle, 0.024 +/- 0.003%/h). These results demonstrate that the rate of human musculoskeletal tissue collagen synthesis can be directly and robustly measured using stable isotope methodology.
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Louise Deldicque, Magali Louis, Daniel Theisen, Henri Nielens, Mischaël Dehoux, Jean-Paul Thissen, Michael J Rennie, Marc Francaux (2005)  Increased IGF mRNA in human skeletal muscle after creatine supplementation.   Med Sci Sports Exerc 37: 5. 731-736 May  
Abstract: PURPOSE: We hypothesized that creatine supplementation would facilitate muscle anabolism by increasing the expression of growth factors and the phosphorylation of anabolic signaling molecules; we therefore tested the responses of mRNA for IGF-I and IGF-II and the phosphorylation state of components of anabolic signaling pathways p70(s6k) and 4E-BP1 to a bout of high-intensity resistance exercise after 5 d of creatine supplementation. METHODS: In a double-blind cross-over design, muscle biopsies were taken from the m. vastus lateralis at rest and 3 and 24 h postexercise in subjects who had taken creatine or placebo for 5 d (21 g x d(-1)). For the first 3 h postexercise, the subjects were fed with a drink containing maltodextrin (0.3 g x kg(-1) body weight x h(-1)) and protein (0.08 g x kg(-1) body weight x h(-1)). RESULTS: After creatine supplementation, resting muscle expressed more mRNA for IGF-I (+30%, P < 0.05) and IGF-II (+40%, P = 0.054). Exercise caused an increase by 3 h postexercise in IGF-I (+24%, P < 0.05) and IGF-II (+48%, P < 0.05) and by 24 h postexercise in IGF-I (+29%, P < 0.05), but this effect was not potentiated by creatine supplementation. The phosphorylation states of p70(s6k) and 4E-BP1 were not affected by creatine at rest; phosphorylation of both increased (150-400%, P < 0.05) to similar levels under placebo and creatine conditions at 3 h postexercise plus feeding. However, the phosphorylation state of 4E-BP1 was higher in the creatine versus placebo condition at 24 h postexercise. CONCLUSION: The increase in lean body mass often reported after creatine supplementation could be mediated by signaling pathway(s) involving IGF and 4E-BP1.
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John A Babraj, Kenneth Smith, Daniel J R Cuthbertson, Peter Rickhuss, James S Dorling, Michael J Rennie (2005)  Human bone collagen synthesis is a rapid, nutritionally modulated process.   J Bone Miner Res 20: 6. 930-937 Jun  
Abstract: We developed a direct assay of human bone collagen synthesis using [13C] or [15N] proline and applied it to determine the effects of feeding in young healthy men. Surprisingly, postabsorptive bone collagen synthesis is not sluggish, being approximately 0.07%/h more rapid than that of muscle protein, and capable of being stimulated within 4 h of intravenous feeding by 66 +/- 13%. INTRODUCTION: All current methods for estimation of bone collagen turnover are indirect, depending on the assay of collagen "markers." Our aim was to develop a direct method for human bone collagen synthesis to be used to study its physiology and pathology, and specifically, in the first instance, the effect of feeding. MATERIALS AND METHODS: We applied, over 2 h, flooding doses of [13C] and [15N] proline to label iliac crest bone collagen in eight young healthy men. The rate of collagen synthesis was determined as the rate of labeling of collagen hydroxyproline (assayed by gas chromatography-combustion-isotope ratio mass spectrometry in collagen extracted by differential solubility) compared with plasma proline labeling (assayed by gas chromatography-mass spectrometry). We also determined (in a second group of eight young healthy men) the effect of intravenous nutrition (glucose, lipid emulsion, and amino acids (in the ratio of 55%:30%:15% energy, respectively). RESULTS: Free bone proline labeling was 92 +/- 6% of that of plasma proline, supporting the flooding dose assumption. Human iliac crest bone collagen is heterogeneous, with NaCl-EDTA, 0.5 M acetic acid, pepsin-acetic acid, and hot water-extractable pools being responsible for approximately 1%, 3%, 8%, and 81% of content, respectively. The synthetic rates were 0.58 +/- 0.1, 0.24 +/- 0.05, 0.07 +/- 0.02, and 0.06 +/- 0.01%/h, respectively, giving an average rate of approximately 0.066%/h. [13C] and [15N] proline gave identical results. Intravenous nutrition caused the disappearance of proline label from the procollagen pool and its increased appearance in the less extractable pools, suggesting nutritional stimulation of collagen processing. CONCLUSION: The results show (1) that iliac crest bone collagen synthesis is faster than generally assumed and of the same order as muscle protein turnover and (2) that feeding increases synthesis by approximately 66%. Given its ability to detect physiologically meaningful responses, the method should provide a new approach to studying the regulation of bone collagen turnover.
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Michael J Rennie, Emilie A Wilkes (2005)  Maintenance of the musculoskeletal mass by control of protein turnover: the concept of anabolic resistance and its relevance to the transplant recipient.   Ann Transplant 10: 4. 31-34  
Abstract: Although the overall size of the musculoskeletal mass is constrained by genetic limitations, both the day to day maintenance and muscle wasting and rehabilitation are regulated by protein synthesis (particularly the initiation and elongation stages of translation) and by protein breakdown. These are directly influenced by the nutritional state (size and composition of meals) and type, mode and duration of exercise. In the context of food-related changes, recent work has demonstrated that human muscle protein synthesis is almost entirely controlled by the availability of essential amino acids and protein breakdown by availability of insulin. Muscle protein synthesis is also markedly stimulated by preceding exercise in a manner independent of but additive to any effect of food. The sensing and signalling pathways within muscle are activated by food and exercise in normal healthy subjects to elevate net muscle balance for many hours after strenuous exercise. In many circumstances such as immobilisation, ageing and many chronic diseases of the lung, kidney, heart, etc (such as those often suffered by pre-transplant patients), the general debilitation includes muscle wasting. In these subjects there appears to be a general failure to respond adequately to food--so called "anabolic resistance". It seems highly likely that this circumstance will also apply to transplant recipients. It is also likely that anabolic resistance can be, to some extent, reversed by regular physical activity which may "tune up" the anabolic pathways to act in a more normal fashion. Nevertheless, the extent of re-growth and adaptation of composition of muscle in transplant patients could be hindered by drug treatment including the use of rapamycin (sirolimus) cyclosporine and corticosteroids. These predictions should be tested by examining longitudinal effects of different modes of exercise and nutritional regimens on rehabilitation of muscle in transplant patients.
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Benjamin F Miller, Jens L Olesen, Mette Hansen, Simon Døssing, Regina M Crameri, Rasmus J Welling, Henning Langberg, Allan Flyvbjerg, Michael Kjaer, John A Babraj, Kenneth Smith, Michael J Rennie (2005)  Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise.   J Physiol 567: Pt 3. 1021-1033 Sep  
Abstract: We hypothesized that an acute bout of strenuous, non-damaging exercise would increase rates of protein synthesis of collagen in tendon and skeletal muscle but these would be less than those of muscle myofibrillar and sarcoplasmic proteins. Two groups (n = 8 and 6) of healthy young men were studied over 72 h after 1 h of one-legged kicking exercise at 67% of maximum workload (W(max)). To label tissue proteins in muscle and tendon primed, constant infusions of [1-(13)C]leucine or [1-(13)C]valine and flooding doses of [(15)N] or [(13)C]proline were given intravenously, with estimation of labelling in target proteins by gas chromatography-mass spectrometry. Patellar tendon and quadriceps biopsies were taken in exercised and rested legs at 6, 24, 42 or 48 and 72 h after exercise. The fractional synthetic rates of all proteins were elevated at 6 h and rose rapidly to peak at 24 h post exercise (tendon collagen (0.077% h(-1)), muscle collagen (0.054% h(-1)), myofibrillar protein (0.121% h(-1)), and sarcoplasmic protein (0.134% h(-1))). The rates decreased toward basal values by 72 h although rates of tendon collagen and myofibrillar protein synthesis remained elevated. There was no tissue damage of muscle visible on histological evaluation. Neither tissue microdialysate nor serum concentrations of IGF-I and IGF binding proteins (IGFBP-3 and IGFBP-4) or procollagen type I N-terminal propeptide changed from resting values. Thus, there is a rapid increase in collagen synthesis after strenuous exercise in human tendon and muscle. The similar time course of changes of protein synthetic rates in different cell types supports the idea of coordinated musculotendinous adaptation.
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P J Atherton, J Babraj, K Smith, J Singh, M J Rennie, H Wackerhage (2005)  Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation.   FASEB J 19: 7. 786-788 May  
Abstract: Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the "AMPK-PKB switch." We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.
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Daniel R Moore, Stuart M Phillips, John A Babraj, Kenneth Smith, Michael J Rennie (2005)  Myofibrillar and collagen protein synthesis in human skeletal muscle in young men after maximal shortening and lengthening contractions.   Am J Physiol Endocrinol Metab 288: 6. E1153-E1159 Jun  
Abstract: We aimed to determine whether there were differences in the extent and time course of skeletal muscle myofibrillar protein synthesis (MPS) and muscle collagen protein synthesis (CPS) in human skeletal muscle in an 8.5-h period after bouts of maximal muscle shortening (SC; average peak torque = 225 +/- 7 N.m, means +/- SE) or lengthening contractions (LC; average peak torque = 299 +/- 18 N.m) with equivalent work performed in each mode. Eight healthy young men (21.9 +/- 0.6 yr, body mass index 24.9 +/- 1.3 kg/m2) performed 6 sets of 10 maximal unilateral LC of the knee extensors on an isokinetic dynamometer. With the contralateral leg, they then performed 6 sets of maximal unilateral SC with work matched to the total work performed during LC (10.9 +/- 0.7 vs. 10.9 +/- 0.8 kJ, P = 0.83). After exercise, the participants consumed small intermittent meals to provide 0.1 g.kg(-1).h(-1) of protein and carbohydrate. Prior exercise elevated MPS above rest in both conditions, but there was a more rapid rise after LC (P < 0.01). The increases (P < 0.001) in CPS above rest were identical for both SC and LC and likely represent a remodeling of the myofibrillar basement membrane. Therefore, a more rapid rise in MPS after maximal LC could translate into greater protein accretion and muscle hypertrophy during chronic resistance training utilizing maximal LC.
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Michael J Rennie (2005)  Body maintenance and repair: how food and exercise keep the musculoskeletal system in good shape.   Exp Physiol 90: 4. 427-436 Jul  
Abstract: This article provides a personal view of how feeding and exercise acutely modify protein metabolism of human skeletal muscle, with discussion of the anabolic signalling mechanisms involved and some new findings on the metabolism of the turnover of collagen, tendon and bone.
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M Kjaer, H Langberg, B F Miller, R Boushel, R Crameri, S Koskinen, K Heinemeier, J L Olesen, S Døssing, M Hansen, S G Pedersen, M J Rennie, P Magnusson (2005)  Metabolic activity and collagen turnover in human tendon in response to physical activity.   J Musculoskelet Neuronal Interact 5: 1. 41-52 Mar  
Abstract: Connective tissue of the human tendon plays an important role in force transmission. The extracellular matrix turnover of tendon is influenced by physical activity. Blood flow, oxygen demand, and the level of collagen synthesis and matrix metalloproteinases increase with mechanical loading. Gene transcription and especially post-translational modifications of proteins of the extracellular matrix are enhanced following exercise. Conversely, inactivity markedly decreases collagen turnover. Training leads to a chronically increased collagen turnover, and dependent on the type of collagen also to some degree of net collagen synthesis. These changes modify the biomechanical properties of the tissue (for example, viscoelastic characteristics) as well as the structural properties of the in collagen (for example, cross-sectional area). Mechanical loading of human tendon does result in a marked interstitial increase in growth factors that are known potentially to stimulate synthesis of collagen and other extracellular matrix proteins. Taken together, human tendon tissue mounts a vigorous acute and chronic response to mechanical loading in terms of metabolic-circulatory changes as well as of extracellular matrix formation. These changes may contribute to training-induced adaptation of biomechanical properties consisting of altered resistance to loading and enhanced tolerance to strenuous exercise. Understanding of such changes is a pre-requisite in the development of measures aimed at prevention of overuse tendon injuries occurring during sport, work or leisure-related activities.
