Adaptations In Human Skeletal Muscle Research Articles

Effect of caffeine on mitochondrial biogenesis in the skeletal muscle - A narrative review.

Caffeine is one of the most widely used substances as recreational drug for performance-enhancement in sport, underpinned by a strong evidence base. Although the effects of caffeine are widely investigated within the scope of performance physiology, the molecular effects of caffeine within skeletal muscle remain unclear. Evidence from invitro and invivo models suggest that caffeine regulates the glucose metabolism in the skeletal muscle. Moreover, caffeine seems to stimulate CaMKII, PPARδ/β, AMPK and PGC1α, classical markers of exercise-adaptations, including mitochondrial biogenesis and mitochondrial content. This review summarizes evidence to suggest caffeine-effects within skeletal muscle fibers, focusing on the putative role of caffeine on mitochondrial biogenesis to explore whether caffeine supplementation might be a strategy to enhance mitochondrial biogenesis.

The Effect Of Percussive Massage On Skeletal Muscle Mitochondrial Respiration And Hydrogen Peroxide Production

PURPOSE: Mitochondrial dysfunction is associated with many conditions including muscle atrophy, dystrophy, and obesity-induced insulin resistance. Increases in mitochondrial-derived reactive oxygen species have been attributed to some of these adverse conditions. Emerging evidence suggests that mechanical stimulation may affect mitochondrial homeostasis and adaptation. However, the direct effect of isolated mechanical stimulation on mitochondrial adaptation in human skeletal muscle needs to be determined. Therefore, this study investigated the effect of percussive massage as a practical form of mechanical stimulation on skeletal muscle mitochondrial respiration and H2O2 production. METHODS: 10 healthy young men and women (22 ± 4 yr) received 18 sessions of 30-min-percussive massage on their right thigh over the course of 6 weeks. Subcutaneous fat was imaged and measured using ultrasound on both the treated and contralateral thighs. Muscle samples were collected one week before the start of massage sessions and 48 h after the last session from the participants treated vastus lateralis. Permeabilized muscle fibers were assessed for maximal respiratory capacity, fat oxidative capacity, and H2O2 flux using high-resolution respirometry (Oroboros O2k). RESULTS Percussive massage treatment significantly increased maximal mitochondrial fat oxidation supported by octanoylcarnitine, malate, and ADP from 13.16 ± 4.9 pmolO2/(s*mg) to 17.33 ± 3.59 pmolO2/(s*mg) (p = 0.032). In accordance with this finding, subcutaneous fat thickness of the treated thigh decreased by 7.3% ± 5.1, which was significantly higher than the contralateral thigh (0.8% ± 5.2; p = 0.004). H2O2 production, was reduced following massage treatment in the presence of glutamate, malate, succinate, and 12.5 μM, 25 μM, 100 μM and 2.5 mM ADP (48.87% ± 29.58, p = 0.034; 54.15% ± 29.33, p = 0.035; 71.76% ± 13.2, p = 0.006; 59.76% ± 53.22 p = 0.011, respectively). However, coupled respiration supported by glutamate, malate, and ADP remained unchanged after 6 weeks of massage treatment (p = 0.8) CONCLUSION: 6 weeks of percussive massage improves mitochondrial fat oxidation and decreases subcutaneous fat thickness and maximal H2O2 production but does not change maximal coupled respiration.

Molecular Regulators of Muscle Mass and Mitochondrial Remodeling Are Not Influenced by Testosterone Administration in Young Women.

