Adaptive Response Of Skeletal Muscle Research Articles

Muscle Metabolic Modulation by Chronic Hypoxia

De Palma et al. published a research paper in which they describe the effect of chronic hypoxia on rat skeletal muscle metabolism by means of a comparative proteomic analysis (J. Proteome Res. 2007, 6(5), 1974-1984). For this, relatively young animals were used. In our communication, we note that, based on other literature, it is likely that the adaptive response of skeletal muscle to hypoxia attenuates with age.

Alterations in soleus muscle gene expression associated with a metabolic endpoint following exercise training by lean and obese Zucker rats

Exercise training decreases insulin resistance and increases glucose tolerance in conditions of prediabetes and overt Type 2 diabetes. However, the adaptive responses in skeletal muscle at the molecular and genetic level for these effects of exercise training have not been clearly established in an animal model of prediabetes. The present study identifies alterations in muscle gene expression that occur with exercise training in prediabetic, insulin-resistant obese Zucker rats and insulin-sensitive lean Zucker rats and are associated with a well-defined metabolic outcome. Treadmill running for up to 4 wk caused significant enhancements of glucose tolerance as assessed by the integrated area under the curve for glucose (AUCg) during an oral glucose tolerance test. Using microarray analysis, we identified a set of only 12 genes as both significantly altered by exercise training (>1.5-fold change; P < 0.05) and significantly correlated (P < 0.05) with the AUCg. Two genes, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) and protein kinase C-zeta (PKC-zeta), are involved in the regulation of muscle glucose transport, and we provide the first evidence that PKC-zeta gene expression is enhanced by exercise training in insulin-resistant muscle. Protein expression of PGC-1alpha and PKC-zeta were positively correlated with the mRNA expression for these two genes. Overall, we have identified a limited number of genes in soleus muscle of lean and obese Zucker rats that are associated with both decreased insulin resistance and increased glucose tolerance following endurance exercise training. These findings could guide the development of pharmaceutical "exercise mimetics" in the treatment of insulin-resistant, prediabetic, or Type 2 diabetic individuals.

Oxidative Phenotype Protects Myofibers from Pathological Insults Induced by Chronic Heart Failure in Mice

The fiber specificity of skeletal muscle abnormalities in chronic heart failure (CHF) has not been defined. We show here that transgenic mice (8 weeks old) with cardiac-specific overexpression of calsequestrin developed CHF (50.9% decrease in fractional shortening and 56.4% increase in lung weight, P<0.001), cachexia (37.8% decrease in body weight, P<0.001), and exercise intolerance (69.3% decrease in running distance to exhaustion, P<0.001) without a significant change in muscle fiber-type composition. Slow oxidative soleus muscle maintained muscle mass, whereas fast glycolytic tibialis anterior and plantaris muscles underwent atrophy (11.6 and 13.3%, respectively; P<0.05). In plantaris muscle, glycolytic type IId/x and IIb, but not oxidative type I and IIa, fibers displayed significant decreases in cross-sectional area (20.3%, P<0.05). Fast glycolytic white vastus lateralis muscle showed sarcomere degeneration and decreased cytochrome c oxidase IV (39.5%, P<0.01) and peroxisome proliferator-activated receptor gamma co-activator 1alpha protein expression (30.3%, P<0.01) along with a dramatic induction of the MAFbx/Atrogin-1 mRNA. These findings suggest that exercise intolerance can occur in CHF without fiber type switching in skeletal muscle and that oxidative phenotype renders myofibers resistant to pathological insults induced by CHF.

Metabolic Functions of Peroxisome Proliferator-Activated Receptorβ/δin Skeletal Muscle

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that act as lipid sensors and adapt the metabolic rates of various tissues to the concentration of dietary lipids. PPARs are pharmacological targets for the treatment of metabolic disorders. PPARα and PPARγ are activated by hypolipidemic and insulin-sensitizer compounds, such as fibrates and thiazolidinediones. The roles of PPARβ/δ in metabolic regulations remained unclear until recently. Treatment of obese monkeys and rodents by specific PPARβ/δ agonists promoted normalization of metabolic parameters and reduction of adiposity. Recent evidences strongly suggested that some of these beneficial actions are related to activation of fatty acid catabolism in skeletal muscle and also that PPARβ/δ is involved in the adaptive responses of skeletal muscle to environmental changes, such as long-term fasting or physical exercise, by controlling the number of oxidative myofibers. These observations indicated that PPARβ/δ agonists might have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption in skeletal muscle and reducing obesity.