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2004
Michael J Rennie, Henning Wackerhage, Espen E Spangenburg, Frank W Booth (2004)  Control of the size of the human muscle mass.   Annu Rev Physiol 66: 799-828  
Abstract: This review is divided into two parts, the first dealing with the cell and molecular biology of muscle in terms of growth and wasting and the second being an account of current knowledge of physiological mechanisms involved in the alteration of size of the human muscle mass. Wherever possible, attempts have been made to interrelate the information in each part and to provide the most likely explanation for phenomena that are currently only partially understood. The review should be of interest to cell and molecular biologists who know little of human muscle physiology and to physicians, physiotherapists, and kinesiologists who may be familiar with the gross behavior of human muscle but wish to understand more about the underlying mechanisms of change.
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F E Baird, K J Beattie, A R Hyde, V Ganapathy, M J Rennie, P M Taylor (2004)  Bidirectional substrate fluxes through the system N (SNAT5) glutamine transporter may determine net glutamine flux in rat liver.   J Physiol 559: Pt 2. 367-381 Sep  
Abstract: System N (SNAT3 and SNAT5) amino acid transporters are key mediators of glutamine transport across the plasma membrane of mammalian cell types, including hepatocytes and astrocytes. We demonstrate that SNAT5 shows simultaneous bidirectional glutamine fluxes when overexpressed in Xenopus oocytes. Influx and efflux are both apparently Na+ dependent but, since they are not directly coupled, the carrier is capable of mediating net amino acid movement across the cell membrane. The apparent Km values for glutamine influx and efflux are similar (approximately 1 mm) and the transporter behaviour is consistent with a kinetic model in which re-orientation of the carrier from outside- to inside-facing conformations (either empty or substrate loaded) is the limiting step in the transport cycle. In perfused rat liver, the observed relationship between influent (portal) glutamine concentration and net hepatic glutamine flux may be described by a simple kinetic model, assuming the balance between influx and efflux through System N determines net flux, where under physiological conditions efflux is generally saturated owing to high intracellular glutamine concentration. SNAT5 shows a more periportal mRNA distribution than SNAT3 in rat liver, indicating that SNAT5 may have particular importance for modulation of net hepatic glutamine flux.
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2003
Magali Louis, Jacques R Poortmans, Marc Francaux, Eric Hultman, Jacques Berre, Nathalie Boisseau, Vernon R Young, Kenneth Smith, Wolfram Meier-Augenstein, John A Babraj, Tom Waddell, Michael J Rennie (2003)  Creatine supplementation has no effect on human muscle protein turnover at rest in the postabsorptive or fed states.   Am J Physiol Endocrinol Metab 284: 4. E764-E770 Apr  
Abstract: Dietary creatine supplementation is associated with increases in muscle mass, but the mechanism is unknown. We tested the hypothesis that creatine supplementation enhanced myofibrillar protein synthesis (MPS) and diminished muscle protein breakdown (MPB) in the fed state. Six healthy men (26 +/- 7 yr, body mass index 22 +/- 4 kg/m(2)) were studied twice, 2-4 wk apart, before and after ingestion of creatine (21 g/day, 5 days). We carried out two sets of measurements within 5.5 h of both MPS (by incorporation of [1-(13)C]leucine in quadriceps muscle) and MPB (as dilution of [1-(13)C]leucine or [(2)H(5)]phenylalanine across the forearm); for the first 3 h, the subjects were postabsorptive but thereafter were fed orally (0.3 g maltodextrin and 0.083 g protein. kg body wt(-1) x h(-1)). Creatine supplementation increased muscle total creatine by approximately 30% (P < 0.01). Feeding had significant effects, doubling MPS (P < 0.001) and depressing MPB by approximately 40% (P < 0.026), but creatine had no effect on turnover in the postabsorptive or fed states. Thus any increase in muscle mass accompanying creatine supplementation must be associated with increased physical activity.
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Julien Bohé, Aili Low, Robert R Wolfe, Michael J Rennie (2003)  Human muscle protein synthesis is modulated by extracellular, not intramuscular amino acid availability: a dose-response study.   J Physiol 552: Pt 1. 315-324 Oct  
Abstract: To test the hypothesis that muscle protein synthesis (MPS) is regulated by the concentration of extracellular amino acids, we investigated the dose-response relationship between the rate of human MPS and the concentrations of blood and intramuscular amino acids. We increased blood mixed amino acid concentrations by up to 240 % above basal levels by infusion of mixed amino acids (Aminosyn 15, 44-261 mg kg-1 h-1) in 21 healthy subjects, (11 men 10 women, aged 29 +/- 2 years) and measured the rate of incorporation of D5-phenylalanine or D3-leucine into muscle protein and blood and intramuscular amino acid concentrations. The relationship between the fold increase in MPS and blood essential amino acid concentration ([EAA], mM) was hyperbolic and fitted the equation MPS = (2.68 x [EAA])/(1.51 + [EAA]) (P < 0.01). The pattern of stimulation of myofibrillar, sarcoplasmic and mitochondrial protein was similar. There was no clear relationship between the rate of MPS and the concentration of intramuscular EAAs; indeed, when MPS was increasing most rapidly, the concentration of intramuscular EAAs was below basal levels. We conclude that the rates of synthesis of all classes of muscle proteins are acutely regulated by the blood [EAA] over their normal diurnal range, but become saturated at high concentrations. We propose that the stimulation of protein synthesis depends on the sensing of the concentration of extracellular, rather than intramuscular EAAs.
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J Dorrens, M J Rennie (2003)  Effects of ageing and human whole body and muscle protein turnover.   Scand J Med Sci Sports 13: 1. 26-33 Feb  
Abstract: Prevalence of sarcopenia is up to 60% of those individuals over 80 years of age and is associated with increased disability. The causes behind the age-related loss of muscle are difficult to discern. Measurements of protein synthesis/breakdown and net protein balance are important, and further methodological development is warranted. Whole body protein turnover is changed only little - if at all - with ageing, when corrected for fat free mass of the individuals. Discrepancies in reports are often related to inconsistent recordings of energy intake especially protein and variation in subject, gender and physical activity level. Ageing is associated with reduced sensitivity toward amino acids, increased first pass uptake in a splanchnic region and a reduced postprandial stimulation of protein synthesis. Physical activity and amino acids are additive in effect also in elderly individuals, and timing of training and protein intake is crucial, in that early intake of amino acids is advantageous with regards to stimulation of protein synthesis.
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Magali Louis, Jacques R Poortmans, Marc Francaux, Jacques Berré, Nathalie Boisseau, Eric Brassine, Daniel J R Cuthbertson, Kenneth Smith, John A Babraj, Tom Waddell, Michael J Rennie (2003)  No effect of creatine supplementation on human myofibrillar and sarcoplasmic protein synthesis after resistance exercise.   Am J Physiol Endocrinol Metab 285: 5. E1089-E1094 Nov  
Abstract: Muscle hypertrophy during resistance training is reportedly increased by creatine supplementation. Having previously failed to find an anabolic effect on muscle protein turnover at rest, either fed or fasted, we have now examined the possibility of a stimulatory effect of creatine in conjunction with acute resistance exercise. Seven healthy men (body mass index, 23 +/- 2 kg/m2, 21 +/- 1 yr, means +/- SE) performed 20 x 10 repetitions of leg extension-flexion at 75% one-repetition maximum in one leg, on two occasions, 4 wk apart, before and after ingesting 21 g/day creatine for 5 days. The subjects ate approximately 21 g maltodextrin + 6 g protein/h for 3 h postexercise. We measured incorporation of [1-13C]leucine into quadriceps muscle proteins in the rested and exercised legs. Leg protein breakdown (as dilution of [2H5]phenylalanine) was also assessed in the exercised and rested leg postexercise. Creatine supplementation increased muscle total creatine by approximately 21% (P < 0.01). Exercise increased the synthetic rates of myofibrillar and sarcoplasmic proteins by two- to threefold (P < 0.05), and leg phenylalanine balance became more positive, but creatine was without any anabolic effect.
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M J Rennie (2003)  Claims for the anabolic effects of growth hormone: a case of the emperor's new clothes?   Br J Sports Med 37: 2. 100-105 Apr  
Abstract: This review examines the evidence that growth hormone has metabolic effects in adult human beings. The conclusion is that growth hormone does indeed have powerful effects on fat and carbohydrate metabolism, and in particular promotes the metabolic use of adipose tissue triacylglycerol. However, there is no proof that net protein retention is promoted in adults, except possibly of connective tissue. The overexaggeration of the effects of growth hormone in muscle building is effectively promoting its abuse and thereby encouraging athletes and elderly men to expose themselves to increased risk of disease for little benefit.
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Michael J Rennie, Henning Wackerhage (2003)  Connecting the dots for mechanochemical transduction in muscle.   J Physiol 553: Pt 1. Nov  
Abstract: One of the most impressive adaptive physiological responses is that of muscle to high intensity exercise, as espoused by power athletes and body builders, which results in increases in muscle mass. Athletics and vanity aside, there are many reasons for wishing to know more about the mechanisms underlying this hypertrophy, not least being the possibility of pharmacologically enhancing it in sarcopenia. The work of Bolster and colleagues in this issue of The Journal of Physiology brings us nearer to a complete understanding of the relevant subcellular events occurring in response to resistance exercise by providing a time course of activities of signalling proteins involved in regulating the translational phase of muscle protein synthesis.
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2002
Michael J Rennie, Julien Bohé, Robert R Wolfe (2002)  Latency, duration and dose response relationships of amino acid effects on human muscle protein synthesis.   J Nutr 132: 10. 3225S-3227S Oct  
Abstract: The components of the stimulatory effect of food on net deposition of protein are beginning to be identified and separated. One of the most important of these appears to be the effect of amino acids per se in stimulating muscle anabolism. Amino acids appear to have a linear stimulatory effect within the range of normal diurnal plasma concentrations from postabsorptive to postprandial. Within this range, muscle protein synthesis (measured by incorporation of stable isotope tracers of amino acids into biopsied muscle protein) appears to be stimulated approximately twofold; however, little further increase occurs when very high concentrations of amino acids (>2.5 times the normal postabsorptive plasma concentration) are made available. Amino acids provided in surfeit of the ability of the system to synthesize protein are disposed of by oxidation, ureagenesis and gluconeogenesis. The stimulatory effect of amino acids appears to be time dependent; a square wave increase in the availability of amino acids causes muscle protein synthesis to be stimulated and to fall back to basal values, despite continued amino acid availability. The relationship between muscle protein synthesis and insulin availability suggests that most of the stimulatory effects occur at low insulin concentrations, with large increases having no effect. These findings may have implications for our understanding of the body's requirements for protein. The maximal capacity for storage of amino acids as muscle protein probably sets an upper value on the extent to which amino acids can be stored after a single meal.
