Abstract: In skeletal muscle there is good evidence to suggest that locally produced insulin-like growth factor-1 (IGF-I), rather than circulating IGF-I, is important in regard to muscle mass maintenance, repair and hypertrophy. This "mature" IGF-I comprises exons 3 and 4 of the IGF-I gene, but during processing the full length gene (which contains six exons) is subject to a process of alternative splicing. As a result smaller peptides (E peptides) are believed to be cleaved from the mature IGF-I peptide during processing of the prohormone and the likelihood is that they have different biological roles. In human skeletal muscle three transcripts encoding for these splice variants (IGF-IEa, IGF-IEb and IGF-IEc, also known as MGF) can be identified. When studied at the mRNA level these three transcripts are known to be upregulated in the muscles of elderly people following high resistance exercise, albeit with different time courses. However, compared with mature IGF-I relatively little is known about the mechanism of action of the different E peptides.
Abstract: Electrical stimulation (ES) improves muscle properties after spinal cord injury (SCI), but cycling power output (PO) remains low. We investigated the effect of endurance and strength ES training on these parameters. Assessments of quadriceps strength and fatigue resistance, cycling PO, and muscle biopsies were made in four well-trained SCI subjects (three cyclists and one rower) before and after additional weight training in the cyclists and once in the rower. Weight training improved muscle strength, but cycling PO was low in all subjects. There was no effect of training type on biopsy data. Biopsies showed non-specific signs of pathology, predominance of type IIa fibers, and uniform metabolic activity. Oxidative activity was low, as were capillary:fiber ratios in the cyclists. Cycling PO is limited by factors other than muscle strength. Future ES training studies should attempt to improve muscle oxidative capacity to optimize the potential benefits of ES exercise.
Abstract: In an animal model of ALS, intramuscular administration of MGF, the IGF-I Ec gene splice variant, improved muscle strength and increased both motor unit and motor neuron survival. Here we investigated whether there is a deficit in MGF production in the muscles of patients with ALS. We used complementary in vivo and in vitro techniques to study the IGF-I splice variant response of human muscle to exercise or mechanical stretch. We assessed the levels of MGF and IGF-IEa mRNA in muscle biopsy samples from healthy subjects and patients with ALS, before and after exercise. We used primary muscle cells to build three-dimensional collagen constructs and subjected them to a ramp stretch. Patients with ALS had similar baseline levels of MGF and IGF-IEa mRNA to healthy controls. No up-regulation was seen in either group within a short time of a single bout of low intensity exercise. Three-dimensional human muscle constructs also detected no response to a mechanical stretch from either control subjects or ALS. We conclude that the pathology of ALS does not include a deficit in baseline levels of MGF and IGF-IEa mRNA splice variants in muscle.
Abstract: BACKGROUND: Regular and vigorous exercisers appear to be the logical choice for studying the inherent aging process as they are essentially free from the complications of disuse. Cross-sectional studies of aging tend to depict an essentially smooth and progressive decrement of physiological function with increasing chronological age. On closer examination of such data, it is seen that although the young have high functional values and the very old low, between these limits, values are widely scattered. METHODS: We have reevaluated published data from a meta-analysis of 242 studies on men and from a similar study on women. From both data sets, where VO2max was plotted against chronological age, we stratified the VO2max values into bandwidth intervals of 5 ml/kg/minute and then allocated data points to their respective bandwidth irrespective of chronological age. RESULTS: When replotted into bandwidths of functional equivalence, these data show that at the extremes of function, the young are separated from the old. Between these values, each functional bandwidth accommodates a wide age range. The decrement in function with chronological age is not smooth or well defined. CONCLUSIONS: We suggest that participants for research into healthy aging should be initially segregated into bands of functionally equivalent VO2max values irrespective of their chronological age. Subsequently, other physiological measurements should be made on every participant in the band in order to begin to define the physiological profile of the participants. By conducting longitudinal studies on every individual, it will be possible to chart the physiological history of each participant through various ages. Segregating participants into cohorts of functional equivalence with data handling blinded to chronological age may be of great utility in increasing our understanding of the inherent aging process.
Abstract: Impaired physical function and reduced physical activity is a common finding in intensive care unit (ICU) survivors. More importantly, reduced muscle strength during critical illness is an independent predictor of survival. Skeletal muscle wasting as a direct consequence of critical illness has been suggested as the cause. However, data on the physiological processes regulating muscle mass, and function, in these critically-ill patients are limited as this is not only a technically challenging research area, but also the heterogeneity of the patient group adds to complexity to the interpretation of results. Despite this, clinical and research interest in this area is growing. This article highlights the issues involved in measurement of muscle function and mass in critically-ill patients and the physiological complexities involved in studying these patients. Although the data is limited, this article reviews the animal and healthy human data providing a rational approach to the potential pathophysiological mechanisms involved in muscle mass regulation in critically-'risk factors' such as ageing, immobility and systemic inflammation, all of which are common findings in the general critical care population.
Abstract: Using a human primary muscle cell culture model the behaviour of myoblasts (satellite cells) cultured in human serum obtained from either young or elderly individuals was studied. Serum was obtained from a total of 13 young (7 males and 6 females aged, 23-36 years) and 9 elderly (4 males and 5 females aged 69-84 years) subjects and used in a number of experiments. Myoblasts were extracted from human muscle biopsy samples taken from the vastus lateralis. In the first experiment myoblasts were isolated immediately after extraction from the biopsy in media containing human sera to examine its effects on the onset and progression of Ki67 and desmin expression. No effect of the age of the serum was observed at 3, 5 or 7 days of culture. In addition, cells were studied that had been expanded initially in optimum myoblast growth medium (GM, containing foetal calf serum and additional growth factors) prior to culture in medium containing 15% human serum. The proportion of proliferating muscle cells coexpressing desmin and Ki67 antigens after 46 h was again similar in the young and old serum conditions. Culturing these myoblasts in media containing 2% human serum to study their fusion and differentiation also resulted in no difference between young and old serum conditions in terms of the percentage of nuclei inside myosin heavy chain positive myotubes. Despite the variability of different samples of myoblasts, the age of the serum donor has no effect on the expression of any measured index.