Testosterone (T) administration has previously been shown to improve muscle size and oxidative capacity. However, the molecular mechanisms underlying these adaptations in human skeletal muscle remain to be determined. Here, we examined the effect of moderate-dose T administration on molecular regulators of muscle protein turnover and mitochondrial remodeling in muscle samples collected from young women. Forty-eight healthy, physically active, young women (28 ± 4 years) were assigned in a random double-blind fashion to receive either T (10 mg/day) or placebo for 10-weeks. Muscle biopsies collected before and after the intervention period were divided into sub-cellular fractions and total protein levels of molecular regulators of muscle protein turnover and mitochondrial remodeling were analyzed using Western blotting. T administration had no effect on androgen receptor or 5α-reductase levels, nor on proteins involved in the mTORC1-signaling pathway (mTOR, S6K1, eEF2 and RPS6). Neither did it affect the abundance of proteins associated with proteasomal protein degradation (MAFbx, MuRF-1 and UBR5) and autophagy-lysosomal degradation (AMPK, ULK1 and p62). T administration also had no effect on proteins in the mitochondria enriched fraction regulating mitophagy (Beclin, BNIP3, LC3B-I, LC3B-II and LC3B-II/I ratio) and morphology (Mitofilin), and it did not alter the expression of mitochondrial fission- (FIS1 and DRP1) or fusion factors (OPA1 and MFN2). In summary, these data indicate that improvements in muscle size and oxidative capacity in young women in response to moderate-dose T administration cannot be explained by alterations in total expression of molecular factors known to regulate muscle protein turnover or mitochondrial remodeling.

Acute and Chronic Effects of High Frequency Electric Pulse Stimulation on the Akt/mTOR Pathway in Human Primary Myotubes.

Electrical pulse stimulation (EPS) has been suggested to be a useful method to investigate the mechanisms underlying the adaptations of human skeletal muscle to both endurance and resistance exercise. Although different myotube stimulation protocols mimicking acute and chronic endurance exercise have been developed, no convincing protocol mimicking resistance exercise exists. Adaptations to resistance exercise mainly ensue via the Akt/mTOR pathway. Therefore, the aim of this study was to develop a high frequency EPS protocol mimicking resistance exercise both acutely (100 Hz, 15 V, 0.4 ms with 4 s rest between each contraction for 30 min) and chronically (acute EPS protocol repeated on three consecutive days) on human myotubes. Compared to control conditions, the acute EPS protocol increased the phosphorylation of AktSer473 at 0 h (+91%, p = 0.02) and 3 h (+95%, p = 0.01), and mTORSer2448 at 0 h (+93%, p = 0.03), 1 h (+129%, p = 0.01), and 3 h (+104%, p = 0.0250) post-stimulation. The phosphorylation of ERK1/2Thr202/Tyr204 was increased at 0 h (+69%, p = 0.02) and 3 h (+117%, p = 0.003) post-stimulation compared to control conditions. In addition, both S6K1Thr389 (+157%, p = 0.009) and S6Ser240/244 (+153%, p = 0.003) phosphorylation increased 1 h after EPS compared to control conditions. Chronic EPS protocol increased the phosphorylation of S6K1Thr389 1 h (+105%, p = 0.03) and 3 h (+126%, p = 0.02) and the phosphorylation of S6Ser240/244 1 h (+32%, p = 0.02) after the end of the last stimulation. In conclusion, the present work shows that human muscle cells subjected to EPS can be used as an in vitro model of acute and chronic resistance exercise.

Post-exercise carbohydrate and energy availability induce independent effects on skeletal muscle cell signalling and bone turnover: implications for training adaptation.