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J Babraj, D J Cuthbertson, P Rickhuss, W Meier-Augenstein, K Smith, J Bohé, R R Wolfe, J N A Gibson, C Adams, M J Rennie (2002)  Sequential extracts of human bone show differing collagen synthetic rates.   Biochem Soc Trans 30: 2. 61-65 Apr  
Abstract: Type I collagen is the major bone protein. Little is known quantitatively about human bone collagen synthesis in vivo, despite its importance for the understanding of bone formation and turnover. Our aim was to develop a method that could be used for the physiological and pathophysiological investigation of human bone collagen synthesis. We have carried out preliminary studies in patients undergoing hip replacement and in pigs to validate the use of the flooding dose method using (13)C- or (15)N-labelled proline and we have now refined our techniques to allow them to be used in a normal clinical or physiological setting. The results show that the application of a flooding dose causes bone free-proline labelling to equilibrate with that of blood in pigs and human beings, so that only 150 mg of bone will provide enough sample to prepare and measure the labelling of three fractions of bone collagen (dissolved in NaCl, acetic acid and pepsin/acetic acid) which have the same relative labelling (1.0:0.43:0.1) as measured by GC-combustion-isotope ratio MS. The rates of incorporation were substantially faster than in skeletal muscle samples taken at the same time. The results suggest that different fractions of human bone collagen turnover at markedly higher rates than had been previously considered. This approach should allow us to discover how growth and development, food, activity and drugs affect bone collagen turnover and to measure the effects on it of ageing and bone disease.
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Shihab E O Khogali, Stuart D Pringle, Brian V Weryk, Michael J Rennie (2002)  Is glutamine beneficial in ischemic heart disease?   Nutrition 18: 2. 123-126 Feb  
Abstract: OBJECTIVE: Glutamine enhances recovery from acute normothermic ischemia in isolated rat heart by a dose-dependent effect (Khogali et al. J Mol Cell Cardiol 1998;30:819). We compared the cardioprotective effects of equimolar concentrations of glutamine, glutamate, and aspartate in isolated rat heart. We also explored the potential cardioprotective effects of glutamine in patients with chronic stable angina. METHODS: The isolated perfused working rat heart was subjected to ischemia, followed by reperfusion with or without an amino acid (2.5 mM). Patients with chronic stable angina received a single oral dose of glutamine (80 mg/kg) or placebo in a double-blind, random fashion 40 min before a standard Bruce exercise test. RESULTS: Postischemic reperfusion of isolated rat heart with glutamine (but not with glutamate or aspartate) resulted in full recovery of cardiac output. Only glutamine prevented the decrease in the myocardial ratio between adenosine triphosphate to adenosine diphosphate and significantly enhanced the myocardial ratio of reduced to oxidized glutathione. A single oral dose of glutamine given to patients with chronic stable angina significantly increased plasma glutamine concentration from 419 to 649 microM and delayed time to onset of more than 1.0 mm of ST segment depression on the ECG by 38 s. CONCLUSION: Glutamine may be cardioprotective in patients with coronary heart disease.
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Jørn W Helge, Peter W Watt, Erik A Richter, Michael J Rennie, Bente Kiens (2002)  Partial restoration of dietary fat induced metabolic adaptations to training by 7 days of carbohydrate diet.   J Appl Physiol 93: 5. 1797-1805 Nov  
Abstract: We tested the hypothesis that a shift to carbohydrate diet after prolonged adaptation to fat diet would lead to decreased glucose uptake and impaired muscle glycogen breakdown during exercise compared with ingestion of a carbohydrate diet all along. We studied 13 untrained men; 7 consumed a high-fat (Fat-CHO; 62% fat, 21% carbohydrate) and 6 a high-carbohydrate diet (CHO; 20% fat, 65% carbohydrate) for 7 wk, and thereafter both groups consumed the carbohydrate diet for an eighth week. Training was performed throughout. After 8 wk, during 60 min of exercise (71 +/- 1% pretraining maximal oxygen uptake) average leg glucose uptake (1.00 +/- 0.07 vs. 1.55 +/- 0.21 mmol/min) was lower (P < 0.05) in Fat-CHO than in CHO. The rate of muscle glycogen breakdown was similar (4.4 +/- 0.5 vs. 4.2 +/- 0.7 mmol. min(-1). kg dry wt(-1)) despite a significantly higher preexercise glycogen concentration (872 +/- 59 vs. 688 +/- 43 mmol/kg dry wt) in Fat-CHO than in CHO. In conclusion, shift to carbohydrate diet after prolonged adaptation to fat diet and training causes increased resting muscle glycogen levels but impaired leg glucose uptake and similar muscle glycogen breakdown, despite higher resting levels, compared with when the carbohydrate diet is consumed throughout training.
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2001
M J Rennie (2001)  Control of muscle protein synthesis as a result of contractile activity and amino acid availability: implications for protein requirements.   Int J Sport Nutr Exerc Metab 11 Suppl: S170-S176 Dec  
Abstract: The major anabolic influences on muscle are feeding and contractile activity. As a result of feeding, anabolism occurs chiefly by increases in protein synthesis with minor changes in protein breakdown. Insulin has a permissive role in increasing synthesis, but the availability of amino acids is crucial for net anabolism. We have investigated the role of amino acids in stimulating muscle protein synthesis, the synergy between exercise and amino acid availability, and some of the signaling elements involved. The results suggest that muscle is acutely sensitive to amino acids, that exercise probably increases the anabolic effects of amino acids by a separate pathway, and that for this reason it is unlikely that accustomed physical exercise increases protein requirements.
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J W Helge, P W Watt, E A Richter, M J Rennie, B Kiens (2001)  Fat utilization during exercise: adaptation to a fat-rich diet increases utilization of plasma fatty acids and very low density lipoprotein-triacylglycerol in humans.   J Physiol 537: Pt 3. 1009-1020 Dec  
Abstract: 1. This study was carried out to test the hypothesis that the greater fat oxidation observed during exercise after adaptation to a high-fat diet is due to an increased uptake of fat originating from the bloodstream. 2. Of 13 male untrained subjects, seven consumed a fat-rich diet (62 % fat, 21 % carbohydrate) and six consumed a carbohydrate-rich diet (20 % fat, 65 % carbohydrate). After 7 weeks of training and diet, 60 min of bicycle exercise was performed at 68 +/- 1 % of maximum oxygen uptake. During exercise [1-(13)C]palmitate was infused, arterial and venous femoral blood samples were collected, and blood flow was determined by the thermodilution technique. Muscle biopsy samples were taken from the vastus lateralis muscle before and after exercise. 3. During exercise, the respiratory exchange ratio was significantly lower in subjects consuming the fat-rich diet (0.86 +/- 0.01, mean +/- S.E.M.) than in those consuming the carbohydrate-rich diet (0.93 +/- 0.02). The leg fatty acid (FA) uptake (183 +/- 37 vs. 105 +/- 28 micromol min(-1)) and very low density lipoprotein-triacylglycerol (VLDL-TG) uptake (132 +/- 26 vs. 16 +/- 21 micromol min(-1)) were both higher (each P < 0.05) in the subjects consuming the fat-rich diet. Whole-body plasma FA oxidation (determined by comparison of (13)CO(2) production and blood palmitate labelling) was 55-65 % of total lipid oxidation, and was higher after the fat-rich diet than after the carbohydrate-rich diet (13.5 +/- 1.2 vs. 8.9 +/- 1.1 micromol min(-1) kg(-1); P < 0.05). Muscle glycogen breakdown was significantly lower in the subjects taking the fat-rich diet than those taking the carbohydrate-rich diet (2.6 +/- 0.5 vs. 4.8 +/- 0.5 mmol (kg dry weight)(-1) min(-1), respectively; P < 0.05), whereas leg glucose uptake was similar (1.07 +/- 0.13 vs. 1.15 +/- 0.13 mmol min(-1)). 4. In conclusion, plasma VLDL-TG appears to be an important substrate source during aerobic exercise, and in combination with the higher plasma FA uptake it accounts for the increased fat oxidation observed during exercise after fat diet adaptation. The decreased carbohydrate oxidation was apparently due to muscle glycogen sparing and not to diminished plasma glucose uptake.
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J Bohé, J F Low, R R Wolfe, M J Rennie (2001)  Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids.   J Physiol 532: Pt 2. 575-579 Apr  
Abstract: 1. The aim of this study was to describe the time course of the response of human muscle protein synthesis (MPS) to a square wave increase in availability of amino acids (AAs) in plasma. We investigated the responses of quadriceps MPS to a approximately 1.7-fold increase in plasma AA concentrations using an intravenous infusion of 162 mg (kg body weight)(-1) h(-1) of mixed AAs. MPS was estimated from D3-leucine labelling in protein after a primed, constant intravenous infusion of D3-ketoisocaproate, increased appropriately during AA infusion. 2. Muscle was separated into myofibrillar, sarcoplasmic and mitochondrial fractions. MPS, both of mixed muscle and of fractions, was estimated during a basal period (2.5 h) and at 0.5-4 h intervals for 6 h of AA infusion. 3. Rates of mixed MPS were not significantly different from basal (0.076 +/- 0.008 % h(-1)) in the first 0.5 h of AA infusion but then rose rapidly to a peak after 2 h of approximately 2.8 times the basal value. Thereafter, rates declined rapidly to the basal value. All muscle fractions showed a similar pattern. 4. The results suggest that MPS responds rapidly to increased availability of AAs but is then inhibited, despite continued AA availability. These results suggest that the fed state accretion of muscle protein may be limited by a metabolic mechanism whenever the requirement for substrate for protein synthesis is exceeded.
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M J Rennie, J L Bowtell, M Bruce, S E Khogali (2001)  Interaction between glutamine availability and metabolism of glycogen, tricarboxylic acid cycle intermediates and glutathione.   J Nutr 131: 9 Suppl. 2488S-90S; discussion 2496S-7S Sep  
Abstract: After exhaustive exercise, intravenous or oral glutamine promoted skeletal muscle glycogen storage. However, when glutamine was ingested with glucose polymer, whole-body carbohydrate storage was elevated, the most likely site being liver and not muscle, possibly due to increased glucosamine formation. The rate of tricarboxylic acid (TCA) cycle flux and hence oxidative metabolism may be limited by the availability of TCA intermediates. There is some evidence that intramuscular glutamate normally provides alpha-ketoglutarate to the mitochondrion. We hypothesized that glutamine might be a more efficient anaplerotic precursor than endogenous glutamate alone. Indeed, a greater expansion of the sum of muscle citrate, malate, fumarate and succinate concentrations was observed at the start of exercise (70% VO2(max)) after oral glutamine than when placebo or ornithine alpha-ketoglutarate was given. However, neither endurance time nor the extent of phosphocreatine depletion or lactate accumulation during the exercise was altered, suggesting either that TCA intermediates were not limiting for energy production or that the severity of exercise was insufficient for the limitation to be operational. We have also shown that in the perfused working rat heart, there is a substantial fall in intramuscular glutamine and alpha-ketoglutarate, especially after ischemia. Glutamine (but not glutamate, alpha-ketoglutarate or aspartate) was able to rescue the performance of the postischemic heart. This ability appears to be connected to the ability to sustain intracardiac ATP, phosphocreatine and glutathione.