Abstract: Gene doping is the term given to the potential misuse of gene therapy for the purposes of enhancing athletic performance. Insulin like growth factor-I (IGF-I), the prime target of growth hormone action, is one candidate gene for improving performance. In recent years a number of transgenic and somatic gene transfer studies on animals have shown that upregulation of IGF-I stimulates muscle growth and improves function. This increase in muscle IGF-I is not reflected in measurable increases in circulating IGF-I. Whilst the responses obtained in the animal studies would appear to give clear benefits for performance, the transfer of such techniques to humans still presents many technical challenges. Further challenges will also be faced by the anti doping authorities in detecting the endogenously produced products of enhanced gene expression.
Abstract: OBJECTIVE: Elevated growth hormone (GH) levels lead to increased circulating insulin-like growth factor-I (IGF-I), but the effects on localised muscle IGF-I splice variant expression is not known. The effects of rhGH administration, with or without an acute bout of high resistance exercise, were measured on serum IGF-I and on the mRNA levels of IGF-I splice variants in the vastus lateralis muscle of healthy young men. DESIGN: The study was a randomised double blind trial with a crossover design. Seven subjects were randomly assigned to a group receiving daily injections of rhGH (0.075IU kg(-1)day(-1)) or placebo for a two week period. Following a one month washout, the groups were reversed. RESULTS: Administration of rhGH increased circulating IGF-I from 31.8+/-3.2 to 109+/-5.4 nmol/L (p<0.05). There was no effect of the exercise bout. RNA was extracted from muscle biopsies obtained from exercised and non-exercised legs 2.5h after the cessation of the exercise. Transcript expression was measured using Real-time QPCR. There was no effect of either exercise or rhGH administration on IGF-I 5' (Class 1 or Class 2) or 3' (IGF-IEa, or MGF) transcripts. CONCLUSION: Although rhGH administration has an effect on liver IGF-I expression, as shown by increase in circulating IGF-I, muscle IGF-I expression is unaffected in young healthy subjects with normal GH profile. The findings contrast with those of a previous study in which GH deficient elderly men showed higher muscle IGF-I 3' splice variant levels following rhGH administration with and without resistance training. Unlike in the liver, muscle Class1 and 2 IGF-I expression do not change significantly following administration of rhGH.
Abstract: Insulin-like growth factor-I (IGF-I) is a known biomarker of recombinant human growth hormone (rhGH) abuse, and is also used clinically to confirm acromegaly. The protein leucine-rich alpha-2-glycoprotein (LRG) was recently identified as a putative biomarker of rhGH administration. The combination of an ACN depletion method and a 5-min ultra-high-performance liquid chromatography/tandem mass spectrometry (uHPLC/MS/MS)-based selected reaction monitoring (SRM) assay detected both IGF-I and LRG at endogenous concentrations. Four eight-point standard addition curves of IGF-I (16-2000 ng/mL) demonstrated good linearity (r(2) = 0.9991 and coefficients of variance (CVs) <13%). Serum samples from two rhGH administrations were extracted and their uHPLC/MS/MS-derived IGF-I concentrations correlated well against immunochemistry-derived values. Combining IGF-I and LRG data improved the separation of treated and placebo states compared with IGF-I alone, further strengthening the hypothesis that LRG is a biomarker of rhGH administration. Artificial neural networks (ANNs) analysis of the LRG and IGF-I data demonstrated an improved model over that developed using IGF-I alone, with a predictive accuracy of 97%, specificity of 96% and sensitivity of 100%. Receiver operator characteristic (ROC) analysis gave an AUC value of 0.98. This study demonstrates the first large scale and high throughput uHPLC/MS/MS-based quantitation of a medium abundance protein (IGF-I) in human serum. Furthermore, the data we have presented for the quantitative analysis of IGF-I suggest that, in this case, monitoring a single SRM transition to a trypsin peptide surrogate is a valid approach to protein quantitation by LC/MS/MS.
Abstract: Recovery from micro damage resulting from intensive exercise has been shown to take longer in older muscles. To investigate the factors that may contribute to muscle repair, we have studied the expression of two splice variants of the insulin-like growth factor-I (IGF-I) gene. IGF-IEa and mechano growth factor (MGF) were studied in response to 1 h of eccentric cycling exercise in young and old individuals. Subjects (nine young, aged 20-27 years and eight elderly, aged 67-75 years) completed an eccentric exercise protocol that consisted of 60 min of reverse pedal cycling. Workloads were chosen to give the same relative increases in oxygen uptake (VO2max) and heart rate in young and old subjects. Muscle biopsy samples were obtained from the quadriceps muscle before and 2 1/4 h after completion of the exercise bout and were analyzed for IGF-IEa and MGF mRNA levels using real-time quantitative PCR. No difference was observed between the baseline levels of the two splice variants between the two subject groups. Eccentric cycling exercise resulted in a significant increase in the mean MGF mRNA in both young and old subjects but did not alter IGF-IEa mRNA levels in either age group. As reported previously (Toft et al., 2002), the levels of serum creatine kinase and myoglobin, markers of muscle damage, were increased significantly from baseline and to 5 days after exercise in both young and old subjects. This supports previous research in suggesting that the MGF splice variant is sensitive to muscle damage-inducing exercise and is differentially regulated compared with IGF-IEa.