Nutritional Interventions to Promote Post-Exercise Muscle Protein Synthesis

Resistance exercise is a powerful stimulus to augment muscle protein anabolism, as it can improve the balance between muscle protein synthesis and breakdown. However, the intake of food during post-exercise recovery is necessary for hypertrophy to occur. Therefore, athletes need to ingest protein following exercise to attain a positive protein balance and maximise their skeletal muscle adaptive response. The interaction between exercise and nutrition is not only important for athletes, but is also of important clinical relevance in the elderly. Exercise interventions combined with specific nutritional modulation provide an effective strategy to counteract or reduce the loss of skeletal muscle mass with aging.

Role of calcineurin in exercise-induced mitochondrial biogenesis

Raising cytosolic Ca2+ induces an increase in mitochondrial biogenesis in myotubes. This phenomenon mimics the adaptive responses of skeletal muscle to exercise. It has been hypothesized that increases in cytosolic Ca2+ during motor nerve activity stimulate mitochondrial biogenesis by activating calcineurin. Overexpression of constitutively active calcineurin increases expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and induction of genes involved in mitochondrial energy metabolism in muscle cells. The purpose of this study was to determine whether calcineurin plays a role in the stimulation of mitochondrial biogenesis by exercise. Rats were exercised on 5 successive days by means of swimming. Inhibition of calcineurin with cyclosporin did not prevent the exercise-induced increases in PGC-1alpha and a range of mitochondrial proteins. In contrast to the other mitochondrial proteins, the increases in cytochrome oxidase (COX)-I and -IV proteins were blocked by cyclosporin treatment. This inhibitory effect of cyclosporin occurred at the posttranscriptional level, as evidenced by normal increases in COX-I and COX-IV mRNAs in response to exercise in the cyclosporin-treated rats. This toxic effect of cyclosporin may account for the decrease in muscle respiratory capacity reported to occur with cyclosporin treatment. In conclusion, inhibition of calcineurin does not prevent the exercise-induced increase in mitochondrial biogenesis in skeletal muscles, providing evidence that the adaptive response is not mediated by activation of calcineurin.

Muscle Stem Cells and Exercise Training

Adult skeletal muscle fibers are terminally differentiated such that hypertrophy and regeneration require resident stem cell populations. This review examines the current understanding of the factors regulating muscle stem cells in response to exercise and identify the role of these cells in the adaptive response of skeletal muscle to endurance and resistance exercise training.

Regulatory role of peroxisome proliferator-activated receptor delta (PPARδ) in muscle metabolism. A new target for metabolic syndrome treatment?

Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in both developmental and metabolic functions. There are activated by fatty acids, fatty acid metabolites, and synthetic compounds marketed for their lipid-lowering and antidiabetic actions. It was clearly established that activation of PPARα and PPARγ, by fibrates and thiazolidinediones, respectively, impair metabolic disorders. The implication of the third member of the PPAR family, PPARδ, remained evasive until recently. These past few years, it has been demonstrated that treatment with PPARδ agonists normalizes blood lipids, reduces insulin resistance and adiposity in rodent and primate. Utilization of both cellular and animal models revealed that the nuclear receptor plays a central role in the control of fatty acid burning in adipose tissue and skeletal muscle. Furthermore, PPARδ appeared to be important for adaptive response of skeletal muscle to environmental changes, such as physical exercise.

Skeletal muscle adaptation in response to voluntary running in Ca2+/calmodulin-dependent protein kinase IV-deficient mice.