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M J O'Leary, C N Ferguson, M J Rennie, C J Hinds, J H Coakley, V R Preedy (2001)  Sequential changes in in vivo muscle and liver protein synthesis and plasma and tissue glutamine levels in sepsis in the rat.   Clin Sci (Lond) 101: 3. 295-304 Sep  
Abstract: We have investigated sequential changes in skeletal muscle and hepatic protein synthesis following sepsis, and their relationship to changes in circulating and tissue glutamine concentrations. Male Wistar rats underwent caecal ligation and puncture (CLP) or sham operation, with starvation, and were killed 24, 72 or 96 h later. A group of non-operated animals were killed at the time of surgery. Protein synthesis was determined using a flooding dose of L-[4-(3)H] phenylalanine, and glutamine concentrations were measured by an enzymic fluorimetric assay. Protein synthesis in gastrocnemius muscle fell in all groups. Gastrocnemius total protein content was reduced after CLP and at 72 and 96 h after sham operation. After CLP, protein synthesis was lower at 24 h, and total protein content was lower at 72 and 96 h, than in sham-operated animals. CLP was associated with increased liver protein synthesis at all time points, whereas there was no change after sham operation. Liver protein content did not change after CLP, but was lower at 72 and 96 h after sham operation than in non-operated animals. Plasma glutamine concentrations were reduced at 24 h after sham operation, and at 72 and 96 h after CLP. Muscle glutamine concentrations were reduced in all groups, with the decrease being greater following CLP than after sham operation. In the liver, glutamine concentrations were unchanged after CLP, but increased after sham operation. In rats with sepsis, decreases in muscle protein synthesis and content are associated with markedly reduced muscle glutamine concentrations. Plasma glutamine concentrations are initially maintained, but fall later. In liver, protein synthesis is increased, while glutamine concentrations are preserved. These results support a peripheral-to-splanchnic glutamine flux in sepsis.
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2000
J L Bowtell, K Gelly, M L Jackman, A Patel, M Simeoni, M J Rennie (2000)  Effect of different carbohydrate drinks on whole body carbohydrate storage after exhaustive exercise.   J Appl Physiol 88: 5. 1529-1536 May  
Abstract: Seven untrained male subjects participated in a double-blind, crossover study conducted to determine the efficacy of different carbohydrate drinks in promoting carbohydrate storage in the whole body and skeletal muscle during recovery from exhaustive exercise. The postabsorptive subjects first completed an exercise protocol designed to deplete muscle fibers of glycogen, then consumed 330 ml of one of three carbohydrate drinks (18.5% glucose polymer, 18.5% sucrose, or 12% sucrose; wt/vol) and also received a primed constant infusion of [1-(13)C]glucose for 2 h. Nonoxidative glucose disposal (3.51 +/- 0.28, 18.5% glucose polymer; 2.96 +/- 0.32, 18.5% sucrose; 2.97 +/- 0.16, 12% sucrose; all mmol. kg(-1). h(-1)) and storage of muscle glycogen (5.31 +/- 1.11, 18.5% glucose polymer; 4.07 +/- 1.05, 18.5% sucrose; 3.45 +/- 0.85, 12% sucrose; all mmol. kg wet wt(-1). h(-1); P < 0.05) were greater after consumption of the glucose polymer drink than after either sucrose drink. The results suggest that the consumption of a glucose polymer drink (containing 61 g carbohydrate) promotes a more rapid storage of carbohydrate in the whole body, skeletal muscle in particular, than an isoenergetic sucrose drink.
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M J Rennie (2000)  When having the nerve is helped by having the muscle.   J Physiol 522 Pt 1: Jan  
Abstract: Suppose just now you had picked up this journal, flipped it open and started to read this article. When this started to happen we might assume that there would be some physiological changes in the brain to support this extra brain work and indeed neuroscientists can now put together a rather plausible description of what they might be. On the basis of evidence from the study of the brain, not only in vitro, but also in vivo, with tools like positron emission tomography and magnetic resonance spectroscopy, the story goes something like this. The arousal associated with reading and making sense of the words would have activated various areas of your brain and the fuel metabolism of neurons (and almost immediately of astrocytes also) would have increased to support the increased nervous activity. Release and re-uptake of neurotransmitters, and pumping of ions across cell membranes and between sub-cellular compartments is energetically expensive. Accordingly, soon after an activating stimulus it is possible to detect markedly increased glycolytic lactate production, probably occurring almost exclusively in astroglia in response to glutamate stimulation, followed by a rise in accumulation of extracellular lactate, then a fall as it is taken up and oxidised completely in neurons. The initial burst of glycolysis probably takes place at the expense of blood glucose transported rapidly through the blood-brain barrier, but there is a substantial back-up of astroglial glycogen which can be used if the demand exceeds the supply of glucose for a variety of reasons (or if there is hypoxia when glycolysis is the only energy-producing process).
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M J Rennie, K D Tipton (2000)  Protein and amino acid metabolism during and after exercise and the effects of nutrition.   Annu Rev Nutr 20: 457-483  
Abstract: Sustained dynamic exercise stimulates amino acid oxidation, chiefly of the branched-chain amino acids, and ammonia production in proportion to exercise intensity; if the exercise is intense enough, there is a net loss of muscle protein (as a result of decreased protein synthesis, increased breakdown, or both); some of the amino acids are oxidized as fuel, whereas the rest provide substrates for gluconeogenesis and possibly for acid-based regulation. Protein balance is restored after exercise, but no hypertrophy occurs with habitual dynamic exercise. Resistance exercise causes little change in amino acid oxidation but probably depresses protein synthesis and elevates breakdown acutely. After exercise, protein synthesis rebounds for </=48 h, but breakdown remains elevated, and net positive balance is achieved only if amino acid availability is increased. There is no evidence that habitual exercise increases protein requirements; indeed protein metabolism may become more efficient as a result of training.
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J L Bowtell, G P Leese, K Smith, P W Watt, A Nevill, O Rooyackers, A J Wagenmakers, M J Rennie (2000)  Effect of oral glucose on leucine turnover in human subjects at rest and during exercise at two levels of dietary protein.   J Physiol 525 Pt 1: 271-281 May  
Abstract: The aim of this study was to determine the effect of glucose supplementation on leucine turnover during and after exercise and whether variation in the previous dietary protein content modulated this effect. Postabsorptive subjects received a primed constant [1-13C, 15N]leucine infusion for 6 h, after previous consumption of a high (1.8 g kg-1 day-1, HP, n = 16) or low (0.7 g kg-1 day-1, LP, n = 16) protein diet for 7 days. The subjects were studied at rest; during 2 h of exercise, during which half of the subjects from each dietary protocol received 0.75 g kg-1 h-1 glucose (HP + G, LP + G) and the other half received water (HP + W, LP + W); then again for 2 h of rest. Glucose supplementation suppressed leucine oxidation (P < 0.01) by 20% in subjects consuming the high protein diet (58.2 +/- 2.8 micromol kg-1 h-1, HP + G; 72.4 +/- 3.9 micromol kg-1 h-1, HP + W) but not the low protein diet (51.1 +/- 5.9 micromol kg-1 h-1, LP + G; 51.7 +/- 5.5 micromol kg-1 h-1, LP + W), with no difference in skeletal muscle branched-chain 2-oxo acid dehydrogenase (BCOADH) activity between groups. Glucose supplementation did not alter the rate of whole-body protein synthesis or breakdown. The sparing effect of glucose on leucine oxidation appears only to occur if previous protein intake was high. It was not mediated by a suppression of BCOADH fractional activity but may be due to reduced substrate availability.
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1999
J L Bowtell, K Gelly, M L Jackman, A Patel, M Simeoni, M J Rennie (1999)  Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise.   J Appl Physiol 86: 6. 1770-1777 Jun  
Abstract: The purpose of this study was to determine the efficacy of glutamine in promoting whole body carbohydrate storage and muscle glycogen resynthesis during recovery from exhaustive exercise. Postabsorptive subjects completed a glycogen-depleting exercise protocol, then consumed 330 ml of one of three drinks, 18.5% (wt/vol) glucose polymer solution, 8 g glutamine in 330 ml glucose polymer solution, or 8 g glutamine in 330 ml placebo, and also received a primed constant infusion of [1-13C]glucose for 2 h. Plasma glutamine concentration was increased after consumption of the glutamine drinks (0.7-1.1 mM, P < 0.05). In the second hour of recovery, whole body nonoxidative glucose disposal was increased by 25% after consumption of glutamine in addition to the glucose polymer (4.48 +/- 0.61 vs. 3.59 +/- 0.18 mmol/kg, P < 0.05). Oral glutamine alone promoted storage of muscle glycogen to an extent similar to oral glucose polymer. Ingestion of glutamine and glucose polymer together promoted the storage of carbohydrate outside of skeletal muscle, the most feasible site being the liver.
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M J Rennie (1999)  Teasing out the truth about collagen.   J Physiol 521 Pt 1: Nov  
Abstract: Of all of the non-mineral constituents of the mammalian body there is more collagen than anything else except water and possibly fat. Nevertheless our understanding of the physiology of collagen is rudimentary. All cells and tissues are supported by a network of collagen fibres, the arrangement of which appears to be specifically site adaptive. We know a lot about the biochemistry of collagen, and its many subtypes: for example, all collagen molecules are made within fibroblasts (or modifications of them such as osteocytes), then the oversized collagen molecule is secreted in a soluble form, with hydrophilic ends which are enzymatically cleaved to leave the insoluble core collagen (tropocollagen) beached in the extracellular space. We know that collagen is made relatively immortal by being cross-linked and rather impervious to proteolysis. However, we do not know much about what governs collagen synthesis or its breakdown in the human body. It is important to know, not simply because like Everest, collagen presents a large unignorable mass. We need to understand collagen metabolism in order to understand how we grow, adapt to the environment, maintain our adult shapes and then wrinkle and crumble as we age. Collagen diseases are relatively common and almost certainly if we knew more about how, for example, the collagen framework of bone is laid down and turned over we would understand much more about osteopenia of old age. The problem in finding out has been that collagen is so difficult to study. It turns over relatively slowly, and that part of it that is cross-linked and forms mature collagen is, it seems, with us for life come hell, high-water or famine. The body reduces to mainly skin and bone-collagen in extremis. Because the system as a whole is so sluggish, it is difficult to see changes in indices of collagen metabolism. However, not all the body collagen seems to be as fixed, and indeed collagen in some tissues must turn over, enabling remodelling and adaptation, rather quickly. Think about the stiffness and discomfort that accompanies un-accustomed exercise, which not only abates with time but ceases to occur once the exercise has become customary. What is happening to collagen protein turnover in these circumstances? One obvious way to study protein turnover, even of collagen, is to follow the incorporation of stable isotope markers such as proline into the tissue (although the breakdown is harder to quantify), but this is technically difficult and requires biopsy of the tissue in question. Another way is to follow the appearance in biological fluids of markers of collagen turnover. Since the propeptides which make collagen soluble are cleaved as collagen is deposited extracellularly, their concentration is an index of the rate of collagen synthesis; similarly when tropocollagen is degraded by extracellular proteases, specific N- and C-terminal fragments are released, the amount of which scales with the rate of collagen breakdown. These bits of collagen find their way into the blood. However, assaying them there introduces non-specificity and dilution, rendering interpretation difficult. The ideal would be to measure them in the extracellular fluid at the site of production. This of course is not easy in vivo. One of the delights of the paper by Langberg and colleagues in this issue of The Journal of Physiology (Langberg et al. 1999) is the sheer cheek with which the authors decided to use the microdialysis technique to do this. Microdialysis is a technique whereby a slowly perfused, thin-walled membranous tube is introduced into the extracellular space and the collected fluid assayed for molecules which have diffused into it. Until now the idea of using microdialysis to measure concentrations of molecules much bigger than 300 Da would be regarded as ludicrous. (ABSTRACT TRUNCATED)
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M J Rennie (1999)  An introduction to the use of tracers in nutrition and metabolism.   Proc Nutr Soc 58: 4. 935-944 Nov  
Abstract: The present article is a review written at a level suitable for students and new workers to the field of techniques in common current use for the measurement of static and dynamic features of metabolism, especially nutritional metabolism. It covers the nature of radioactive and stable-isotope tracers, the means of measuring them, and the advantages and disadvantages of their use. The greater part of the review deals with methods for the measurement of pool sizes and metabolic processes, with the emphasis being on protein metabolism, a field the author knows best. The examples given are from a variety of sources, including the work of the author, but the principles underlying the techniques are universally applicable to all metabolic investigations using tracers.