Abstract: Gene doping is the misuse of gene therapy to enhance athletic performance. It has recently been recognised as a potential threat and subsequently been prohibited by the World Anti-Doping Agency. Despite concerns with safety and efficacy of gene therapy, the technology is progressing steadily. Many of the genes/proteins which are involved in determining key components of athletic performance have been identified. Naturally occurring mutations in humans as well as gene-transfer experiments in adult animals have shown that altered expression of these genes does indeed affect physical performance. For athletes, however, the gains in performance must be weighed against the health risks associated with the gene-transfer process, whereas the detection of such practices will provide new challenges for the anti-doping authorities.
Abstract: Human skeletal muscle is a highly heterogeneous tissue, able to adapt to the different challenges that may be placed upon it. When overloaded, a muscle adapts by increasing its size and strength through satellite-cell-mediated mechanisms, whereby protein synthesis is increased and new nuclei are added to maintain the myonuclear domain. This process is regulated by an array of mechanical, hormonal and nutritional signals. Growth factors, such as insulin-like growth factor I (IGF-I) and testosterone, are potent anabolic agents, whilst myostatin acts as a negative regulator of muscle mass. Insulin-like growth factor I is unique in being able to stimulate both the proliferation and the differentiation of satellite cells and works as part of an important local repair and adaptive mechanism. Speed of movement, as characterized by maximal velocity of shortening (V(max)), is regulated primarily by the isoform of myosin heavy chain (MHC) contained within a muscle fibre. Human fibres can express three MHCs: MHC-I, -IIa and -IIx, in order of increasing V(max) and maximal power output. Training studies suggest that there is a subtle interplay between the MHC-IIa and -IIx isoforms, with the latter being downregulated by activity and upregulated by inactivity. However, switching between the two main isoforms appears to require significant challenges to a muscle. Upregulation of fast gene programs is caused by prolonged disuse, whilst upregulation of slow gene programs appears to require significant and prolonged activity. The potential mechanisms by which alterations in muscle composition are mediated are discussed. The implications in terms of contractile function of altering muscle phenotype are discussed from the single fibre to the whole muscle level.
Abstract: OBJECTIVES: To evaluate and compare the effectiveness and cost-effectiveness of a leisure centre-based exercise programme, an instructor-led walking programme and advice-only in patients referred for exercise by their GPs. DESIGN: A single-centre, parallel-group, randomised controlled trial, consisting of three arms, with the primary comparison at 6 months. SETTING: Assessments were carried out at Copthall Leisure Centre in Barnet, an outer London borough, and exercise programmes conducted there and at three other leisure centres and a variety of locations suitable for supervised walking throughout the borough. PARTICIPANTS: Participants were aged between 40 and 74 years, not currently physically active and with at least one cardiovascular risk factor. INTERVENTIONS: The 943 patients who agreed to participate in the trial were assessed in cohorts and randomised to one of the following three arms: a 10-week programme of supervised exercise classes, two to three times a week in a local leisure centre; a 10-week instructor-led walking programme, two to three times a week; an advice-only control group who received tailored advice and information on physical activity including information on local exercise facilities. After 6 months the control group were rerandomised to one of the other trial arms. Assessments took place before randomisation, at 10 weeks (in a random 50% subsample of participants), 6 months and 1 year in the leisure centre and walking arms. The control participants were similarly assessed up to 6 months and then reassessed at the same intervals as those initially randomised to the leisure centre and walking groups. MAIN OUTCOME MEASURES: The primary outcome measures were changes in self-reported exercise behaviour, blood pressure, total cholesterol and lipid subfractions. Secondary outcomes included changes in anthropometry, cardiorespiratory fitness, flexibility, strength and power, self-reported lifestyle behaviour, general and psychological health status, quality of life and health service usage. The costs of providing and making use of the service were quantified for economic evaluation. RESULTS: There was a net increase in the proportion of participants achieving at least 150 minutes per week of at least moderate activity in the sport/leisure and walking categories in all three study groups: at 6 months, the net increases were 13.8% in the leisure centre group, 11.1% in the walking group and 7.5% in the advice-only group. There were significant reductions in systolic and diastolic blood pressure in all groups at each assessment point compared with baseline. There were also significant and sustained improvements in cardiorespiratory fitness and leg extensor power, and small reductions in total and low-density lipoprotein cholesterol in all groups, but there were no consistent differences between the groups for any parameter over time. All three groups showed improvement in anxiety and mental well-being scores 6 months after the beginning of the trial. Leisure centre and walking groups maintained this improvement at 1 year. There were no differences between groups. Costs to the participants amounted to pound 100 for the leisure centre scheme and pound 84 for the walking scheme, while provider costs were pound 186 and pound 92, respectively. Changes in overall Short Form 36 scores were small and advice only appeared the most cost-effective intervention. CONCLUSIONS: The results of this trial suggest that referral for tailored advice, supported by written materials, including details of locally available facilities, supplemented by detailed assessments may be effective in increasing physical activity. The inclusion of supervised exercise classes or walks as a formal component of the scheme may not be more effective than the provision of information about their availability. On cost-effectiveness grounds, assessment and advice alone from an exercise specialist may be appropriate to initiate action in the first instance. Subsidised schemes may be best concentrated on patients at higher absolute risk, or with specific conditions for which particular programmes may be beneficial. Walking appears to be as effective as leisure centre classes and is cheaper. Efforts should be directed towards maintenance of increased activity, with proven measures such as telephone support. Further research should include an updated meta-analysis of published exercise interventions using the standardised mean difference approach.