Reduced carbohydrate (CHO) availability before and after exercise may augment endurance training-induced adaptations of human skeletal muscle, as mediated via modulation of cell signalling pathways. However, it is not known whether such responses are mediated by CHO restriction, energy restriction or a combination of both. In recovery from a twice per day training protocol where muscle glycogen concentration is maintained within 200-350mmolkg-1 dry weight (dw), we demonstrate that acute post-exercise CHO and energy restriction (i.e. <24h) does not potentiate potent cell signalling pathways that regulate hallmark adaptations associated with endurance training. In contrast, consuming CHO before, during and after an acute training session attenuated markers of bone resorption, effects that are independent of energy availability. Whilst the enhanced muscle adaptations associated with CHO restriction may be regulated by absolute muscle glycogen concentration, the acute within-day fluctuations in CHO availability inherent to twice per day training may have chronic implications for bone turnover. We examined the effects of post-exercise carbohydrate (CHO) and energy availability (EA) on potent skeletal muscle cell signalling pathways (regulating mitochondrial biogenesis and lipid metabolism) and indicators of bone metabolism. In a repeated measures design, nine males completed a morning (AM) and afternoon (PM) high-intensity interval (HIT) (8×5min at 85% ) running protocol (interspersed by 3.5h) under dietary conditions of (1) high CHO availability (HCHO: CHO ∼12gkg-1 , EA∼ 60kcalkg-1 fat free mass (FFM)), (2) reduced CHO but high fat availability (LCHF: CHO ∼3(-1 , EA∼ 60kcalkg-1 FFM) or (3), reduced CHO and reduced energy availability (LCAL: CHO ∼3gkg-1 , EA∼ 20kcalkg-1 FFM). Muscle glycogen was reduced to ∼200mmolkg-1 dw in all trials immediately post PM HIT (P<0.01) and remained lower at 17h (171, 194 and 316mmolkg-1 dw) post PM HIT in LCHF and LCAL (P<0.001) compared to HCHO. Exercise induced comparable p38MAPK phosphorylation (P<0.05) immediately post PM HIT and similar mRNA expression (all P<0.05) of PGC-1α, p53 and CPT1 mRNA in HCHO, LCHF and LCAL. Post-exercise circulating βCTX was lower in HCHO (P<0.05) compared to LCHF and LCAL whereas exercise-induced increases in IL-6 were larger in LCAL (P<0.05) compared to LCHF and HCHO. In conditions where glycogen concentration is maintained within 200-350mmolkg-1 dw, we conclude post-exercise CHO and energy restriction (i.e. <24h) does not potentiate cell signalling pathways that regulate hallmark adaptations associated with endurance training. In contrast, consuming CHO before, during and after HIT running attenuates bone resorption, effects that are independent of energy availability and circulating IL-6.

Impact of repeated local heat stress on skeletal muscle structure and function in humans

IntroductionShort‐term exposure to heat stress has been shown to enhance muscle strength and elicit mitochondrial adaptations in human skeletal muscle. We recently documented that exposure to five sessions of heat therapy (HT) accelerates the recovery of fatigue resistance following exercise‐induced muscle damage in humans. However, the long‐term impact of repeated exposure to local heat stress on contractile function and skeletal muscle structure remains unknown. The purpose of the present study was to examine the effects of 8 weeks of daily treatment with local HT on muscle strength, fatigability, fiber size and mitochondrial content in humans.MethodsTwelve healthy young adults (23.6±1.4 years, BMI 24.9±0.9 kg/m2) had one randomly selected thigh treated with daily HT for 8 consecutive weeks while the opposite thigh served as a control. A water‐circulating garment perfused with water at ~52ºC was used to apply HT for 90 min daily. Knee extensor strength (single peak torque during 3 repetition maximums at 180°/s and 60°/s) and fatigue resistance (total work during 40 repetition maximums at 180°/s) were assessed using isokinetic dynamometry before and after 4 and 8 weeks of treatment. Biopsies were obtained from the vastus lateralis muscle for the determination of myofiber cross‐sectional area and maximal citrate synthase activity.ResultsTreatment with HT elicited an increase in thigh skin temperature (39.8±0.1ºC), while skin temperature remained at baseline levels in the control thigh (32.4± 0.1ºC). A significant treatment effect was observed for the changes from baseline in peak isokinetic torque at 180º/s (p=0.04). On average, the changes in peak isokinetic torque from baseline for HT were ~2 fold higher than control at week 4 (Control: 4.1±3.7 Nm vs. HT: 9±4.6 Nm) and ~4 fold higher at week 8 (Control: 1.7±2.7 Nm vs. HT: 7.7±2.9 Nm). There were no differences between treatments for peak isokinetic torque at 60º/s, myofiber cross‐sectional area and citrate synthase activity.ConclusionThese results indicate that daily exposure to HT for 8 weeks enhances muscle strength in humans. Local HT may be a practical therapeutic approach to improve muscle function in individuals with limited mobility and skeletal muscle weakness.Support or Funding InformationSupport: American College of Sports Medicine Research EndowmentThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Molecular stressors underlying exercise training‐induced improvements in K+ regulation during exercise and Na+,K+‐ATPase adaptation in human skeletal muscle

