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Sickle cell disease (SCD) patients display skeletal muscle hypotrophy, altered oxidative capacity, exercise intolerance and poor quality of life. We previously demonstrated that moderate-intensity endurance training is beneficial for improving muscle function and quality of life of patients. The present study evaluated the effects of this moderate-intensity endurance training program on skeletal muscle structural and metabolic properties. Of the 40 randomized SCD patients, complete data sets were obtained from 33. The training group (n = 15) followed a personalized moderate-intensity endurance training program, while the non-training (n = 18) group maintained a normal lifestyle. Biopsies of the vastus lateralis muscle and submaximal incremental cycling tests were performed before and after the training program. Endurance training increased type I muscle fiber surface area (P = .038), oxidative enzyme activity [citrate synthase, P

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) originated in China in late 2019 and has since spread rapidly to every continent in the world. This pandemic continues to cause widespread personal suffering, along with severe pressure on medical and health care providers. The symtoms of SARS‐CoV‐2 and the subsequent prognosis is worsened in individuals who have pre‐exisiting comorbidities prior to infection by the virus. Individuals with obesity/overweight, insulin resistance and diabetes typically have chronic low‐grade inflammation characterized by increased levels of several pro‐inflammatory cytokines and the inflammasome: this state predisposes to greater risk for infection along with more adverse outcomes. Here we consider whether a high level of cardiorespiratory fitness induced by prior exercise training may confer some innate immune‐protection against Covid‐19 by attenuating the “cytokine storm syndrome” often experienced by “at risk” individuals.

To improve muscle healing upon injury, it is of importance to understand the interplay of key signaling pathways during muscle regeneration. To study this, mice were injected with cardiotoxin (CTX) or PBS in the Tibialis Anterior muscle and were sacrificed 2, 5 and 12 days upon injection. The time points represent different phases of the regeneration process, i.e. destruction, repair and remodeling, respectively. Two days upon CTX-injection, p-mTORC1 signaling and stress markers such as BiP and p-ERK1/2 were upregulated. Phospho-ERK1/2 and p-mTORC1 peaked at d5, while BiP expression decreased towards PBS levels. Phospho-FOXO decreased 2 and 5 days following CTX-injection, indicative of an increase in catabolic signaling. Furthermore, CTX-injection induced a shift in the fiber type composition, characterized by an initial loss in type IIa fibers at d2 and at d5. At d5, new type IIb fibers appeared, whereas type IIa fibers were recovered at d12. To conclude, CTX-injection severely affected key modulators of muscle metabolism and histology. These data provide useful information for the development of strategies that aim to improve muscle molecular signaling and thereby recovery. ispartof: Journal Of Muscle Research And Cell Motility vol:41 issue:4 pages:375-387 ispartof: location:Netherlands status: published

The aim of this study was to examine the activation of skeletal muscle signaling pathways related to protein synthesis and the gene expression of regeneration/degradation markers following repeated bouts of eccentric cycling. Nine untrained men (25.4 ± 1.9 yr) performed two 30-min eccentric cycling bouts (ECC1, ECC2) at 85% of maximal concentric workload, separated by 2 wk. Muscle biopsies were taken from the vastus lateralis before and 2 h after each bout. Indirect markers of muscle damage were assessed before and 24–48 h after exercise. Changes in the Akt/mammalian target of rapamycin (mTOR)/rbosomal protein S6 kinase 1 (S6K1)/ribosomal protein S6 (rpS6) and MAPK signaling pathways were measured by Western blot and changes in mRNA expression of IL-6 and IL-1β, and myogenic regulatory factors (MRFs) were measured by real-time PCR. ECC1 induced greater increases in indirect markers of muscle damage compared with ECC2. Phosphorylation of S6K1 and rpS6 increased after both exercise bouts ( P < 0.05), whereas phosphorylation of mTOR increased after ECC2 only ( P = 0.03). Atrogin-1 mRNA expression decreased after ECC1 and ECC2 ( P < 0.05) without changes in muscle RING-finger protein-1 mRNA. Basal mRNA levels of myoblast determination protein-1 (MyoD), MRF4, and myogenin were higher 2 wk after ECC1 ( P < 0.05). MRF4 mRNA increased after ECC1 and ECC2 ( P < 0.05), whereas MyoD mRNA expression increased only after ECC1 ( P = 0.03). Phosphorylation of JNK and p38 MAPK increased after both exercise bouts ( P < 0.05), similar to IL-6 and IL-1β mRNA expression. All together, these results suggest that differential regulation of the mTOR pathway and MRF expression could mediate the repeated bout effect observed between an initial and secondary bout of eccentric exercise.