Abstract: PURPOSE: Aging is associated with a decline in muscle volume, power output, and the velocity at which peak power (Vopt) occurs. The current study aimed to examine the relationship between lower-limb power output characteristics, muscle myosin heavy chain (MHC) composition, and lean limb volume. METHODS: Lower-limb power output during repeated efforts on an inertial sprint cycle and single-leg thrusts on the modified Nottingham power rig was studied in seven young and seven old males in relation to muscle MHC isoform composition of the vastus lateralis. RESULTS: Older subjects produced significantly lower power outputs and Vopt under all conditions (P < 0.01) and had lower proportions of fast MHC isoforms (P< 0.05). Peak power output during cycling was significantly related to lower-limb lean volume (r = 0.92, P < 0.05), whereas Vopt during sprint cycling was closely related to vastus lateralis MHC-II composition (r = 0.80, P < 0.05). CONCLUSIONS: These results provide further evidence of the importance of fast myosin isoform composition in the maintenance of dynamic muscle function in later life and particularly for maximal cycling performance.
Abstract: It is generally believed that the maximum shortening velocity (V(o)) of a skeletal muscle fiber type does not vary unless a change in myosin heavy chain (MHC) isoform composition occurs. However, recent findings have shown that V(o) of a given fiber type can change after training, suggesting the hypothesis that the function of myosin can vary without a change in isoform. The present study addressed the latter hypothesis by studying the function of isolated myosin isoforms by the use of the in vitro motility assay (IVMA) technique. Four young (age 23-29 yr, YO) and four elderly men (age 68-82 yr, EL) underwent a 12-wk progressive resistance training program of the knee extensor muscles and to one pre- and one posttraining biopsy of the vastus lateralis muscle. The significant increase in one-repetition maximum posttraining in both YO and EL indicated that training was effective. After training, MHC isoform composition showed a shift from MHC(2X) toward MHC(2A) in YO and no shift in EL. The velocity of sliding (V(f)) of actin filaments on pure myosin isoforms extracted from single fibers was studied in IVMA. One hundred sixty IVMA samples were prepared from 480 single fibers, and at least 50 filaments were analyzed in each experiment. Whereas no training-induced change was observed in V(f) of myosin isoform 1 either in YO or in EL, a significant increase in V(f) of myosin isoform 2A after training was observed in both YO (18%) and EL (19%). The results indicate that resistance training can change the velocity of the myosin molecule.
Abstract: OBJECTIVE: Studies in animals and human muscle have demonstrated differential splicing of the insulin-like growth factor-1 gene in response to mechanical strain and damage. We conducted a study on the expression of insulin-like growth factor-1 splice variants in the levator ani muscle after the first vaginal delivery. STUDY DESIGN: Ten women were recruited after the first vaginal delivery. Biopsy specimens were taken vaginally of the pubovisceral component of the levator ani muscle. Five nonpregnant women were recruited as control subjects. Samples were processed with real-time quantitative polymerase chain reaction, with specific primers for the insulin-like growth factor-1 splice variants. RESULTS: Insulin-like growth factor splice variants mechano growth factor and insulin-like growth factor-1Ea were significantly up-regulated (100- and 1000-fold) in the delivery population, compared with control subjects (P=.012 and .04, respectively). Statistical analysis indicated a correlation between the expression of the insulin-like growth factor-1 splice variants and the length of the second stage. CONCLUSION: These results show that damaged levator ani muscle results from stretch and overload after the first vaginal delivery.
Abstract: The transcription factors myogenin and MyoD have been suggested to be involved in maintaining slow and fast muscle-fiber phenotypes, respectively, in rodents. Whether this is also the case in human muscle is unknown. To test this, 4 wk of chronic, low-frequency electrical stimulation training of the tibialis anterior muscle of paraplegic subjects were used to evoke a fast-to-slow transformation in muscle phenotype. It was hypothesized that this would result from an upregulation of myogenin and a downregulation of MyoD. The training evoked the expected mRNA increase for slow fiber-specific markers myosin heavy chain I and 3-hydroxyacyl-CoA dehydrogenase A, whereas an mRNA decrease was seen for fast fiber-specific markers myosin heavy chain IIx and glycerol phosphate dehydrogenase. Although the slow fiber-specific markers citrate synthase and muscle fatty acid binding protein did not display a significant increase in mRNA, they did tend to increase. As hypothesized, myogenin mRNA was upregulated. However, contrary to the hypothesis, MyoD mRNA also increased, although later than myogenin. The mRNA levels of the other myogenic regulatory factor family members, myogenic factor 5 and myogenic regulatory factor 4, and the myocyte enhancer factor (MEF) family members, MEF-2A and MEF-2C, did not change. The results indicate that myogenin is indeed involved in the regulation of the slow oxidative phenotype in human skeletal muscle fibers, whereas MyoD appears to have a more complex regulatory function.
Abstract: The expression of two isoforms of insulin-like growth factor-I (IGF-I): mechano growth factor (MGF) and IGF-IEa were studied in muscle in response to growth hormone (GH) administration with and without resistance training in healthy elderly men. A third isoform, IGF-IEb was also investigated in response to resistance training only. The subjects (age 74 +/- 1 years, mean +/- S.E.M) were assigned to either resistance training with placebo, resistance training combined with GH administration or GH administration alone. Real-time quantitative RT-PCR was used to determine mRNA levels in biopsies from the vastus lateralis muscle at baseline, after 5 and 12 weeks in the three groups. GH administration did not change MGF mRNA at 5 weeks, but significantly increased IGF-IEa mRNA (237%). After 12 weeks, MGF mRNA was significantly increased (80%) compared to baseline. Five weeks of resistance training significantly increased the mRNA expression of MGF (163%), IGF-IEa (68%) and IGF-IEb (75%). No further changes were observed after 12 weeks. However, after 5 weeks of training combined with GH treatment, MGF mRNA increased significantly (456%) and IGF-IEa mRNA by (167%). No further significant changes were noted at 12 weeks. The data suggest that when mechanical loading in the form of resistance training is combined with GH, MGF mRNA levels are enhanced. This may reflect an overall up-regulation of transcription of the IGF-I gene prior to splicing.