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I M Nakshabendi, R McKee, S Downie, R I Russell, M J Rennie (1999)  Rates of small intestinal mucosal protein synthesis in human jejunum and ileum.   Am J Physiol 277: 6 Pt 1. E1028-E1031 Dec  
Abstract: We investigated possible differences in the rates of mucosal protein synthesis between the proximal and distal regions of the small intestine. We took advantage of access to the gut mucosa available in otherwise healthy patients with ileostomy in whom the terminal ileum was histologically normal. All subjects received primed, continuous intravenous infusions of L-[1-(13)C]leucine after an overnight fast. After 4 h of tracer infusion, jejunal biopsies were obtained using a Crosby-Kugler capsule introduced orally; ileal biopsies were obtained via endoscopy via the ileostomy. Protein synthesis was calculated from protein labeling relative to intracellular leucine enrichment obtained by appropriate mass spectrometric measurements. Rates of jejunal and ileal mucosal protein synthesis were significantly different (P < 0.001) at 2.14 +/- 0.2 and 1.2 +/- 0.2 %/h (means +/- SD). These are lower than rates in normal healthy duodenum (2.53 +/- 0.25 %/h), suggesting a gradation of rates of synthesis along the bowel. Together with other data, these results suggest that mucosae of the bowel contribute not more than 10% to whole body protein turnover.
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I M Nakshabendi, S Downie, R I Russell, M J Rennie (1999)  Small-intestinal mucosal protein synthesis and whole-body protein turnover in alcoholic liver disease.   Clin Sci (Lond) 97: 6. 633-638 Dec  
Abstract: We used stable-isotope-labelled amino acids to measure the effects of alcoholic liver disease (ALD) on whole-body protein turnover and small-intestinal mucosal protein synthesis. Groups comprising eight patients with ALD and eight healthy control subjects were studied. They received primed, continuous intravenous infusions of L-[1-(13)C]leucine after an overnight fast; after 4 h, duodenal biopsies were obtained via endoscopy. Protein synthesis was calculated from protein labelling relative to intracellular leucine enrichment. Rates of duodenal mucosal protein synthesis were 2. 58+/-0.32%.h(-1) (mean+/-S.D.) in the normal subjects and 2.04+/-0. 18%.h(-1) in the ALD patients (P<0.003), despite the fact that the protein synthetic capacity (microgram of RNA/mg of protein) was higher in ALD patients (160+/-14 compared with 137+/-6 microgram/mg; P<0.003). The mucosal cell size (protein/DNA ratio) was lower in ALD patients (9.23+/-0.91 compared with 13+/-2.2 microgram/mg; P<0.002). Although the mean rates of whole-body protein turnover were not significantly different between the two groups (204+/-18 and 196+/-44 micromol leucine.h(-1).kg(-1) for ALD and control subjects respectively), there was, in the ALD patients, an inverse relationship between the rate of small-intestinal mucosal protein synthesis and the severity of ALD; furthermore, there was a direct relationship between the rate of whole-body protein turnover and the severity of ALD. Thus there was an inverse relationship between the rate of small-intestinal mucosal protein synthesis and the rate of whole-body protein turnover in ALD patients, which was not seen in the normal subjects.
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1998
S E Khogali, A A Harper, J A Lyall, M J Rennie (1998)  Effects of L-glutamine on post-ischaemic cardiac function: protection and rescue.   J Mol Cell Cardiol 30: 4. 819-827 Apr  
Abstract: We investigated the effects of L-glutamine (0-20 mM) on cardiac function. The isolated perfused working rat heart (left atrial and aortic pressures of 5 and 70 cm H2O, respectively) was subjected to 20 min of normothermic low-flow ischaemia followed by reperfusion for 35 min. In the absence of glutamine, ischaemia-reperfusion caused an immediate significant (P < 0.01) fall in cardiac output from 46 to 20 ml/min, with a further deterioration to 17 ml/min at 35 min reperfusion. Ischaemia also caused a significant (P < 0.05) fall in myocardial glutamate from 2.6 to 1.8 mumol/g wet weight; and ischaemia-reperfusion caused significant (each P < 0.05) diminutions of myocardial ATP from 3.5 to 1.0 mumol/g wet weight and phosphocreatine from 4.8 to 1.5 mumol/g wet weight and resulted in significant (P < 0.05) accumulation of myocardial lactate from 0.9 to 4.3 mumol/g wet weight. Glutamine, present throughout the perfusion protocol (i.e. prior to ischaemia), at or above 1.25 mM, prevented the post-ischaemic diminution of cardiac output and the deleterious changes in myocardial metabolites. Post-ischaemic treatment with glutamine at 2.5 mM completely prevented the post-ischaemic diminution of cardiac output and restored the myocardial metabolites to normal. CONCLUSIONS: Glutamine may be suitable as a cardioprotective and rescue agent. These effects may be mediated by maintenance of myocardial glutamate, ATP and phosphocreatine: and prevention of lactate accumulation.
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M J Rennie (1998)  Nutritional and pathophysiological modulation of body protein.   Curr Opin Clin Nutr Metab Care 1: 1. 67-71 Jan  
Abstract: This review deals with recent developments in methodology and the effects of nutrition, hormonal modulation and muscular activity on changes in lean body mass and protein turnover in the whole body and in muscle. It also deals with organ-specific protein metabolism of the splanchnic region, particularly the gut, liver and kidney.
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J L Bowtell, G P Leese, K Smith, P W Watt, A Nevill, O Rooyackers, A J Wagenmakers, M J Rennie (1998)  Modulation of whole body protein metabolism, during and after exercise, by variation of dietary protein.   J Appl Physiol 85: 5. 1744-1752 Nov  
Abstract: The aim of this study was to investigate dietary protein-induced changes in whole body leucine turnover and oxidation and in skeletal muscle branched chain 2-oxo acid dehydrogenase (BCOADH) activity, at rest and during exercise. Postabsorptive subjects received a primed constant infusion of L-[1-13C,15N]leucine for 6 h, after previous consumption of a high- (HP; 1.8 g . kg-1 . day-1, n = 8) or a low-protein diet (LP; 0.7 g . kg-1 . day-1, n = 8) for 7 days. The subjects were studied at rest for 2 h, during 2-h exercise at 60% maximum oxygen consumption, then again for 2 h at rest. Exercise induced a doubling of both leucine oxidation from 20 micromol . kg-1 . h-1 and BCOADH percent activation from 7% in all subjects. Leucine oxidation was greater before (+46%) and during (+40%, P < 0.05) the first hour of exercise in subjects consuming the HP rather than the LP diet, but there was no additional change in muscle BCOADH activity. The results suggest that leucine oxidation was increased by previous ingestion of an HP diet, attributable to an increase in leucine availability rather than to a stimulation of the skeletal muscle BCOADH activity.
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M J Rennie, S Y Low, P M Taylor, S E Khogali, P C Yao, A Ahmed (1998)  Amino acid transport during muscle contraction and its relevance to exercise.   Adv Exp Med Biol 441: 299-305  
Abstract: The functional significance of amino acid transport in skeletal muscle has been explored by the use of a variety of techniques including work in isolated perfused organs, isolated incubated organs and tissue culture of muscle cells. The results suggest that although there is a wide variety of amino acid transport systems of different characteristics and with different responses to ionic, hormonal and nervous modulation, the amino acid glutamine (transported by system Nm) demonstrates some unusual properties not observed with amino acids transported by other systems. Glutamine is transported at very high rates in skeletal muscle and heart and both the glutamate and glutamine transporter appear to be adaptively regulated by the availability of glutamine. Glutamine appears to be involved in the regulation of a number of important metabolic processes in heart and skeletal muscle (e.g., regulation of the glutathione reduced/oxidised ratio and regulation of protein and glycogen synthesis). Furthermore, glutamine transport appears to interact with systems for regulation of volume control and many of the metabolic features attributable to changes in glutamine concentration appear to be modulated via alteration in cytoskeletal status.
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K Smith, N Reynolds, S Downie, A Patel, M J Rennie (1998)  Effects of flooding amino acids on incorporation of labeled amino acids into human muscle protein.   Am J Physiol 275: 1 Pt 1. E73-E78 Jul  
Abstract: We investigated the effects of the nature of the flooding amino acid on the rate of incorporation of tracer leucine into human skeletal muscle sampled by biopsy. Twenty-three healthy young men (24.5 +/- 5. 0 yr, 76.2 +/- 8.3 kg) were studied in groups of four or five. First, the effects of flooding with phenylalanine, threonine, or arginine (all at 0.05 g/kg body wt) on the incorporation of tracer [13C]leucine were studied. Then the effects of flooding with labeled [13C]glycine [0.1 g/kg body wt, 20 atoms percent excess (APE)] and [13C]serine (0.05 g/kg body wt, 15 APE) on the incorporation of simultaneously infused [13C]leucine were investigated. When a large dose of phenylalanine or threonine was administered, incorporation of the tracer leucine was significantly increased (from 0.036 to 0. 067 %/h and 0.037 to 0.070 %/h, respectively; each P < 0.01). However, when arginine, glycine, or serine was administered as a flooding dose, no stimulation of tracer leucine incorporation could be observed. These results, together with those previously obtained, suggest that large doses of individual essential, but not nonessential, amino acids are able to stimulate incorporation of constantly infused tracer amino acids into human muscle protein.
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I C Steele, I S Young, H P Stevenson, S Maguire, M B Livingstone, M Rollo, C Scrimgeour, M J Rennie, D P Nicholls (1998)  Body composition and energy expenditure of patients with chronic cardiac failure.   Eur J Clin Invest 28: 1. 33-40 Jan  
Abstract: BACKGROUND: Patients with acute cardiac failure have excess body water, and it is commonly assumed that this is also so in patients with stable chronic cardiac failure (CCF). METHODS: To investigate this, we measured total body water (TBW) using stable isotope dilution and single-frequency bioelectrical impedance (BIA), and also extracellular volume (ECV) using bromide dilution in 12 patients with CCF and eight matched control subjects. RESULTS: TBW [kg(-1) bodyweight] was similar in the two groups [median 18O dilution 53.2% (range 46.5-57.1%) in patients vs. 54.8% (47.9-62.7) in control subjects; BIA 56.6% (42.7-73.1) vs. 58.0% (52.0-68.6)]. ECV was also similar in the two groups [0.25 Lkg(-1) (0.20-0.29) vs. 0.25 (0.19-0.35)]. There was a strong correlation between stable isotope and BIA measurements of TBW for all subjects (r = 0.76), but BIA overestimated TBW by a mean difference of 2.4 kg (limits of agreement of -4.1 kg to +8.9 kg). Body fat content was similar in the two groups, whether measured by skinfold anthropometry, whole-body densitometry or by 18O dilution. Resting energy expenditure (REE), calculated from indirect calorimetry, and total energy expenditure (TEE), calculated from the ratio of 2H to 18O elimination rate after drinking doubly labelled water, were also similar in the two groups. CONCLUSION: It is concluded that the patients with stable CCF in this study had normal ECV and TBW, and so excess body water did not account for their persistent symptoms.