Mammalian skeletal muscles undergo adaptation in response to alteration in functional demands by means of a variety of cellular signaling events. Previous experiments in transgenic mice showed that an active form of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) is capable of stimulating peroxisome proliferator-activated receptor gamma-coactivator 1alpha (PGC-1alpha) gene expression, promoting fast-to-slow fiber type switching and augmenting mitochondrial biogenesis in skeletal muscle. However, a role for endogenous CaMKIV in skeletal muscle has not been investigated rigorously. We report that genetically modified mice devoid of CaMKIV have normal fiber type composition and mitochondrial enzyme expression in fast-twitch skeletal muscles and responded to long-term (4 wk) voluntary running with increased expression of myosin heavy chain type IIa, myoglobin, PGC-1alpha, and cytochrome c oxidase IV proteins in plantaris muscle in a manner similar to that of wild-type mice. Short-term motor nerve stimulation (2 h at 10 Hz) likewise increased PGC-1alpha mRNA expression in tibialis anterior muscles in both Camk4(-/-) and wild-type mice. In addition, we have confirmed that no detectable CaMKIV protein is expressed in murine skeletal muscle. Thus CaMKIV is not required for the maintenance of slow-twitch muscle phenotype and endurance training-induced mitochondrial biogenesis and IIb-to-IIa fiber type switching in murine skeletal muscle. Other protein kinases sharing substrates with constitutively active CaMKIV may function as endogenous mediators of activity-dependent changes in myofiber phenotype.

Myogenic protein expression before and after resistance loading in 26- and 64-yr-old men and women

Based on the growing body of evidence implicating an important role for myogenic regulatory factors (MRFs) in the adaptive responses of skeletal muscle to mechanical load, we tested the hypothesis that protein concentrations of MRFs as well as cell cycle proteins (i.e., cyclins and cyclin-dependent kinase inhibitors) would be altered after heavy leg resistance exercise (RE). Because we and others, however, have shown a blunted adaptive response to long-term resistance training in older (O) women [females (F)] compared with men (M), we also tested the hypothesis that these myogenic responses to RE would be influenced by age and gender. Twenty-two younger (Y) adults (20-35 yr, 11 YF, 11 YM) and 20 O adults (60-75 yr, 9 OF, 11 OM) consented to vastus lateralis muscle biopsy before and 24 h after a bout of RE using a regimen known to induce myofiber hypertrophy when performed 2-3 days/wk for several weeks (3 sets of 80% one-repetition maximum for squat, leg press, and knee extension). Protein concentrations of MRFs (MyoD, myogenin, myf-6), cyclin D1, cyclin B1, alpha-actin, and the cyclin-dependent kinase inhibitor p27kip were determined by immunoblotting. Data were analyzed by using age x gender x load repeated-measures ANOVA. Myogenin expression was 44% higher (P <0.05) in O compared with Y, and myf-6 tended to be higher in OF compared with YF (95%, P=0.059). A significant gender x load interaction indicated that, in F, RE led to a reduction in p27kip (20%; P<0.05), which was driven mainly by a 27% drop in OF. Levels of cyclin D1, cyclin B1, MyoD, myf-6, and alpha-actin were not influenced by age, gender, or loading. We report a novel finding in humans of markedly higher myogenin protein content in older sedentary muscle. The results do not, however, support the hypothesis that myogenic protein expression is altered 24 h after RE, irrespective of age or gender. Although the time point of postexercise muscle biopsy could be viewed as too early to capture maximal effects for most of these proteins, the significant decline in p27kip concentration found in OF suggests that mechanical load may provide one means of overcoming the inhibitory influence of p27kip.

Pattern Dependence in the Stimulation-Induced Type Transformation of Rabbit Fast Skeletal Muscle

Little is known of the events that initiate the adaptive response of skeletal muscle to a sustained change in use. This study was designed to distinguish between the role of the electrical activity pattern and that of the resulting contractile force in driving different aspects of the response. A better understanding of these issues would lead to improved clinical protocols for functional electrical stimulation. Rabbit limb muscles were stimulated continuously for 12weeks either at 2.5Hz or with an equivalent optimized pattern producing peak forces three-fold higher. The two patterns induced similar changes in shortening velocity, myosin isoforms, and fatigue resistance. They had markedly different effects on twitch dynamics and summation ("doublet effect"). This pointed to differences in activation that were not, however, attributable to sarcoplasmic reticulum Ca(2+) transport ATPase activity. The optimized pattern maintained muscle bulk more effectively. We conclude that changes in myosin isoform composition and fatigue resistance are driven by aggregate impulse activity. Changes in Ca(2+) transport and muscle bulk show a distinct pattern dependence.