Abstract: The power-inertial load relationship of the lower limb muscles was studied during a single leg thrust using the Modified Nottingham Power Rig (mNPR) and during cycling exercise in nine young male subjects. The relationship between peak power and inertial load showed a parabolic-like relationship for mNPR exertions, with a peak [937 (SD 246) W] at 0.158 kg m(2), this being significantly (P <0.05) different from the power generated at both the lowest [723 (162) W] and highest [756 (206) W] inertial loads. In contrast, for cycling exercise power output did not differ significantly between inertial loads, except at the lowest inertia where power output was significantly ( P<0.05) less compared with all other inertial loads. Maximum peak power output during cycling was 1,620 (336) W, which was significantly (P <0.05) greater than that recorded on the mNPR. However, a close association was observed between the mean power generated by each method (r=0.84, P<0.05). The results suggest that during a single contraction a range of inertial loads is required to allow peak power to be expressed. Above a certain critical value, this is unnecessary during cycling movements where the load can be repeatedly accelerated.
Abstract: Loss of muscle mass (sarcopenia) is one of the main problems associated with ageing as it has major health care as well as socioeconomic implications. The growth hormone (GH)/IGF-I axis is regarded as an important regulator of muscle mass. However, it is now appreciated that other tissues in addition to the liver express IGF-I and that there are local as well as systemic forms of IGF-I which have different functions. At least two different kinds of IGF-I that are expressed by skeletal muscle are derived from the IGF-I gene by alternative splicing, one of which is expressed in response to physical activity which has now been called 'mechano growth factor' (MGF). The other is similar to the systemic or liver type (IGF-IEa) and is important as the provider of mature IGF-I required for upregulating protein synthesis. MGF differs from systemic IGF-IEa in that it has a different peptide sequence which is responsible for replenishing the satellite (stem) cells in skeletal muscle. The ability to produce MGF declines with age, and this is commensurate with the decline in circulating GH levels. GH treatment up regulates the level of IGF-I gene expression in older people and when combined with resistance exercise more is spliced towards MGF and hence should improve the ability of muscle to respond to physical activity. The possibility of ameliorating sarcopenia using MGF is discussed.
Abstract: Muscle responds to mechanical overload by increasing its size. In contrast, as a muscle gets older it atrophies. The mechanisms regulating these differing responses are not fully understood. Animal studies have shown that older muscles are less well able to repair following contraction-induced injury than young muscles. It is becoming clear that local growth factors produced within the muscle may play important roles in both repair, adaptation and ageing. The growth hormone/insulin like growth factor 1 (GH/IGF-I) axis is important during growth and development, but circulating levels of these hormones decline in later life. However, many tissues including muscle, produce IGF-I for autocrine and paracrine actions. Genetic manipulation of IGF-I in muscle has shown that it has considerable anabolic affects on muscle both in young and old animals. Insulin like growth factor 1 exists in multiple isoforms and one isoform, which differs from the systemic or liver type (IGF-IEa), appears to be particularly sensitive to mechanical signals and to muscle damage. This isoform (IGF-IEc) has been termed mechano growth factor (MGF). The anabolic actions of IGF-I and MGF are through stimulating protein synthesis and by playing a role in the activation, proliferation and differentiation of satellite cells. These effects are discussed in relation to human studies of muscle adaptation to strength training in older people who seem to retain an ability to increase muscle mass and strength through this type of exercise.
Abstract: Paretic human muscle rapidly loses strength and oxidative endurance, and electrical stimulation training may partly reverse this. We evaluated the effects of two training protocols on the contractile and metabolic properties of the wrist extensor in 12 C-5/6 tetraplegic individuals. The wrist extensor muscles were stimulated for 30 min/day, 5 days/week, for 12 weeks, using either a high-resistance (Hr) or a low-resistance (Lr) protocol. Total work output was similar in both protocols. The nontrained arm was used as a control. Maximum voluntary torque increased in the Hr (P < 0.05) but not the Lr group. Electrically stimulated peak tetanic torque at 15 HZ, 30 HZ, and 50 HZ were unchanged in the Lr group and tended to increase only at 15 HZ (P < 0.1) in the Hr group. Resistance to fatigue, however, increased (P < 0.05) in both Hr (42%) and Lr (41%) groups. Muscle metabolism was evaluated by (31)P nuclear magnetic resonance spectroscopy ((31)P-NMRS) during and following a continuous 40-s 10-HZ contraction. In the Hr group the cost of contraction decreased by 38% (P < 0.05) and the half-time of phosphocreatine (PCr) recovery was shortened by 52% (P < 0.05). Thus, long-term electrically induced stimulation of the wrist extensor muscles in spinal cord injury (SCI) increases fatigue resistance independent of training pattern. However, only the Hr protocol increased muscle strength and was shown to improve muscle aerobic metabolism after training. Muscle Nerve 27: 72-80, 2003
Abstract: The mRNA expression of two splice variants of the insulin-like growth factor-I (IGF-I) gene, IGF-IEa and mechano growth factor (MGF), were studied in human skeletal muscle. Subjects (eight young, aged 25-36 years, and seven elderly, aged 70-82 years) completed 10 sets of six repetitions of single legged knee extensor exercise at 80 % of their one repetition maximum. Muscle biopsy samples were obtained from the quadriceps muscle of both the control and exercised legs 2.5 h after completion of the exercise bout. Expression levels of the IGF-I mRNA transcripts were determined using real-time quantitative RT-PCR with specific primers. The resting levels of MGF were significantly (approximately 100-fold) lower than those of the IGF-IEa isoform. No difference was observed between the resting levels of the two isoforms between the two subject groups. High resistance exercise resulted in a significant increase in MGF mRNA in the young, but not in the elderly subjects. No changes in IGF-IEa mRNA levels were observed as a result of exercise in either group. The mRNA levels of the transcription factor MyoD were greater at rest in the older subjects (P < 0.05), but there was no significant effect of the exercise bout. Electrophoretic separation of myosin heavy chain (MHC) isoforms showed the older subjects to have a lower (P < 0.05) percentage of MHC-II isoforms than the young subjects. However, no association was observed between the composition of the muscle and changes in the IGF-I isoforms with exercise. The data from this study show an attenuated MGF response to high resistance exercise in the older subjects, indicative of age-related desensitivity to mechanical loading. The data in young subjects indicate that the MGF and IGF-IEa isoforms are differentially regulated in human skeletal muscle.