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1997
S Y Low, M J Rennie, P M Taylor (1997)  Signaling elements involved in amino acid transport responses to altered muscle cell volume.   FASEB J 11: 13. 1111-1117 Nov  
Abstract: Skeletal muscle glutamine uptake via the transport system Nm is subject to rapid (t(1/2) = approximately 1 min) regulation after changes in cell volume by mechanisms that remain to be elucidated. Wortmannin (phosphatidylinositol 3-kinase inhibitor) but not rapamycin (inhibitor of p70S6 kinase activation) prevents both hypo-osmotic swelling-induced stimulation and hyperosmotic shrinkage-induced inhibition of Na+-dependent glutamine uptake in primary culture of rat skeletal muscle. G-protein inhibitors (cholera, pertussis toxins) also abolished responses of glutamine transport to cell volume changes whereas these responses were sustained in the presence of G-protein activators (MAS 7, lysophosphatidic acid). Swelling-induced activation of glutamine transport does not seem to involve release of autocrine factors because "conditioned" medium from swollen cells has no effect on previously unstimulated cells. System A amino acid transport exhibits responses to cell volume change that are opposite to those of system Nm, but these are also blocked by wortmannin. Active phosphatidylinositol 3-kinase appears to be required to enable muscle cells to exhibit rapid, volume-induced changes in amino acid transport when suitably stimulated.
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K S Mudambo, G P Leese, M J Rennie (1997)  Dehydration in soldiers during walking/running exercise in the heat and the effects of fluid ingestion during and after exercise.   Eur J Appl Physiol Occup Physiol 76: 6. 517-524  
Abstract: The aim of this study was to examine whether ingesting water alone, or dextrose (7.5 g x 100 ml(-1)) with electrolytes, or fructose/corn solids (7.5 g x 100 ml(-1)) (400 ml every 20 min) would reduce the perceived exertion associated with 16 km (3 h) walking/running in the heat compared with that perceived during exercise with no fluid intake. Perceived exertion was assessed at 1-h intervals during exercise. Blood samples, required for analysis of blood glucose, plasma sodium, plasma osmolality and plasma volume, were obtained prior to exercise and at 1-h intervals during the exercise; further samples were obtained 1-h intervals for 3 h following the exercise. Drinking fluids at regular intervals reduced the level of perceived exertion. In the test during which no fluid was ingested, body mass decreased by 4.9 (0.4) kg [mean (SEM)], but decreased less with ingestion of either the dextrose/electrolytes or fructose/corn solids solutions, or water alone [1.3 (0.2) kg, 1.6 (0.3) kg and 2.0 (0.1) kg, respectively]. Plasma volume fell by 17% when taking no fluid, but fell less when ingesting fluids. Blood glucose fell significantly (P < 0.01) when taking no fluid and rose to 8.4 (1.3) mmol x l(-1) (P < 0.001) and 6.8 (1.1) mmol x l(-1) (P < 0.01) with ingestion of the dextrose/electrolytes or fructose/corn solids solutions, respectively. Urine output was greater with ingestion of water than with any of the other drinks. Six subjects experienced fatigue during exercise with no fluid and failed to complete the exercise. These results suggest that fatigue was caused by several interacting factors: a fall in blood glucose and plasma volume, dehydration, and neuroglycopenia. Taking fluids during exercise reduced the strain and the rating of perceived exertion; this was better achieved by ingesting a dextrose/electrolytes solution.
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S Y Low, M J Rennie, P M Taylor (1997)  Involvement of integrins and the cytoskeleton in modulation of skeletal muscle glycogen synthesis by changes in cell volume.   FEBS Lett 417: 1. 101-103 Nov  
Abstract: Muscle glycogen synthesis is modulated by physiologically relevant changes in cell volume. We have investigated the possible involvement of integrin-extracellular matrix interactions in this process using primary cultures of rat skeletal muscle subject to hypo- or hyper-osmotic exposure with integrin binding peptide GRGDTP to disrupt integrin actions and the inactive analogue GRGESP as control. Osmotically induced increases (77%) and decreases (34%) in glycogen synthesis (D-[14C]glucose incorporation into glycogen) were prevented by GRGDTP (but not GRGESP) without affecting glucose transport. Cytoskeletal disruption with cytochalasin D or colchicine had similar effects to GRGDTP. Osmotically induced modulation of muscle glycogen synthesis involves integrin-extracellular matrix interactions and cytoskeletal elements, possibly as components of a cell-volume 'sensing' mechanism.
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K S Mudambo, C M Scrimgeour, M J Rennie (1997)  Adequacy of food rations in soldiers during exercise in hot, day-time conditions assessed by doubly labelled water and energy balance methods.   Eur J Appl Physiol Occup Physiol 76: 4. 346-351  
Abstract: The energy requirements of people doing physical work in hot climates are not clearly understood. In particular, we know little about the combined effects of heat stress and muscular work on energy requirements. During military exercises in the African bush, soldiers are supplied with standard rations, the adequacy of which is unknown. We have now assessed the adequacy of these food and water rations in 12 male Zimbabwean soldiers during 12 days of strenuous, heat-stress exercise in the field. We used two methods to measure energy expenditure: the double-labelled water method (DLW) and the energy balance method (i.e. comparing dietary energy with changes, if any, in body energy stores). Two groups were studied: one group (eight subjects) carried out field exercises; the control group consisted of four soldiers doing normal work. Mean daily energy expenditure as assessed by the DLW method was [mean (SE)] 23 (1.5) MJ x day(-1) for the field group and 14 (0.5) MJ x day(-1) for the control group (P < 0.001). By the energy balance method, daily energy expenditure was calculated to be 26 (0.7) MJ x day(-1) and 15.5 (0.4) MJ x day(-1) for the field group and control group, respectively. Body mass loss was 3 (0.1) kg [4.6 (0.3)% of body mass] for the field group, but the control group gained 1.1 (0.1) kg. Mean daily fluid intake was 11 (0.5) 1 x day(-1), suggesting that the standard ration supplied was inadequate. Body mass loss was caused by both the energy deficit and total body water loss. These results suggest strenuous work in hot, dry field conditions imposes extra energy requirements.
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K S Mudambo, G P Leese, M J Rennie (1997)  Gastric emptying in soldiers during and after field exercise in the heat measured with the [13C]acetate breath test method.   Eur J Appl Physiol Occup Physiol 75: 2. 109-114  
Abstract: The effects of exercise on gastric emptying remain controversial, with some workers reporting that heavy exercise inhibits it to varying degrees whereas others report no effects up to an intensity of 70% maximal oxygen consumption (VO2max). The state of hydration of the subjects and the environmental conditions may influence the rate of gastric emptying during exercise. To understand further the effects of a 3-h, 16-km walk/run carrying 30 kg of equipment under field conditions at 39 degrees C, we estimated gastric emptying using a [13C]acetate breath test method. Breath samples were collected at intervals after giving 150 mg of [13C]acetate. The effects of giving a standard volume (530 ml) of water or dextrose (7.5 g x 100 ml(-1)) with electrolytes or fructose/corn solids (7.5 g 100 ml(-1)) at rest before exercise were compared with those of exercise and of recovery after exercise with or without extra fluids (400 ml each 20 min). At rest, after a standard 530-ml load, gastric emptying times [mean (SE)] were: 37 (2) min (water), 46 (3) min (dextrose/electrolytes) and 47 (5) min (fructose/corn solids) and were significantly slower (P < 0.05) than those occurring after extra fluid ingestion, i.e. 32 (3), 39 (2) and 41 (3) min respectively. After a standard 530-ml load, emptying times during exercise were almost identical to those at rest but, during exercise, extra fluid speeded up gastric emptying more than at rest to 24 (2), 26 (1) and 27 (5) min (P < 0.05) respectively. During resting recovery without extra fluids, gastric emptying was significantly slowed to 60 (2), 71 (5) and 78 (3) min, respectively. Although emptying times during recovery from exercise with extra fluid were faster [49 (6), 55 (2) and 58 (4) min, respectively], they were still slower than before exercise. The results suggest that: (1) extra fluid increases gastric emptying more during exercise than at rest, and (2) gastric emptying during resting recovery from exercise is slower than at rest before exercise whether or not fluid has previously been taken.
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K S Mudambo, W Coutie, M J Rennie (1997)  Plasma arginine vasopressin, atrial natriuretic peptide and brain natriuretic peptide responses to long-term field training in the heat: effects of fluid ingestion and acclimatization.   Eur J Appl Physiol Occup Physiol 75: 3. 219-225  
Abstract: The maintenance of blood volume during exercise, especially in a hot environment, is of major importance for continued performance. In order to investigate the relationships between exercise, type and amount of fluid intake and the degree of acclimatization to heat stress and on responses of arginine vasopressin (AVP), atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), we studied 24 soldiers during and after jogging/walking exercise both before and after acclimatization to field training at [mean (SE)] 40 (0.7) degrees C and 32 (3)% relative humidity. The running exercise was carried out under three conditions, i.e., (1) without any fluid intake, (2) with intake of water or (3) with intake of a dextrose/electrolyte solution. Venous blood samples were drawn before exercise, at the end of exercise and at 15 min and 60 min afterwards. Acclimatization resulted in significant losses of body mass, total body water, plasma volume, ANP and increases in plasma osmolality, packed cell volume and AVP at rest but without any significant changes in BNP. During exercise with no fluid intake, there was a significant rise in plasma osmolality, Na+ and AVP, but no significant alterations in plasma ANP and BNP were observed. When subjects ingested water or dextrose/electrolyte solution during exercise, ANP rose by 234% and 431% respectively and BNP rose by 398% and 583% respectively without any significant increase in AVP. The results suggest that, during acclimatization, the subjects became slightly dehydrated. Alterations in response to changes in body water status appear to be greater for AVP than ANP or BNP at rest. During exercise in the heat ANP and BNP may play complementary roles.
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G E Butterfield, J Thompson, M J Rennie, R Marcus, R L Hintz, A R Hoffman (1997)  Effect of rhGH and rhIGF-I treatment on protein utilization in elderly women.   Am J Physiol 272: 1 Pt 1. E94-E99 Jan  
Abstract: To assess the effect of recombinant human growth hormone (rhGH) and recombinant human insulin-like growth factor I (rhIGF-I) on protein utilization, 14 women, age 66-82 yr, were invited to participate in studies of nitrogen balance (n = 14), whole body protein turnover (n = 14), and muscle protein synthesis (n = 8). They were studied both 1 wk before and during the last week of a 1-mo regimen, to which they had been randomly assigned, of either 0.025 mg rhGH/kg once daily or rhIGF-I at 0.015 (low), 0.03 (mid), or 0.06 (high) mg/kg twice daily. Nitrogen balance increased significantly after 1 wk of treatment in all groups (P < 0.05). After 1 mo, the magnitude of this effect had diminished by 50% in the rhGH group but remained elevated throughout the treatment period with all doses of rhIGF-I. Both protein synthesis and breakdown, measured by a primed constant infusion of [15N]glycine, were significantly increased with rhGH (9% and 8%, respectively), low-dose rhIGF-I (4.5% and 4%), and high-dose rhIGF-I (18% and 17%). Net synthesis was significantly increased with rhGH (48%) and high- and mid-dose rhIGF-I (27% and 196%, respectively). Muscle protein synthesis as measured by incorporation of [1-13C]leucine increased significantly with rhGH (50%) and the mid (67%) and high (57%) doses of rhIGF-I. These data show that whole body and muscle protein synthesis are responsive to growth factor stimulation in elderly women.