Skeletal muscle plasticity: cellular and molecular responses to altered physical activity paradigms.

The goal of this article is to examine our current understanding of the chain of events known to be involved in the adaptive process whereby specific genes and their protein products undergo altered expression; specifically, skeletal muscle adaptation in response to altered loading states will be discussed, with a special focus on the regulation of the contractile protein, myosin heavy chain gene expression. This protein, which is both an important structural and regulatory protein comprising the contractile apparatus, can be expressed as different isoforms, thereby having an impact on the functional diversity of the muscle. Because the regulation of the myosin gene family is under the control of a complex set of processes including, but not limited to, activity, hormonal, and metabolic factors, this protein will serve as a cellular "marker" for studies of muscle plasticity in response to various mechanical perturbations in which the quantity and type of myosin isoform, along with other important cellular proteins, are altered in expression.

Titin and nebulin content in human skeletal muscle following eccentric resistance exercise.

We measured titin and nebulin content in muscle biopsies from the vastus lateralis before and 24 h after one bout of high-intensity eccentric knee extensor resistance exercise in seven men (26 +/- 3 years). Titin and nebulin content were significantly (P < 0.05) reduced after exercise by 30 and 15%, respectively. These results suggest that the structural components of the myofibrillar apparatus are degraded following high-intensity eccentric resistance exercise in humans. Loss of these proteins may have important implications for the mechanisms regulating the adaptive response of skeletal muscle to resistance exercise.

Skeletal muscle adaptations in response to voluntary wheel running in myosin heavy chain null mice.

10.1152/ japplphysiol.00832.2001.-To examine the effects of gene inactivation on the plasticity of skeletal muscle, mice null for a specific myosin heavy chain (MHC) isoform were subjected to a voluntary wheel-running paradigm. Despite reduced running performance compared with nontransgenic C57BL/6 mice (NTG), both MHC IIb and MHC IId/x null animals exhibited increased muscle fiber size and muscle oxidative capacity with wheel running. In the MHC IIb null animals, there was no significant change in the percentage of muscle fibers expressing a particular MHC isoform with voluntary wheel running at any time point. In MHC IId/x null mice, wheel running produced a significant increase in the percentage of fibers expressing MHC IIa and MHC I and a significant decrease in the percentage of fibers expressing MHC IIb. Muscle pathology was not affected by wheel running for either MHC null strain. In summary, despite their phenotypes, MHC null mice do engage in voluntary wheel running. Although this wheel-running activity is lessened compared with NTG, there is evidence of distinct patterns of muscle adaptation in both null strains.

Invited review: Adaptive responses of skeletal muscle to intermittent hypoxia: the known and the unknown.

Intermittent hypoxia (IH) describes conditions of repeated, transient reductions in O2 that may trigger unique adaptations. Rest periods during IH may avoid potentially detrimental effects of long-term O2 deprivation. For skeletal muscle, IH can occur in conditions of obstructive sleep apnea, transient altitude exposures (with or without exercise), intermittent claudication, cardiopulmonary resuscitation, neonatal blood flow obstruction, and diving responses of marine animals. Although it is likely that adaptations in these conditions vary, some patterns emerge. Low levels of hypoxia shift metabolic enzyme activity toward greater aerobic poise; extreme hypoxia shifts metabolism toward greater anaerobic potential. Some conditions of IH may also inhibit lactate release during exercise. Many related cellular phenomena could be involved in the response, including activation of specific O2 sensors, reactive oxygen and nitrogen species, preconditioning, hypoxia-induced transcription factors, regulation of ion channels, and influences of paracrine/hormonal stimuli. The net effect of a variety of adaptive programs to IH may be to preserve contractile function and cell integrity in hypoxia or anoxia, a response that does not always translate into improvements in exercise performance.