Despite substantial progress made towards a better understanding of the importance of skeletal muscle K+ regulation for human physical function and its association with several disease states (eg type-II diabetes and hypertension), the molecular basis underpinning adaptations in K+ regulation to various stimuli, including exercise training, remains inadequately explored in humans. In this review, the molecular mechanisms essential for enhancing skeletal muscle K+ regulation and its key determinants, including Na+ ,K+ -ATPase function and expression, by exercise training are examined. Special attention is paid to the following molecular stressors and signaling proteins: oxygenation, redox balance, hypoxia, reactive oxygen species, antioxidant function, Na+ ,K+ , and Ca2+ concentrations, anaerobic ATP turnover, AMPK, lactate, and mRNA expression. On this basis, an update on the effects of different types of exercise training on K+ regulation in humans is provided, focusing on recent discoveries about the muscle fibre-type-dependent regulation of Na+ ,K+ -ATPase-isoform expression. Furthermore, with special emphasis on blood-flow-restricted exercise as an exemplary model to modulate the key molecular mechanisms identified, it is discussed how training interventions may be designed to maximize improvements in K+ regulation in humans. The novel insights gained from this review may help us to better understand how exercise training and other strategies, such as pharmacological interventions, may be best designed to enhance K+ regulation and thus the physical function in humans.

Distinct patterns of skeletal muscle mitochondria fusion, fission and mitophagy upon duration of exercise training

Healthy ageing interventions encompass regular exercise to prevent mitochondrial dysfunction, key player in sarcopenia pathogenesis. Mitochondrial biogenesis has been well documented, but mitochondrial remodelling in response to exercise training is poorly understood. Here we investigated fusion, fission and mitophagy before and after an exercise intervention in older adults. Skeletal muscle biopsies were collected from 22 healthy sedentary men and women before and after 4months of supervised training. Eight lifelong trained age- and gender-matched volunteers served as positive controls. Transmission electron microscopy was used to estimate mitochondrial content. Western blotting and qRT-PCR were used to detect changes in specific proteins and transcripts. After intervention, mitochondrial content increased to levels of controls. While enhancement of fusion was prevalent after intervention, inhibition of fission and increased mitophagy were dominant in controls. Similarly to PARKIN, BCL2L13 content was higher in controls. The observed molecular adaptations paralleled long-term effects of training on physical fitness, exercise efficiency and oxidative capacity. This study describes distinct patterns of molecular adaptations in human skeletal muscle under chronic exercise training. After 16weeks of exercise, the pattern was dominated by fusion to increase mitochondrial content to the metabolic demands of exercise. In lifelong exercise, the pattern was dominated by mitophagy synchronized with increased fusion and decreased fission, indicating an increased mitochondrial turnover. In addition to these temporally distinct adaptive mechanisms, this study suggests for the first time a specific role of BCL2L13 in chronic exercise that requires constant maintenance of mitochondrial quality.

Effect of aerobic training on baseline expression of signaling and respiratory proteins in human skeletal muscle.

Most studies examining the molecular mechanisms underlying adaptation of human skeletal muscles to aerobic exercise focused on the response to acute exercise. Here, we examined the effect of a 2‐month aerobic training program on baseline parameters in human muscle. Ten untrained males performed a one‐legged knee extension exercise for 1 h with the same relative intensity before and after a 2‐month aerobic training program. Biopsy samples were taken from vastus lateralis muscle at rest before and after the 2 month training program (baseline samples). Additionally, biopsy samples were taken from the exercised leg 1 and 4 h after the one‐legged continuous knee extension exercise. Aerobic training decreases baseline phosphorylation of FOXO1Ser256, increases that of CaMKIIT hr286, CREB1Ser133, increases baseline expression of mitochondrial proteins in respiratory complexes I–V, and some regulators of mitochondrial biogenesis (TFAM, NR4A3, and CRTC2). An increase in the baseline content of these proteins was not associated with a change in baseline expression of their genes. The increase in the baseline content of regulators of mitochondrial biogenesis (TFAM and NR4A3) was associated with a transient increase in transcription after acute exercise. Contrariwise, the increase in the baseline content of respiratory proteins does not seem to be regulated at the transcriptional level; rather, it is associated with other mechanisms. Adaptation of human skeletal muscle to regular aerobic exercise is associated not only with transient molecular responses to exercise, but also with changes in baseline phosphorylation and expression of regulatory proteins.