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1996
S Y Low, P M Taylor, M J Rennie (1996)  Responses of glutamine transport in cultured rat skeletal muscle to osmotically induced changes in cell volume.   J Physiol 492 ( Pt 3): 877-885 May  
Abstract: 1. In order to investigate the relationship between cellular hydration state and the rate of glutamine transport, tracer glutamine uptake into primary rat myotubes was studied at external osmolalities of 170, 320 or 430 mosmol kg-1. 2. Incubation of myotubes with glutamine (2 mM; 30 min) at 320 mosmol kg-1 increased cell volume and glutamine transport (by 35 and 36%, respectively); insulin (66 nM; 30 min) also increased cell volume and glutamine transport (by 22 and 40%, respectively) and the effects of insulin and glutamine combined were additive. The increase in glutamine uptake following glutamine pre-incubation represented an increase in Vmax of Na(+)-dependent glutamine transport. 3. There was an inverse relationship between myotube glutamine transport and external osmolality after 30 min exposure. 4. During hyposmotic (170 mosmol kg-1) exposure there were large, rapid increases of cell volume and glutamine transport; the latter increased transiently (during the cell swelling phase) by a maximum of approximately 80% at 2 min, (due to an increased Vmax for Na(+)-dependent glutamine transport) then decayed to a new elevated steady state after 30 min exposure. 5. During hyperosmotic (430 mosmol kg-1) exposure there were rapid decreases in glutamine transport and myotube cell volume (both by approximately 30%) to values which were maintained for at least 15 min. 6. The volume-sensitive glutamine transport process features characteristics of the insulin-sensitive system Nm transporter. 7. Modulation of Na(+)-dependent glutamine transport by insulin and cell volume changes may contribute towards regulation of muscle metabolism.
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M J Rennie, A Ahmed, S E Khogali, S Y Low, H S Hundal, P M Taylor (1996)  Glutamine metabolism and transport in skeletal muscle and heart and their clinical relevance.   J Nutr 126: 4 Suppl. 1142S-1149S Apr  
Abstract: The glutamine and glutamate transporters in skeletal muscle and heart appear to play a role in control of the steady-state concentration of amino acids in the intracellular space and, in the case of skeletal muscle at least, in the rate of loss of glutamine to the plasma and to other organs and tissues. This article reviews what is currently known about transporter characteristics and mechanisms in skeletal muscle and heart, the alterations in transport activity in pathophysiological conditions and the implications for anabolic processes and cardiac function of altering the availability of glutamine. The possibilities that glutamine pool size is part of an osmotic signaling mechanism to regulate whole body protein metabolism is discussed and evidence is shown from work on cultured muscle cells. The possible uses of glutamine in maintaining cardiac function perioperatively and in promoting glycogen metabolism are discussed.
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G P Leese, J Thompson, C M Scrimgeour, M J Rennie (1996)  Exercise and the oxidation and storage of glucose, maize-syrup solids and sucrose determined from breath 13CO2.   Eur J Appl Physiol Occup Physiol 72: 4. 349-356  
Abstract: In order to determine which of maize syrup solids, glucose and sucrose were more readily oxidised during exercise and least readily oxidised afterwards, the rates of oxidation of three almost identical isoenergetic solutions of carbohydrates (330 ml of 18.5% w/v solutions of glucose, maize syrup solids and sucrose, 989-1050 kJ total energy) naturally enriched with 13C were examined at rest and during and after 1 h uphill walking at 75% maximum oxygen uptake (VO2max) in nine subjects [mean (SEM) VO2max, 45.4 (0.9) ml.kg-1.min-1]. Rates of production of expired 13CO2 were used to estimate rates of oxidation of each exogenous substrate. Energy expenditure and the contributions from total carbohydrate and fat oxidation were calculated from whole-body gas exchange. At rest, maize syrup solids were oxidised less than sucrose during the 1st h [glucose 2.7 (0.2) g.h-1, maize syrup solids 1.9 (0.3) g.h-1, sucrose 3.7 (0.2) g.h-1; maize syrup solids vs sucrose P < 0.01], but this difference disappeared after a further 3 h at rest [glucose 8.3 (0.5) g.h-1, maize syrup solids 7.7 (0.5) g.h-1, sucrose 8.1 (0.4) g.h-1]. During exercise, all the carbohydrates were oxidised to the same extent [glucose 23.0 (2.8) g.h-1, maize syrup solids 23.9 (3.4) g.h-1, sucrose 27.5 (2.6) g.h-1) but during 4 h of recovery after exercise, maize syrup solids were oxidised least [glucose 4.6 (0.1) g.h-1, maize syrup solids 3.7 (0.1) g.h-1, sucrose 6.4 (0.1) g.h-1; P < 0.05] suggesting that it may be stored to a greater extent. The results suggest that 18.5% glucose, maize syrup solids and sucrose solutions were equally well oxidised during exercise. During recovery from exercise maize syrup solids were oxidised less than glucose, which in turn was oxidised less than sucrose.
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I M Nakshabendi, S Downie, R I Russell, M J Rennie (1996)  Increased rates of duodenal mucosal protein synthesis in vivo in patients with untreated coelia disease.   Gut 39: 2. 176-179 Aug  
Abstract: BACKGROUND AND AIMS: A robust, reproducible method for the measurement of protein synthesis in the gastrointestinal mucosa was applied to investigate possible differences between the rate of duodenal mucosal protein synthesis in coeliac patients and normal control subjects. PATIENTS AND METHODS: Eight patients, means (SD) (51 (10) years, 57 (11) kg, 160 (6) cm) with newly diagnosed untreated coeliac disease and seven control subjects (48 (11) years, 71.5 (12) kg, 172 (10) cm) received primed, continuous, intragastric (IG) and intravenous (i.v.) infusions of L-[1-13C]leucine and L-[1-13C]valine after an overnight fast. Distal duodenal biopsy specimens were obtained at endoscopy performed after 240 minutes of infusion. Protein synthesis was calculated from protein labelling relative to intracellular free amino acid enrichment, after appropriate mass spectrometric measurements. RESULTS: Rates of duodenal protein synthesis were significantly greater in coeliac patients than in control subjects (i.v. tracer, coeliac v control, 3.58 (0.45) v 2.26 (0.22)%/h, p< 0.05; IG tracer, 6.25 (0.97) v 2.34 (0.52)%/h respectively, p < 0.01). The rates of mucosal protein synthesis calculated on the basis of the tracer infused via the intragastric route were higher in patients with coeliac disease than in control subjects. Tissue protein/DNA ratios were significantly reduced in coeliac patients (coeliac v control, 9.2 (1.6) mg/micrograms v 13.0 (2.2) mg/micrograms respectively, p < 0.05) suggesting smaller mucosal cell size in coeliac patients. CONCLUSIONS: Despite the villous atrophy and reduced cell size observed in coeliac disease, the rates of mucosal protein synthesis are considerably increased. These results suggest that a high rate of protein synthesis may be adaptive to a high rate of protein breakdown or mucosal cell loss in coeliac patients.
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S J Blakemore, P K Rickhuss, P W Watt, M J Rennie, H S Hundal (1996)  Effects of limb immobilization on cytochrome c oxidase activity and GLUT4 and GLUT5 protein expression in human skeletal muscle.   Clin Sci (Lond) 91: 5. 591-599 Nov  
Abstract: 1. We investigated the effects of limb immobilization (for 1 or 6 weeks) in a long leg cast after a closed tibial fracture (n = 11). Biopsies of vastus lateralis were taken on admission and after either 1 week (n = 5) or 6 weeks (n = 6) and analysed for muscle fibre type characteristics, cytochrome c oxidase activity and the abundance of GLUT4 and GLUT5 hexose transporters. 2. After 1 week of immobilization there was a significant decrease (8%) in the cross-sectional area of type I, but not type II, muscle fibers and in the protein-DNA ratio (16%) compared with the initial biopsy. Six weeks of immobilization led to further muscle atrophy compared with the initial biopsy and a further reduction in the cross-sectional area of both type I and II fibres (29% and 36% decrease respectively) and in the protein-DNA ratio (25%). No changes were observed in the free leg after 1 week. However, at th end of the 6 week study period, the cross-sectional area of boty type I and II fibres of the free leg were increased (7% and 5%) and there was significant increase in the protein-DNA ratio (14%), indicating a net increase in muscle protein content. 3. Assay for cytochrome c oxidase activity showed significant reduction after 1 (30%) or 6 weeks (36%) of immobilization, reflecting a reduced capacity for oxidative metabolism. No significant changes in activity were observed in muscle from the free leg after 1 or 6 weeks of study. 4. The concentrations of GLUT4 and GLUT5 protein were determined by Western blot analysis. Limb immobilization induced a marked (50%) reduction in muscle GLUT4 protein concentration after 1 week that persisted for 6 weeks. A transient but significant increase (approximately twofold) in GLUT4 concentration was detected in muscle from the free leg after 1 week, but this returned to pre-imobilization values at 6 week. Unlike GLUT4, no significant changes in the abundance of the GLUT5 protein were detected in either the immobilized or free leg at the end of the 1 or 6 week periods. 5. The present findings indicate that disuse rapidly induces a selective loss of activity and abundance of some non-myofibrillar proteins in humans. The decrease in GLUT4 protein abundance and cytochrome c oxidase activity during muscle disuse is consistent with a decreased capacity for glucose uptake and with a lower oxidative potential of inactive muscle. The lack of any major changes in GLUT5 protein abundance during limb immobilization indicates that the expression of some non-myofibrillar proteins is differentially regulated in response to muscle disuse.
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J C Konje, D J Taylor, M J Rennie (1996)  Application of ultrasonic transit time flowmetry to the measurement of umbilical vein blood flow at caesarean section.   Br J Obstet Gynaecol 103: 10. 1004-1008 Oct  
Abstract: OBJECTIVES: To determine the applicability of ultrasonic transit time flowmetry to the measurement at caesarean section of umbilical vein blood flow rate and to examine the relationship between flow rates and birthweight for gestational age. DESIGN: Umbilical vein blood flow was measured at caesarean section using a transonic time flow probe on a loop of the umbilical cord in 33 appropriate and 21 small for gestational age fetuses. RESULTS: The mean (SD) umbilical vein blood flow in the 54 fetuses was 78.4 (23.1) ml kg-1 min-1. There was a linear relation between umbilical vein blood flow measured by ultrasonic transit time flowmetry and birthweight (r = 0.63, P < 0.0001). The mean umbilical vein blood flow in appropriate for gestational age fetuses [90 (18) ml kg-1 min-1] was greater than that in the small for gestational age group [66 (23) ml kg-1 min-1], P < 0.04). CONCLUSIONS: Umbilical vein blood flow measurements obtained by the ultrasonic transit time flowmetry technique are simple to perform and compare well with reported values obtained by the Doppler ultrasound technique (when vessel diameter is greater than 4 mm). Umbilical venous blood flow rate is significantly lower in small for gestational age fetuses.