Commentary

HIGHLIGHTED TOPICScommentaryPublished Online:01 Mar 2001https://doi.org/10.1152/jappl.2001.90.3.1165MoreSectionsPDF (47 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat The first Highlighted Topics article in this issue of the Journal of Applied Physiology, “IGF-I antibody prevents increases in protein synthesis in epitrochlearis muscles from refed, diabetic rats,” by Fedele et al. (p. 1166–1173), shows a potential compensatory role of insulin-like growth factor I (IGF-I) for stimulating skeletal muscle protein synthesis in diabetic rats. This study tested the effect of immune neutralization of locally produced IGF-I on rates of protein turnover in incubated epitrochlearis muscles after fasting and subsequent refeeding. Antibodies against IGF-I reduced protein synthesis rates in muscles from both diabetic and nondiabetic animals. Muscles from diabetic rats that were incubated with anti-IGF-I did not increase protein synthesis as a result of refeeding after a 48-h fast. However, muscles from control diabetic animals as well as muscles from control and antibody-treated nondiabetic animals all exhibited higher protein synthesis rates after refeeding. The deleterious effects of immunoneutralizing IGF-I were thus most pronounced in the diabetic animals during conditions that necessitated an anabolic response. The findings from this study suggest that IGF-I may compensate for insulin during hypoinsulinemic conditions to facilitate anabolism.The second Highlighted Topics article featured in this issue, “Skeletal muscle focal adhesion kinase, paxillin, and serum response factor are loading dependent,” by Gordon et al. (p. 1174–1183), focuses on skeletal muscle adaptations in response to mechanical loading. A complete picture of the molecular events linking mechanical loading to the size and strength of skeletal muscle is still largely unknown. Although calcineurin has been implicated in the hypertrophic response of skeletal muscle to increased physiological loads, a recent study suggests that calcineurin overexpression alone does not result in skeletal muscle hypertrophy and that calcineurin requires upstream activity-dependent effectors (possibly nerve-mediated activity or mechanical loading) (Dunn et al.,J Cell Biol 151: 663–672, 2000). In their study, Gordon et al. show that the mechanochemical signaling protein focal adhesion kinase (FAK) varies its concentration and/or phosphorylation state in skeletal muscle in association with muscle loading status. In addition, the investigators found that changes in FAK were associated with changes in the concentration of the serum response factor (SRF), which is necessary for skeletal α-actin gene transcription and has been shown to lie downstream of FAK in cultured myoblasts (Wei et al.,Am J Physiol Heart Circ Physiol 278: H1736–H1743, 2000). Thus FAK may be a potential upstream mechanochemical signaling component of the SRF pathway or even other pathways (e.g., calcineurin), all of which may be involved in loading-induced regulation of skeletal muscle mass.This article has no references to display. Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 90Issue 3March 2001Pages 1165-1165 Copyright & PermissionsCopyright © 2001 the American Physiological Societyhttps://doi.org/10.1152/jappl.2001.90.3.1165History Published online 1 March 2001 Published in print 1 March 2001 Metrics

Adaptations to training in endurance cyclists: implications for performance.

Our present scientific knowledge of the effects of specific training interventions undertaken by professional cyclists on selected adaptive responses in skeletal muscle and their consequences for improving endurance performance is limited: sport scientists have found it difficult to persuade elite cyclists to experiment with their training regimens and access to muscle and blood samples from these athletes is sparse. Owing to the lack of scientific study we present a theoretical model of some of the major training-induced adaptations in skeletal muscle that are likely to determine performance capacity in elite cyclists. The model includes, but is not limited to, skeletal muscle morphology, acid-base status and fuel supply. A working premise is that the training-induced changes in skeletal muscle resulting from the high-volume, high-intensity training undertaken by elite cyclists is at least partially responsible for the observed improvements in performance. Using experimental data we provide evidence to support the model.