Repeated exposure to heat stress induces mitochondrial adaptation in human skeletal muscle.

The heat stress response is associated with several beneficial adaptations that promote cell health and survival. Specifically, in vitro and animal investigations suggest that repeated exposures to a mild heat stress (~40°C) elicit positive mitochondrial adaptations in skeletal muscle comparable to those observed with exercise. To assess whether such adaptations translate to human skeletal muscle, we produced local, deep tissue heating of the vastus lateralis via pulsed shortwave diathermy in 20 men and women ( n = 10 men; n = 10 women). Diathermy increased muscle temperature by 3.9°C within 30 min of application. Immediately following a single 2-h heating session, we observed increased phosphorylation of AMP-activated protein kinase and ERK1/2 but not of p38 MAPK or JNK. Following repeated heat exposures (2 h daily for 6 consecutive days), we observed a significant cellular heat stress response, as heat shock protein 70 and 90 increased 45% and 38%, respectively. In addition, peroxisome proliferator-activated receptor gamma, coactivator-1 alpha and mitochondrial electron transport protein complexes I and V expression were increased after heating. These increases were accompanied by augmentation of maximal coupled and uncoupled respiratory capacity, measured via high-resolution respirometry. Our data provide the first evidence that mitochondrial adaptation can be elicited in human skeletal muscle in response to repeated exposures to mild heat stress. NEW & NOTEWORTHY Heat stress has been shown to elicit mitochondrial adaptations in cell culture and animal research. We used pulsed shortwave diathermy to produce deep tissue heating and explore whether beneficial mitochondrial adaptations would translate to human skeletal muscle in vivo. We report, for the first time, positive mitochondrial adaptations in human skeletal muscle following recurrent heat stress. The results of this study have clinical implications for many conditions characterized by diminished skeletal muscle mitochondrial function.

Protein Availability and Satellite Cell Dynamics in Skeletal Muscle.

Human skeletal muscle satellite cells are activated in response to both resistance and endurance exercise. It was initially proposed that satellite cell proliferation and differentiation were only required to support resistance exercise-induced hypertrophy. However, satellite cells may also play a role in muscle fibre remodelling after endurance-based exercise and extracellular matrix regulation. Given the importance of dietary protein, particularly branched chain amino acids, in supporting myofibrillar and mitochondrial adaptations to both resistance and endurance-based training, a greater understanding of how protein intake impacts satellite cell activity would provide further insight into the mechanisms governing skeletal muscle remodelling with exercise. While many studies have investigated the capacity for protein ingestion to increase post-exercise rates of muscle protein synthesis, few investigations have examined the role for protein ingestion to modulate satellite cell activity. Here we review the molecular mechanisms controlling the activation of satellite cells in response to mechanical stress and protein intake in both in vitro and in vivo models. We provide a mechanistic framework that describes how protein ingestion may enhance satellite activity and promote exercise adaptations in human skeletal muscle.

GeneXX: an online tool for the exploration of transcript changes in skeletal muscle associated with exercise.