Acute hypoxia has previously been suggested to potentiate resistance training-induced hypertrophy by activating satellite cell-dependent myogenesis rather than an improvement in protein balance in human. Here, we tested this hypothesis after a 4-week hypoxic vs normoxic resistance training protocol. For that purpose, 19 physically active male subjects were recruited to perform 6 sets of 10 repetitions of a one-leg knee extension exercise at 80% 1-RM 3 times/week for 4 weeks in normoxia (FiO2 : 0.21; n = 9) or in hypoxia (FiO2 : 0.135, n = 10). Blood and skeletal muscle samples were taken before and after the training period. Muscle fractional protein synthetic rate was measured over the whole period by deuterium incorporation into the protein pool and muscle thickness by ultrasound. At the end of the training protocol, the strength gain was higher in the hypoxic vs the normoxic group despite no changes in muscle thickness and in the fractional protein synthetic rate. Only early myogenesis, as assessed by higher MyoD and Myf5 mRNA levels, appeared to be enhanced by hypoxia compared to normoxia. No effects were found on myosin heavy chain expression, markers of oxidative metabolism and lactate transport in the skeletal muscle. Though the present study failed to unravel clearly the mechanisms by which hypoxic resistance training is particularly potent to increase muscle strength, it is important message to keep in mind that this training strategy could be effective for all athletes looking at developing and optimizing their maximal muscle strength.

Over the last three decades, the combination of a sedentary lifestyle and excessive food intake has led to a significant increase in the prevalence of obesity. The latter favors a chronic low-grade inflammatory state and an over-activation of the innate immune system, which contribute to insulin resistance and type 2 diabetes. Physical exercise is a powerful preventive tool and treatment for several diseases as it induces metabolic and immune effects that provide health benefits. Exercise is known to reduce inflammation; however, the underlying mechanisms responsible are not fully elucidated. One proposed mechanism is a reduced expression and/or activation of pro-inflammatory toll-like receptors (TLRs) on innate immune cells after exercise, which could contribute to the protective effect of exercise against insulin resistance and the prevention of the development of metabolic diseases. The aim of the present study is therefore to review the current evidence about the anti-inflammatory effects of exercise and toll-like receptors regulation on immune cells in humans.Key PointsObesity leads to a low-grade chronic inflammatory state and an over-activation of the innate immune system that is directly involved in the develop metabolic syndrome.The anti-inflammatory effect of exercise has been previously suggested through the reduction of the expression and/or activation of pro-inflammatory toll-like receptors (TLRs) in innate immune cells, which represent one of the main inflammatory responses triggered by obesityThe underlying mechanisms in which toll-like receptors expression modulate the reduction of chronic inflammation are not fully elucidated.

This study aimed to investigate the mechanisms known to regulate glucose homeostasis in human skeletal muscle of healthy and prediabetic subjects exercising in normobaric hypoxia. Seventeen healthy (H; 28.8 ± 2.4 yr; maximal oxygen consumption (V̇O): 45.1 ± 1.8 mL·kg·min) and 15 prediabetic (P; 44.6 ± 3.9 yr; V̇O: 30.8 ± 2.5 mL·kg·min) men were randomly assigned to two groups performing an acute exercise bout (heart rate corresponding to 55% V̇O) either in normoxic (NE) or in hypoxic (HE; fraction of inspired oxygen [Formula: see text] 14.0%) conditions. An oral glucose tolerance test (OGTT) was performed in a basal state and after an acute exercise bout. Muscle biopsies from m. vastus lateralis were taken before and after exercise. Venous blood samples were taken at regular intervals before, during, and after exercise. The two groups exercising in hypoxia had a larger area under the curve of blood glucose levels during the OGTT after exercise compared with baseline (H: +11%; P: +4%). Compared with pre-exercise, an increase in p-TBC1D1 Ser237 and in p-AMPK Thr172 was observed postexercise in P NE (+95%; +55%, respectively) and H HE (+91%; +43%, respectively). An increase in p-ACC Ser212 was measured after exercise in all groups (H NE: +228%; P NE: +252%; H HE: +252%; P HE: +208%). Our results show that an acute bout of exercise in hypoxia reduces glucose tolerance in healthy and prediabetic subjects. At a molecular level, some adaptations regulating glucose transport in muscle were found in all groups without associations with glucose tolerance after exercise. The results suggest that hypoxia negatively affects glucose tolerance postexercise through unidentified mechanisms. The molecular mechanisms involved in glucose tolerance after acute exercise in hypoxia have not yet been elucidated in human. Due to the reversible character of their status, prediabetic individuals are of particular interest for preventing the development of type 2 diabetes. The present study is the first to investigate muscle molecular mechanisms during exercise and glucose metabolism after exercise in prediabetic and healthy subjects exercising in normoxia and normobaric hypoxia.