Abstract: Sarcopenia is the loss of muscle mass associated with the aging process. Although systemic or circulating growth hormone and insulin-like growth factor-1 levels fall as we age, this is likely to be of lesser importance in regard to muscle mass than the role of locally produced insulin-like growth factor-1s generated in the muscle in response to exercise.
Abstract: The tibialis anterior muscle of nine paraplegic men was chronically stimulated (2-6 h per day; at 10 Hz, 5 s on, 5 s off) under isometric loading conditions for 5 days per week for 4 weeks. After 4 weeks of training, muscle fatigue resistance in an electrically evoked test had increased by an average of 75% (P <.01, n = 9), but there were no changes in the relative composition of the three myosin heavy chain (MHC) isoforms. Five of the subjects continued training for an additional 5 weeks (2 h per day, 3 days per week). Although there was a tendency for twitch time to peak torque to increase after this additional period, no change occurred in relative MHC isoform content. However, in situ hybridization analysis revealed that even after 2 weeks of stimulation, there was evidence of upregulation of the mRNA for the MHC-I isoform and downregulation of the MHC-IIX isoform, a development that continued in weeks 4 and 9. This study provides evidence, at the level of gene transcription, that a fast-to-slow change in MHC isoform composition may be possible in human muscle when its usage is significantly increased.
Abstract: PURPOSE: To determine whether explosive power and isometric strength of the lower-limb muscles in elite master Olympic weightlifters declines at a similar rate to nontrained healthy controls with increasing age. METHODS: 54 elite level masters weightlifters (aged 40-87), who were competitors at the World Masters Weightlifting Championships (1999), were compared with a similar number of aged-matched, healthy untrained individuals. Isometric knee extensor strength and lower-limb explosive power were tested. Extent of antagonist co-contraction during isometric knee extension was determined by EMG and power loading characteristics by using a variable inertial system. Muscle volume was estimated using anthropometry. RESULTS: On average, the weightlifters were able to generate 32% more peak power (P < 0.05) in the lower limbs and 32% more isometric knee extensor force (P < 0.05) than the control subjects. No significant differences in lower-leg volume were observed between the two groups. Peak power declined at a similar rate with increasing age in the weightlifters and controls (1.2 and 1.3% of a 45-yr-old's value per year), as did strength, but at a lower rate (0.6 and 0.5% per year). The inertial load at which the weightlifters achieved their maximal peak power output was greater (P < 0.05) than the controls. The torque generated at this optimal inertia was also greater in the weightlifters (P < 0.05), whereas the time taken for the weightlifters to reach their maximal peak power was on average 13% shorter (P < 0.05). No differences in antagonist co-contraction during isometric knee extension were observed between the two groups. CONCLUSIONS: Muscle power and isometric strength decline at a similar rate with increasing age in elite master weightlifters and healthy controls. In spite of inertial load optimization, muscle power declined in both groups at approximately twice the rate of isometric strength. Although similar rates of decline were observed, the absolute differences between the weightlifters and controls were such that an 85-yr-old weightlifter was as powerful as a 65-yr-old control subject. This would therefore represent an apparent age advantage of approximately 20 yr for the weightlifters.
Abstract: PURPOSE: A flywheel system of variable inertia is described for inferring the mechanical properties of human muscle during a single explosive movement. METHODS: The system consists of a lightweight aluminum disk mounted on a shaft onto which a driving cog is mounted. The inertia of the system can be varied from 0.024 to 0.69 kg.m(2) by attaching semicircular steel plates to the disk. A rotary encoder detects displacement of the wheel with a resolution of 1 degrees. Digital signals from the encoder are collected using an A/D converter interfaced to a PC. The data are then processed for the calculation of torque, velocity, power, work done, and acceleration. The mechanical properties of the muscles employed are inferred from calculations of flywheel displacement, time, and force. In addition, a pretension release mechanism can be incorporated into the system to allow isometric force to be developed before movement. This can increase power generation at the low inertias where the time of contraction is typically less than 200 ms. Seven subjects were test-retested using the device. Measures of both average and peak power were made. RESULTS: When mounted in the apparatus described by Bassey and Short, the maximum values for peak and average power were on average 965 +/- 103 and 448 +/- 47 W, respectively. Upon retesting, these results were found to be reliable (cv = 3.3% and 3.0%, respectively). CONCLUSIONS: The inertial system described has been shown to have validity in reproducibility and provided a suitable method of determining a number of muscle output properties during short-term single exertions. This tool could prove useful in a research or clinical setting and may also prove useful as a training device as it negates the need for a strain gauge or goniometer attachment.
Abstract: Muscle strength, activation, and size were studied in 11 very elderly subjects (8 women and 3 men; age range, 85-97 years) who completed 12 weeks of strength training of the knee extensor muscles. Training increased the maximum amount of weight that could be lifted once (134%; P < 0.05) and maximum voluntary isometric strength, measured as both force recorded at the ankle with the knee flexed 90 degrees (17%, ns) and as torque with the knee flexed 60 degrees (37%; P < 0.05). Anatomical lean quadriceps cross-sectional area (LCSA) measured at midthigh using magnetic resonance imaging increased from 27.5 +/- 9.6 cm2 to 30.2 +/- 10.0 cm2 (9.8%; P < 0. 05) after training. Both before and after training, isometric strength was closely related to LCSA, but training resulted in no significant change in muscle force per unit area of quadriceps muscle. Using the twitch interpolation technique, muscle activation during a maximal voluntary isometric contraction was shown to be incomplete in all subjects before training (ranging from 69% to 93%) and was not significantly increased after training. An increase in skeletal muscle mass may have important functional and metabolic benefits for very elderly people.