Exercise stimulates a wide array of biological processes, but the mechanisms involved are incompletely understood. Many previous studies have adopted transcriptomic analyses of skeletal muscle to address particular research questions, a process that ultimately results in the collection of large amounts of publicly available data that has not been fully integrated or interrogated. To maximize the use of these available transcriptomic exercise data sets, we have downloaded and reanalyzed them and formulated the data into a searchable online tool, geneXX. GeneXX is highly intuitive and free and provides immediate information regarding the response of a transcript of interest to exercise in skeletal muscle. To demonstrate its utility, we carried out a meta-analysis on the included data sets and show transcript changes in skeletal muscle that persist regardless of sex, exercise mode, and duration, some of which have had minimal attention in the context of exercise. We also demonstrate how geneXX can be used to formulate novel hypotheses on the complex effects of exercise, using preliminary data already generated. This resource represents a valuable tool for researchers with interests in human skeletal muscle adaptation to exercise.

Greater Oxidative Capacity in Primary Myotubes from Endurance-trained Women.

Exercise training promotes skeletal muscle mitochondrial biogenesis and an increase in maximal oxygen consumption. Primary myotubes retain some metabolic properties observed in vivo but it is unknown whether this includes exercise-induced mitochondrial adaptations. The goal of this study was to test if primary myotubes from exercise-trained women have higher mitochondrial content and maximal oxygen consumption compared with untrained women. Six trained and nine untrained white women participated in this study. Muscle biopsies from the vastus lateralis muscle of the right leg were obtained and primary muscle cells were isolated. Maximal respiration rates, mitochondrial mRNA and protein content, and succinate dehydrogenase activity were measured in skeletal muscle and primary myotubes from trained and untrained women. Trained women, compared with untrained women, had higher maximal whole-body oxygen consumption (+18%, P = 0.03), in vivo maximal skeletal muscle oxidative capacity measured with near infrared spectroscopy (+48%, P < 0.01), and maximal oxygen consumption in permeabilized muscle fibers (+38%, P = 0.02), which coincided with higher protein levels of muscle mitochondrial enzymes. Primary myotubes from trained women had higher maximal oxygen consumption (+38%, P = 0.03), suggesting that some elements of exercise-induced metabolic programming persists ex vivo. Consistent with this idea, myotubes from trained women had higher mRNA levels of transcriptional regulators of mitochondrial biogenesis in addition to higher protein levels of mitochondrial enzymes. These data suggest the existence of an "exercise metabolic program," where primary myotubes isolated from exercise-trained individuals exhibit greater mitochondrial content and oxidative capacity compared with untrained individuals. These myotubes may be a useful model to study molecular mechanisms relevant to exercise adaptations in human skeletal muscle.

Cold-water immersion following sprint interval training does not alter endurance signaling pathways or training adaptations in human skeletal muscle.

We investigated the underlying molecular mechanisms by which postexercise cold-water immersion (CWI) may alter key markers of mitochondrial biogenesis following both a single session and 6 wk of sprint interval training (SIT). Nineteen men performed a single SIT session, followed by one of two 15-min recovery conditions: cold-water immersion (10°C) or a passive room temperature control (23°C). Sixteen of these participants also completed 6 wk of SIT, each session followed immediately by their designated recovery condition. Four muscle biopsies were obtained in total, three during the single SIT session (preexercise, postrecovery, and 3 h postrecovery) and one 48 h after the last SIT session. After a single SIT session, phosphorylated (p-)AMPK, p-p38 MAPK, p-p53, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA were all increased (P < 0.05). Postexercise CWI had no effect on these responses. Consistent with the lack of a response after a single session, regular postexercise CWI had no effect on PGC-1α or p53 protein content. Six weeks of SIT increased peak aerobic power, maximal oxygen consumption, maximal uncoupled respiration (complexes I and II), and 2-km time trial performance (P < 0.05). However, regular CWI had no effect on changes in these markers, consistent with the lack of response in the markers of mitochondrial biogenesis. Although these observations suggest that CWI is not detrimental to endurance adaptations following 6 wk of SIT, they question whether postexercise CWI is an effective strategy to promote mitochondrial biogenesis and improvements in endurance performance.

Roux-en-Y gastric bypass surgery enhances contraction-mediated glucose metabolism in primary human myotubes.