Skeletal muscle adaptations to prolonged training, overtraining and detraining in horses.

Thirteen standard-bred horses were trained intensively for 34 weeks and detrained for 6 weeks to study skeletal muscle adaptations to prolonged training, overtraining and detraining. Training included endurance (phase 1, 7 weeks), high-intensity (phase 2, 9 weeks) and overload training (OLT) (phase 3, 18 weeks). During phase 3, horses were divided into two groups, OLT and control (C), with OLT horses performing greater intensities and durations of exercise than C horses. Overtraining was evident in OLT horses after week 31 and was defined as a significant reduction in treadmill run time in response to a standardised exercise test (P<0.05). Relationships between peripheral (skeletal muscle) and whole body (maximum O2 uptake, V.O2, max, treadmill run time) adaptations to training were determined. Prolonged training resulted in significant adaptations in morphological characteristics of skeletal muscle but the adaptations were limited and largely completed by 16 weeks of training. Fibre area increased in all fibres while the number of capillaries per fibre increased and the diffusional index (area per capillary) decreased. Mitochondrial volume density continued to increase throughout 34 weeks of training and paralleled increases in V.O2,max and treadmill run time. Significant correlations were noted between mitochondrial volume and V.O2,max (R=0.71), run time and V.O2,max (R=0.83) and mitochondrial volume and run time (R=0.57). We conclude that many of adaptive responses of muscle fibre area and capillarity occur in the initial training period but that markers of oxidative capacity of muscle indicate progressive increases in aerobic capacity with increases in training load. The lack of differences between C and OLT groups indicated that there may be an upper limit to the ability of training stimulus to evoke skeletal muscle adaptive responses. There was no effect of overtraining or detraining on any of the adaptive responses measured.

Hypertrophy of rat plantaris muscle fibers after voluntary running with increasing loads.

There have been no systematic comparisons of skeletal muscle adaptations in response to voluntary wheel running under controlled loading conditions. To accomplish this, a voluntary running wheel for rats and mice was developed in which a known load can be controlled and monitored electronically. Five-week-old male Sprague-Dawley rats (10 rats/group) were assigned randomly to either a 1) sedentary control group (Control); 2) voluntary exercised with no load (Run-No-Load) group; or 3) voluntary exercised with additional load (Run-Load) group for 8 wk. The load for the Run-Load group was progressively increased to reach approximately 60% of body weight during the last week of training. The proportions of fast glycolytic (FG), fast oxidative glycolytic (FOG), or slow oxidative (SO) fibers in the plantaris were similar in all groups. The absolute and relative plantaris weights were greater in the Run-Load group compared with the Control and Run-No-Load groups. The mean fiber cross-sectional areas of FG, FOG, and SO fibers were 20, 25, and 15% greater in the Run-Load than in Control rats. In addition, these fiber types were 16, 21, and 12% larger in Run-Load than in Run-No-Load rats. The muscle weights and mean cross-sectional areas of each fiber type were highly correlated with the average running distances and total work performed in the Run-Load, but not the Run-No-Load, group. The slope of the relationship between fiber size and running distance and total work performed was significant for each fiber type but was higher for FG and FOG fibers compared with SO fibers. These data show that the load on a rat running voluntarily can determine the magnitude of a hypertrophic response and the population of motor units that are recruited to perform at a given loading condition.

Changes in nuclear protein composition in response to chronic electrical stimulation of skeletal muscle.

The adaptive response of skeletal muscle to increased functional demand involves phenotypic changes that affect contractile properties, energy metabolism and calcium kinetics. Some of these changes are known to be initiated at a pre-translational level, but the underlying regulatory mechanisms have not yet been identified. In this study we used chronic electrical stimulation (10 Hz, continuous) to initiate fast-to-slow muscle fibre-type transformation, and two-dimensional electrophoresis (2-DE) to assess changes in nuclear protein composition after 24 and 72 h. We report an early and sustained increase in the level of a 3 kDa protein in stimulated fast muscle (n = 6). The presence of the same protein in control slow muscle is consistent with a possible functional role in the determination of the slow phenotype.