Abstract: A long-term paraplegic man presented exclusively (>99%) myosin heavy chain I (MHC I) in the tibialis anterior muscle (TA). This was coupled to a slow speed of contraction, a high resistance to fatigue, and a rapid resynthesis of phosphocreatine after an electrically evoked fatiguing contraction when compared with the TA muscles of 9 other paraplegic individuals. In contrast, the MHC composition of his vastus lateralis, gastrocnemius, and soleus muscles was that expected of a muscle from a spinal cord injured individual. This information may be of clinical importance in terms of the expected morphological and functional adaptations of skeletal muscle to different types of electrical stimulation therapy.
Abstract: Sprint training represents the condition in which increases in muscle shortening speed, as well as in strength, might play a significant role in improving power generation. This study therefore aimed to determine the effects of sprint training on 1) the coupling between myosin heavy chain (MHC) isoform expression and function in single fibers, 2) the distribution of MHC isoforms across a whole muscle, and 3) in vivo muscle function. Seven young male subjects completed 6 wk of training (3-s sprints) on a cycle ergometer. Training was without effect on maximum shortening velocity in single fibers or in the relative distribution of MHC isoforms in either the soleus or the vastus lateralis muscles. Electrically evoked and voluntary isometric torque generation increased (P < 0.05) after training in both the plantar flexors (+8% at 50 Hz and +16% maximal voluntary contraction) and knee extensors (+8% at 50 Hz and +7% maximal voluntary contraction). With the shortening potential of the muscles apparently unchanged, the increased strength of the major lower limb muscles is likely to have contributed to the 7% increase (P < 0.05) in peak pedal frequency during cycling.
Abstract: The knee extensor and plantar flexor muscle groups of elderly men (age 70-100 years, N = 15), who since adolescence had maintained an extremely high level of endurance-based physical activity (maximal oxygen uptake 41.9 +/- 4.8 mL.kg-1min-1 in subjects < 80 years, (N = 8) and 27.1 +/- 5.4 mL.kg-1min-1 in those > 80 years, N = 5), were compared in terms of maximum voluntary isometric strength and twitch contractile properties with the muscles of elderly men of a similar age who did not undertake any regular physical exercise (68-92 years, N = 18) and of young control subjects who were recreationally active (21-36 years, N = 17). No difference was observed in the maximum voluntary strength of the knee extensors (338 +/- 130 N vs 341 +/- 137 N) or plantar flexor muscle groups (106 +/- 24 Nm vs 115 +/- 46 Nm) between the endurance-trained and elderly control subjects. This was still the case when the subjects were divided into those above and below 80 years of age, or when the data were expressed relative to body weight. Both groups of elderly subjects were markedly weaker than the young control subjects. In the plantar flexors, twitch time to peak tension (TPT) was significantly (p < 0.05) prolonged in both groups of elderly subjects vs the young control subjects. In the knee extensors, however, TPT was only prolonged in the endurance-trained athletes. Half relaxation time was prolonged in the knee extensors of both groups of elderly subjects, but only prolonged in the plantar flexors of the control subjects. The data raise the question of specificity of muscle usage, and its effect on skeletal muscle function, and suggest that endurance-based physical exercise may be of little value in maintaining muscle strength and speed of contraction in old age.
Abstract: The contractile characteristics of three human muscle groups (triceps surae, quadriceps femoris and triceps brachii) of seven young male subjects were examined. The contractile properties were determined from electrically evoked isometric responses and compared with fibre type composition determined from needle biopsy samples. Fibre types were identified using myosin heavy chain (MHC) isoforms as molecular markers with gel electrophoresis (SDS-PAGE) and histochemical ATPase staining. Four contractile parameters (twitch time to peak torque, the maximal rate of torque development, frequency response and fatiguability) were found to be related to fibre type composition. From the biopsy samples, single muscle fibres were isolated and chemically skinned. Isometric tension (Po) unloaded shortening velocity (Vo) and rate of tension rise (dP/dt) were determined. Each fibre was classified on the basis of its MHC isoform composition determined by SDS-PAGE. Fibres belonging to the same type showed identical contractile parameters regardless of the muscle of origin, except minor differences in Po of the fast fibres and dP/dt of slow fibres. The results are in favour of the conclusion that fibre type composition, determined using MHC isoforms as markers, is the major determinant of the diversity of contractile properties among human muscle groups.
Abstract: Whole muscle contractile characteristics and fatigue resistance were studied in male patients with chronic heart failure (n = 6) and in healthy control subjects (n = 6). Maximum voluntary isometric strength in the major muscle groups of leg (plantar flexors and knee extensors) and arm (elbow extensors and elbow flexors), was found to be similar for both groups of subjects. However, a faster isometric twitch time course was observed in the plantar flexor and knee extensor muscles of heart failure chronic patients. The poor resistance to fatigue in the knee extensors of chronic heart failure patients was confirmed in the present study, but using twitch interpolation this was shown not to be due to poor activation. The plantar flexors of chronic heart failure patients also showed a tendency to be less resistant to fatigue, even when the muscle was activated by direct electrical stimulation. The present study shows that independent of muscle strength, patients with chronic heart failure may possess muscles that are faster to contract and less resistant to fatigue. However, it seems this increased fatigability is not due to poor muscle activation.