Contractile activity (e.g., exercise) evokes numerous metabolic adaptations in human skeletal muscle, including enhanced insulin action and substrate oxidation. However, there is intersubject variation in the physiological responses to exercise, which may be linked with factors such as the degree of obesity. Roux-en-Y gastric bypass (RYGB) surgery reduces body mass in severely obese (body mass index ≥ 40 kg/m2) individuals; however, it is uncertain whether RYGB can potentiate responses to contractile activity in this potentially exercise-resistant population. To examine possible interactions between RYGB and contractile activity, muscle biopsies were obtained from severely obese patients before and after RYGB, differentiated into myotubes, and electrically stimulated, after which changes in insulin action and glucose oxidation were determined. Before RYGB, myotubes were unresponsive to electrical stimulation, as indicated by no changes in insulin-stimulated glycogen synthesis and basal glucose oxidation. However, myotubes from the same patients at 1 mo after RYGB increased insulin-stimulated glycogen synthesis and basal glucose oxidation when subjected to contraction. While unresponsive before surgery, contraction improved insulin-stimulated phosphorylation of AS160 (Thr642, Ser704) after RYGB. These data suggest that RYGB surgery may enhance the ability of skeletal muscle from severely obese individuals to respond to contractile activity.

Decreased transcriptional corepressor p107 is associated with exercise-induced mitochondrial biogenesis in human skeletal muscle.

Increased mitochondrial content is a hallmark of exercise‐induced skeletal muscle remodeling. For this process, considerable evidence underscores the involvement of transcriptional coactivators in mediating mitochondrial biogenesis. However, our knowledge regarding the role of transcriptional corepressors is lacking. In this study, we assessed the association of the transcriptional corepressor Rb family proteins, Rb and p107, with endurance exercise‐induced mitochondrial adaptation in human skeletal muscle. We showed that p107, but not Rb, protein levels decrease by 3 weeks of high‐intensity interval training. This is associated with significant inverse association between p107 and exercise‐induced improved mitochondrial oxidative phosphorylation. Indeed, p107 showed significant reciprocal correlations with the protein contents of representative markers of mitochondrial electron transport chain complexes. These findings in human skeletal muscle suggest that attenuated transcriptional repression through p107 may be a novel mechanism by which exercise stimulates mitochondrial biogenesis following exercise.

Extracellular matrix remodeling and its contribution to protective adaptation following lengthening contractions in human muscle.

This study determined the contribution of extracellular matrix (ECM) remodeling to the protective adaptation of human skeletal muscle known as the repeated-bout effect (RBE). Muscle biopsies were obtained 3 hours, 2 days, and 27 days following an initial bout (B1) of lengthening contractions (LCs) and 2 days following a repeated bout (B2) in 2 separate studies. Biopsies from the nonexercised legs served as controls. In the first study, global transcriptomic analysis indicated widespread changes in ECM structural, deadhesive, and signaling transcripts, 3 hours following LC. To determine if ECM remodeling is involved in the RBE, we conducted a second study by use of a repeated-bout paradigm. TNC immunoreactivity increased 10.8-fold following B1, was attenuated following B2, and positively correlated with LC-induced strength loss (r(2) = 0.45; P = 0.009). Expression of collagen I, III, and IV (COL1A1, COL3A1, COL4A1) transcripts was unchanged early but increased 5.7 ± 2.5-, 3.2 ± 0.9-, and 2.1 ± 0.4-fold (P < 0.05), respectively, 27 days post-B1 and were unaffected by B2. Likewise, TGF-β signaling demonstrated a delayed response following LC. Satellite cell content increased 80% (P < 0.05) 2 days post-B1 (P < 0.05), remained elevated 27 days post-B1, and was unaffected by B2. Collectively, the data suggest sequential ECM remodeling characterized by early deadhesion and delayed reconstructive activity that appear to contribute to the RBE.

Carbohydrate availability and exercise training adaptation: Too much of a good thing?