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K Smith, M J Rennie (1996)  The measurement of tissue protein turnover.   Baillieres Clin Endocrinol Metab 10: 4. 469-495 Oct  
Abstract: Tissue protein turnover can be assessed by a number of semi-, quantitative and qualitative methods. There are a number of static indices of the state of turnover of protein, for example amount of RNA per DNA or protein, the state of aggregation of ribosomes (i.e. the polyribosome index), the abundance of mRNA for particular proteins, and the enzymatic activity of proteins such as proteases, ribonuclease, etc. In addition, the concentration of particular amino acids such as glutamine or non-re-utilizable amino acids, formed post-translationally, such as 3-methylhistidine or hydroxyproline, are able to provide snapshot indices. However, since turnover is a dynamic process it should, ideally, be probed using methods such as the incorporation of tracer amino acids into protein or the dilution of tracer amino acids in the free pool by protein breakdown. The combination of tracer and tissue or limb balance methods is especially powerful since all the dynamic processes can potentially be quantified. The use of stable isotopes to label metabolic tracers has dramatically increased the feasibility of carrying out measurements of protein synthesis and breakdown and there has been a substantial growth in the application of the methods to a wide variety of tissues sampled by biopsy or at operation. Summaries of a number of currently feasible methods are provided, together with commentary on the relative efficacy of the methods and of the instrumental techniques required. There is also a discussion of suitable tracer labels and amino acids, plus a summary of the most reliable current values for protein turnover in a variety of tissues. The review also contains descriptions of potential methods which have not yet been applied in human beings but which are feasible, given the current recent increases in the accuracy and sensitivity of instrumentation for measurement of stable isotope labelling.
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S Y Low, M J Rennie, P M Taylor (1996)  Modulation of glycogen synthesis in rat skeletal muscle by changes in cell volume.   J Physiol 495 ( Pt 2): 299-303 Sep  
Abstract: 1. The hypothesis that cellular hydration state modulates muscle glycogen synthesis was tested by measuring the incorporation of [14C]glucose into glycogen (glycogen synthesis) in primary rat myotubes after experimentally induced volume changes. 2. Glycogen synthesis in myotubes increased (by 75%, P < 0.01) after swelling induced by 60 min exposure to hyposmotic media (170 mosmol kg-1) relative to isosmotic control (300 mosmol kg-1) values, it decreased (by 31%, P < 0.05) after shrinkage induced by 60 min exposure to hyperosmotic (430 mosmol kg-1) media. Myotube 2-deoxy-D-glucose (0.05 mM) uptake was unaffected by changes in external osmolality. 3. Wortmannin (100 nM; 60 min), a phosphatidylinositol 3-kinase inhibitor, decreased basal glycogen synthesis by 28% whereas rapamycin (100 nM; 60 min), which blocks the activation of p70 S6 kinase, had no effect. Both wortmannin (100 nM; 60 min) and rapamycin (100 nM; 60 min) blocked the changes in glycogen synthesis resulting from hypo- and hyperosmotic exposure. 4. Myotube glycogen synthesis is modulated by volume changes independently of changes in glucose uptake. The phenomenon may be physiologically important in promoting glycogen storage during circumstances of myofibrillar swelling, e.g. after feeding or exercise.
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1995
M E Corbett, E J Boyd, J G Penston, K G Wormsley, P W Watt, M J Rennie (1995)  Pentagastrin increases pepsin secretion without increasing its fractional synthetic rate.   Am J Physiol 269: 3 Pt 1. E418-E425 Sep  
Abstract: We studied the effects of increasing doses of pentagastrin on gastric secretion of pepsin and on incorporation of L-[1-13C]leucine into gastric aspirate protein as an index of pepsin synthesis. Pentagastrin (0.25-4.0 micrograms.kg-1.h-1) significantly increased pepsin output from basal 76 mg/h to < or = 181 mg/h but did not significantly alter incorporation of L-[1-13C]leucine from the basal fractional synthetic rate of 3.63 +/- 0.05%/h. In four subjects in whom infusion of tracer leucine was continued for > 1 day, aspiration of pepsin between 24 and 27 h demonstrated that plateau 13C labeling of leucine in pepsin had been attained, but at a value that was only 48% of the 13C labeling of plasma alpha-ketoisocaproic acid (alpha-KIC) [0.730 +/- 0.02 (SE) vs. 1.520 +/- 0.14 atoms %excess]. This suggests that actual rates of pepsin synthesis were approximately double those calculated on the basis of alpha-KIC labeling. The results are consistent with an interpretation that increasing doses of pentagastrin cause increased secretion of pepsinogen by recruitment of gastric chief cells, each synthesizing pepsinogen at an unaltered rate. Plateau 13C enrichment of alpha-KIC may not be a valid surrogate for plateau 13C leucine enrichment when fractional synthetic rates of some secreted proteins are calculated.
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I M Nakshabendi, W Obeidat, R I Russell, S Downie, K Smith, M J Rennie (1995)  Gut mucosal protein synthesis measured using intravenous and intragastric delivery of stable tracer amino acids.   Am J Physiol 269: 6 Pt 1. E996-E999 Dec  
Abstract: We measured the rates of mucosal protein synthesis during the simultaneous delivery of [1-13C]leucine and [1-13C]valine delivered either intragastrically or intravenously to investigate any influence of the route of supply of the tracers. Dependent on the route, there were marked differences in the gradient of labeling between the plasma and intramucosal leucine and valine; i.e., for intravenous tracers the ratio was 1.73 +/- 0.16, but for intragastric tracers it was 0.65 +/- 0.12 (P < 0.05). Incorporation of intravenous tracer into mucosal protein was linear with time, and irrespective of tracer route, the calculated fractional rates of protein synthesis were identical when based on the intracellular labeling of the leucine or valine tracer, i.e., with intravenous 2.58 +/- 0.32%/h and with intragastric 2.45 +/- 0.36%/h. The results demonstrate that a robust and reproducible method of measurement of gastrointestinal mucosal protein synthesis has been developed and that use of either intragastric or intravenous routes of tracer administration gives comparable results. The high rates measured suggest that the gastrointestinal mucosa contributes substantially to whole body protein synthesis in normal healthy subjects.
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M Varnier, G P Leese, J Thompson, M J Rennie (1995)  Stimulatory effect of glutamine on glycogen accumulation in human skeletal muscle.   Am J Physiol 269: 2 Pt 1. E309-E315 Aug  
Abstract: To determine whether glutamine can stimulate human muscle glycogen synthesis, we studied in groups of six subjects the effect after exercise of infusion of glutamine, alanine+glycine, or saline. The subjects cycled for 90 min at 70-140% maximal oxygen consumption to deplete muscle glycogen; then primed constant infusions of glutamine (30 mg/kg; 50 mg.kg-1.h-1) or an isonitrogenous, isoenergetic mixture of alanine+glycine or NaCl (0.9%) were administered. Muscle glutamine remained constant during saline infusion, decreased 18% during alanine+glycine infusion (P < 0.001), but rose 16% during glutamine infusion (P < 0.001). By 2 h after exercise, muscle glycogen concentration had increased more in the glutamine-infused group than in the saline or alanine+glycine controls (+2.8 +/- 0.6, +0.8 +/- 0.4, and +0.9 +/- 0.4 mumol/g wet wt, respectively, P < 0.05, glutamine vs. saline or alanine+glycine). Labeling of glycogen by tracer [U-13C]glucose was similar in glutamine and saline groups, suggesting no effect of glutamine on the fractional rate of blood glucose incorporation into glycogen. The results suggest that, after exercise, increased availability of glutamine promotes muscle glycogen accumulation by mechanisms possibly including diversion of glutamine carbon to glycogen.
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P K Chong, R T Jung, M J Rennie, C M Scrimgeour (1995)  Energy expenditure in type 2 diabetic patients on metformin and sulphonylurea therapy.   Diabet Med 12: 5. 401-408 May  
Abstract: Insulin and sulphonylurea therapies have both been reported to cause weight gain in Type 2 diabetic patients whereas metformin does not have this adverse effect. The mechanism for this difference is unclear. We have investigated in a cross-over study the effect of sulphonylurea and metformin therapy on energy expenditure and body composition in 10 Type 2 diabetic patients (7 females, 3 males) of various weights (mean body mass index 33.4 (SD 7.6 kg m-2)). Free living total energy expenditure was measured over 14 days by the doubly labelled water method adjusted for urinary glucose energy losses and resting energy expenditure by ventilated hood indirect calorimetry. Overall, total energy expenditure (12.88 +/- 4.17 vs 13.1 +/- 3.69 MJ 24 h-1) and resting metabolic rate (7.30 +/- 1.75 vs 7.23 +/- 1.74 MJ 24 h-1) were similar on metformin and sulphonylurea therapy, respectively. When adjusted for differences in fat free mass, resting metabolic rate on sulphonylurea therapy was slightly but significantly lower (mean difference -5.5 kJ 24 h-1 kg-1, 95% CI -1.2, -9.9 kJ 24 h-1 kg-1, p < 0.05). Fat free mass also increased significantly by 1.3 kg (95% CI 0.4, 2.4 kg, p < 0.05) when on sulphonylurea therapy, thus compensating for the lower resting metabolic rate per kg fat free mass to leave overall resting metabolic rate unchanged compared to metformin therapy. We also investigated the effect of adding metformin to six Type 2 diabetic patients already on insulin. This did not lead to any measurable changes in any of the components of energy expenditure.(ABSTRACT TRUNCATED AT 250 WORDS)
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G P Leese, J Bowtell, S Mudambo, N Reynolds, J Thompson, C M Srimgeour, M J Rennie (1995)  Post-exercise gastric emptying of carbohydrate solutions determined using the 13C acetate breath test.   Eur J Appl Physiol Occup Physiol 71: 4. 306-310  
Abstract: In an attempt to measure gastric emptying of carbohydrate solutions after exercise, we used the 13C acetate breath test to differentiate the gastric emptying of three approximately isoenergetic carbohydrate solutions (i.e. glucose, glucose polymer and sucrose) from each other and from water. On four separate occasions, six post-absorptive subjects walked on an inclined treadmill at 70% maximum oxygen uptake for 1 h and were then given 330 ml of one of the solutions in which 150 mg of sodium 1-[13C] acetate had been dissolved. Breath samples were collected at regular (2-30 min) intervals over the next 3.5 h for analysis of expired 13CO2 by isotope ratio mass spectrometry. When water was given, all subjects reached peak breath enrichment after 30 min, and had a mean (SE) gastric emptying time of 33.2 (1.6) min. Peak breath enrichment occurred later for sucrose and glucose polymer at 54.3 (3.1) min and 59.0 (2.1) min respectively (P < 0.01), and for glucose this was even later, at 62.3 (1.0) min (P < 0.05). Calculated gastric emptying times for sucrose and glucose polymer were almost identical [66.5 (2.5) and 69.8 (2.9) min respectively], whereas that for glucose was significantly slower [76.8 (3.2) min; P < 0.02], probably reflecting the effects of increased osmolality. The gastric emptying of all carbohydrates were significantly longer than for water (P < 0.01). These results show that in the post-exercise state the 13C acetate breath test can be used to differentiate the gastric emptying rates of water and carbohydrate solutions of different properties.
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A Ahmed, G J Peter, P M Taylor, A A Harper, M J Rennie (1995)  Sodium-independent currents of opposite polarity evoked by neutral and cationic amino acids in neutral and basic amino acid transporter cRNA-injected oocytes.   J Biol Chem 270: 15. 8482-8486 Apr  
Abstract: To elucidate the electrical events associated with the movement of amino acids by the neutral and basic amino acid transporter (NBAT)-encoded protein (Yan, N., Mosckovitz, R., Ge