To investigate in vivo the adaptations of satellite cell induced by exercise performed in acute or chronic hypoxic conditions and their contribution to muscle remodeling and hypertrophy. Search terms related to exercise, hypoxia and satellite cells were entered on Embase, PubMed and Scopus. Studies were selected for their relevance in terms of regulation of satellite cells by in vivo exercise and muscle contraction in hypoxic conditions. Satellite cell activation and proliferation seem to be enabled after acute hypoxic exercise via regulations induced by myogenic regulatory factors. Several studies reported also a role of the inflammatory pathway nuclear factor-kappa B and angiogenic factors such as vascular endothelial growth factor, both known to upregulate myogenesis. By stimulating angiogenesis, repeated exercise performed in acute hypoxia might contribute to satellite cell activation. Contrary to such exercise conditions, chronic exposure to hypoxia downregulates myogenesis despite the maintenance of physical activity. This impaired myogenesis might be induced by excessive oxidative stress and proteolysis. In vivo studies suggest that, in comparison to exercise or hypoxia alone, exercise performed in a hypoxic environment, may improve or impair muscle remodeling induced by contractile activity depending upon the duration of hypoxia. Satellite cells seem to be major actors in these dichotomous adaptations. Further research on the role of angiogenesis, types of contraction and autophagy is needed for a better understanding of their respective role in hypoxic exercise-induced modulations of satellite cell activity in human.

Simple Summary Muscle wasting during cancer is recognized as an independent predictor of mortality. The aim of this study was to characterize the changes in the muscle secretome associated with cancer cachexia to gain a better understanding of the mechanisms involved and to identify secreted proteins which may reflect this wasting process. Our study demonstrated that skeletal muscle is a source of several acute phase reactants during cancer cachexia that may hold the key to a cachexia-specific signature. Future work will have to determine whether some of these acute phase reactants contribute to and/or reflect the muscle atrophy caused by cancer, therefore representing potential therapeutic targets and/or biomarkers of cancer cachexia. Abstract Loss of skeletal muscle mass in cancer cachexia is recognized as a predictor of mortality. This study aimed to characterize the changes in the muscle secretome associated with cancer cachexia to gain a better understanding of the mechanisms involved and to identify secreted proteins which may reflect this wasting process. The changes in the muscle proteome of the C26 model were investigated by label-free proteomic analysis followed by a bioinformatic analysis in order to identify potentially secreted proteins. Multiple reaction monitoring and Western blotting were used to verify the presence of candidate proteins in the circulation. Our results revealed a marked increased muscular production of several acute phase reactants (APR: Haptoglobin, Serine protease inhibitor A3N, Complement C3, Serum amyloid A-1 protein) which are released in the circulation during C26 cancer cachexia. This was confirmed in other models of cancer cachexia as well as in cancer patients. Glucocorticoids and proinflammatory cytokines are responsible for an increased production of APR by muscle cells. Finally, their muscular expressions are strongly positively correlated with body weight loss as well as the muscular induction of atrogens. Our study demonstrates therefore a marked increased production of APR by the muscle in cancer cachexia.