Traditional nutritional approaches to endurance training have typically promoted high carbohydrate (CHO) availability before, during and after training sessions to ensure adequate muscle substrate to meet the demands of high daily training intensities and volumes. However, during the past decade, data from our laboratories and others have demonstrated that deliberately training in conditions of reduced CHO availability can promote training-induced adaptations of human skeletal muscle (i.e. increased maximal mitochondrial enzyme activities and/or mitochondrial content, increased rates of lipid oxidation and, in some instances, improved exercise capacity). Such data have led to the concept of ‘training low, but competing high’ whereby selected training sessions are completed in conditions of reduced CHO availability (so as to promote training adaptation), but CHO reserves are restored immediately prior to an important competition. The augmented training response observed with training-low strategies is likely regulated by enhanced activation of key cell signalling kinases (e.g. AMPK, p38MAPK), transcription factors (e.g. p53, PPARδ) and transcriptional co-activators (e.g. PGC-1α), such that a co-ordinated up-regulation of both the nuclear and mitochondrial genomes occurs. Although the optimal practical strategies to train low are not currently known, consuming additional caffeine, protein, and practising CHO mouth-rinsing before and/or during training may help to rescue the reduced training intensities that typically occur when ‘training low’, in addition to preventing protein breakdown and maintaining optimal immune function. Finally, athletes should practise ‘train-low’ workouts in conjunction with sessions undertaken with normal or high CHO availability so that their capacity to oxidise CHO is not blunted on race day.

Molecular adaptation of skeletal muscle to high‐intensity resistance exercise in aged males

Impaired contractile‐induced muscle growth may contribute to sarcopenia: the age‐associated loss of muscle mass and function that is manifested by loss of strength, contractile capacity and endurance. MicroRNAs (miRNAs) are novel posttranscriptional regulators that may play an important role in contractile‐induced adaptations in human skeletal muscle. We performed a study comparing global changes in gene expression using DNA microarrays and PCR arrays targeting 60 specific microRNAs (miRNA) that regulate skeletal muscle metabolism (myo‐miRs), in young (YNG, 22±0.06 yrs) and older (OLD, 74±1.5 yrs) males 6 hours (6H) after a single bout of high‐intensity resistance exercise (RE). We observed in OLD only 48 genes were altered 6H after RE while in YNG there were 201 genes altered by RE. There was no change in the expression of myo‐miRs in OLD after RE and in contrast the expression of myo‐miRs were generally decreased in YNG. These results reveal a significant decrease in the contractile capacity of aging skeletal muscle and may highlight a significant role of myo‐miRs in this decreased response.

The time course of the adaptations of human muscle proteome to bed rest and the underlying mechanisms

In order to get a comprehensive picture of the complex adaptations of human skeletal muscle to disuse and further the understanding of the underlying mechanisms, we participated in two bed rest campaigns, one lasting 35 days and one 24 days. In the first bed rest (BR) campaign, myofibrillar proteins, metabolic enzymes and antioxidant defence systems were found to be down-regulated both post-8 days and post-35 days BR by proteomic analysis of vastus lateralis muscle samples from nine subjects. Such profound alterations occurred early (post-8 days BR), before disuse atrophy developed, and persisted through BR (post-35 days BR). To understand the mechanisms underlying the protein adaptations observed, muscle biopsies from the second bed rest campaign (nine subjects) were used to evaluate the adaptations of master controllers of the balance between muscle protein breakdown and muscle protein synthesis (MuRF-1 and atrogin-1; Akt and p70S6K), of autophagy (Beclin-1, p62, LC3, bnip3, cathepsin-L), of expression of antioxidant defence systems (NRF2) and of energy metabolism (PGC-1α, SREBP-1, AMPK). The results indicate that: (i) redox imbalance and remodelling of muscle proteome occur early and persist through BR; (ii) impaired energy metabolism is an early and persistent phenomenon comprising both the oxidative and glycolytic one; (iii) although both major catabolic systems, ubiquitin proteasome and autophagy, could contribute to the progression of atrophy late into BR, a decreased protein synthesis cannot be ruled out; (iv) a decreased PGC-1α, with the concurrence of SREBP-1 up-regulation, is a likely trigger of metabolic impairment, whereas the AMPK pathway is unaltered.