Abstract: The present investigation examined the relationship between the pressor response during electrically evoked isometric ankle plantar flexion and the contractile protein profile of the active muscle in seven young men [mean (SD) age, 26 (6) years] and five older men [70 (4) years]. Muscle biopsy samples were taken from lateral gastrocnemius (LG) and soleus (SOL) of each subject. These were analysed for isomyosin composition using non-denaturing pyrophosphate polyacrylamide gel electrophoresis. The degree of association was examined between the cardiovascular changes and the fast isomyosin content of LG and SOL individually and in combination (SOL/LG). In the total subject group there was no association between the heart rate response or the change in systolic blood pressure (BP) and the fast isomyosin composition. However, the change in diastolic BP was significantly associated with the fast isomyosin composition of SOL/LG (delta diastolicBP = 0.31 + 0.045% FM SOL/LG, r = 0.65, P = 0.029). These findings suggest that the magnitude of the peripheral reflex mediated pressor response to isometric exercise and the fast isomyosin content of the active muscle are related.
Abstract: The electrically evoked isokinetic torque-velocity relationship of the triceps surae of eight elderly and four non-trained young men was examined in relation to the isomyosin composition of the soleus and the gastrocnemius muscles, determined under non-denaturing conditions using pyrophosphate gel electrophoresis. The angle specific torque-velocity properties of the triceps surae were measured using maximal percutaneous electrical stimulation at 50 Hz and a release technique. The elderly subjects generated significantly (P < 0.05) less absolute torque at all angular velocities when compared with the young subjects. When the isokinetic data were normalized to the isometric torque, the lower normalized torques generated by the elderly subjects were not statistically different from the young. The total fast isomyosin (FM) content of the soleus and gastrocnemius in the elderly subjects was 22 +/- 13 and 35+/- 18%, respectively. This compared with 29 +/- 8 (n.s) and 44 +/- 8% (n.s.) in the young subjects. When the gastrocnemius and soleus muscles were given an equal weighting and considered together to represent the whole triceps surae, the normalized torque at the fixed angular velocity of 5 rads s-1 was significantly associated with %FM (r = 0.90, P < 0.01), and the isomyosin bands %FM1 (r = 0.90, P < 0.01) and %FM2 (r = 0.93, P < 0.001) when only the elderly subjects were considered. No relationships were observed between contractile characteristics and contractile protein profile when only the young subjects were considered. This was despite the inclusion of a further two sprint and three endurance trained athletes to increase the range of contractile characteristics and differences in muscle composition.
Abstract: The influence of muscle activation and the time allowed for torque generation on the angle-specific torque-velocity relationship of the triceps surae was studied during plantar flexion using supramaximal electrical stimulation and a release technique on six male subjects [mean (SD) age 25 (4) years]. Torque-velocity data were obtained under different levels of constant muscle activation by varying the stimulus frequency and the time allowed for isometric torque generation prior to release and isokinetic shortening. To eliminate the effects of the frequency response on absolute torque the isokinetic data were normalized to the maximum isometric torque values at 0.44 rad. There were no significant differences in the normalized torques generated at any angular velocity using stimulus frequencies of 20, 50 or 80 Hz. When the muscle was stimulated at 50 Hz the torques obtained after a 400 ms and 1 s pre-release isometric contraction did not differ significantly. However, with no pre-release contraction significantly less torque was generated at all angular velocities beyond 1.05 rad.s-1 when compared with either the 200, 400 ms or 1 s condition. With a 200 ms pre-release contraction significantly less torque was generated at angular velocities beyond 1.05 rad.s-1 when compared with the 400 ms or 1 s conditions. It would seem that the major factor governing the shape of the torque-velocity curve at a constant level of muscle activation is the time allowed for torque generation.
Abstract: The angle-specific isokinetic torque- and power-velocity relationships of the triceps surae were examined in ten male sprint athletes aged [mean (SD)] 22.4 (3.2) years, ten non-trained adult men aged 27.4 (4.8) years and six elderly male subjects aged 68.5 (2.4) years. Normal voluntary contractions were compared with those obtained using maximal tetanic stimulation and a release technique which standardised the level of muscle activation during isokinetic contractions. When the isokinetic data was normalized to the maximum isometric torque the stimulated release contractions at 5.18-5.29 rad.s-1 produced significantly (P < 0.05) greater torque than the voluntary no-release contractions at the same angular velocity in each group of subjects. The three subject groups generated their peak power at 3.07 rad.s-1 during the voluntary no release contractions. However, with the stimulated release contractions, power had still not reached a peak at 5.29 rad.s-1, the highest angular velocity that could be tested. It appears that at higher angular velocities the triceps surae is capable of greater torque and power generation when contractions are evoked using a stimulated release technique. It is suggested that the stimulated release technique gives a more complete picture of the torque-velocity characteristics of the contractile component of the triceps surae.
Abstract: The influence of preceding diet (mixed, MD; carbohydrate CD; protein PD) on performance during high intensity endurance cycling was examined in six middle distance runners. Subjects undertook cycle ergometer exercise at a workload equivalent to 80% VO2 max until exhaustion following each of the three dietary regimens. Dietary analyses were performed using a computerised evaluation technique and cardiorespiratory, blood glucose and lactate responses to exercise were measured along with exercise time to exhaustion. Significant differences in carbohydrate and protein intakes were noted between respective diets as well as significantly higher total energy intake in MD (P less than 0.05). A significant relationship was observed between carbohydrate intake and exercise time to exhaustion (r = 0.59, P less than 0.05). No significant differences were noted in cardiorespiratory measures or blood glucose response after exhaustive exercise between the three dietary regimens but peak blood lactate concentration was lower following PD (P less than 0.05). Total time to exhaustion was significantly higher on CD (1070.0 +/- 106.7 s) than on PD (642.5 +/- 84.3 s, P less than 0.01). Performance time on MD (895.7 +/- 84.3 s) did not differ significantly for performance time on either CD or PD. It was concluded that dietary manipulation significantly improves exercise time to exhaustion during short term, high intensity cycling.