This study identified the changes in hypertrophy/atrophy and mitochondrial-related signaling in human skeletal muscle following whole-body (WB) and localized single leg (SL) heat treatment. Nine active male participants were administered either 60 min of passive WB (44–50°C, 50% humidity) or SL (water-perfused suit at 49.5 ± 1.4°C) heat treatment at least 1 week apart in a counterbalanced order. The untreated leg during SL was considered as control (CON). Core, skin, and quadriceps muscle temperature were monitored throughout the experimental trials. Muscle microbiopsy samples were obtained prior to (PRE), and 30 min and 3 h post (POST) following heat treatment. Muscle temperature increased with time (p < 0.0001) in both WB and SL, with no differences between conditions (38.8 ± 0.5°C vs. 38.1 ± 0.6°C, p = 0.065). Core temperature increased only following WB, and was significantly higher compared with SL (39.1 ± 0.3°C vs. 37.1 ± 0.1, p < 0.0001). Compared with PRE, WB up-regulated the phosphorylation status of the majority of the Akt/mTOR pathway (Akt, mTOR, S6K1, rpS6, and p-eIF4E; p ≤ 0.050), with the exception of 4EBP1 (p = 0.139). WB also increased the mRNA of HSPs 72, 90, and 25 (all p < 0.021), and increased or tended to increase the phosphorylation of FOXO1 (p = 0.066) and FOXO3a (p = 0.038). In addition, most (NRF1, NRF2, COX2, and COX4-I2; all p ≤ 0.050), but not all (CS, Cyt c, and COX4-I1; p > 0.441) mRNA content indicative of mitochondrial biogenesis were increased following WB, with no changes evident in these parameters in SL or CON (all p > 0.090). These results indicate that 1 h of WB heat treatment enhanced anabolic (Akt/mTOR), mitochondrial, and cyto-protective signaling (HSP), with a concomitant possible inhibition of FOXO transcription factors.

BACKGROUND: A light but regular combined training program is sufficient to improve health in obese adolescents. Hypoxia is known to potentiate the effects of a high intensity period of combined training on exercise performance and glucose metabolism in this population. Here, we tested the effects of a less intensive hypoxic combined training program on exercise performance and health-related markers in obese adolescents. METHODS: Fourteen adolescents volunteered to participate to a 30-week combined training protocol whether in normoxia (FiO2 21%, NE, N.=7) or in hypoxia (FiO2 15%, HE, N.=7). Once a week, adolescents exercised for 50-60min including 12min on a cycloergometer and strength training of the abdominal, quadriceps and biceps muscles. RESULTS: Combined training reduced body mass (NE: -12%; HE: -8%), mainly due to a loss in fat mass (NE: -26%; HE: -15%), similarly in both the hypoxic and normoxic groups. After training, maximal O2 consumption (VO2max) (NE: +30%; HE: +25%,), maximal aerobic power (MAP) (NE: +20%; HE: +36%), work capacity and one-repetition maximum (1RM) for the quadriceps (NE: +26%; HE: +12%), abdominal (NE: +48%; HE: +36%) and biceps muscles (NE: +26%; HE: +16%) were increased similarly in both groups but insulin sensitivity markers were not modified. CONCLUSIONS: Except for insulin sensitivity, 1h a week of combined training for 30 weeks improved morphological and health-related markers as well as exercise performance in obese adolescents in both normoxic and hypoxic conditions. This is of particular importance for motivating those adolescents, who often are reluctant to exercise. Even a low dose of exercise per week can induce positive health outcomes.

Muscle regeneration is regulated through interaction between muscle and immune cells. Studies showed that treatment with supra-physiological doses of Non-Steroidal Anti-Inflammatory Drug (NSAID) abolished inflammatory signaling and impaired muscle recovery. The present study examines the effects of pharmacologically-relevant NSAID treatment on muscle regeneration. C57BL/6 mice were injected in the tibialis anterior (TA) with either PBS or cardiotoxin (CTX). CTX-injected mice received ibuprofen (CTX-IBU) or were untreated (CTX-PLAC). After 2 days, Il-1beta and Il-6 expression was upregulated in the TA of CTX-IBU and CTX-PL vs. PBS. However, Cox-2 expression and macrophage infiltration were higher in CTX-PL vs. PBS, but not in CTX-IBU. At the same time, anabolic markers were higher in CTX-IBU vs. PBS, but not in CTX-PL. Nevertheless, ibuprofen did not affect muscle mass or muscle fiber regeneration. In conclusion, mild ibuprofen doses did not worsen muscle regeneration. There were even signs of a transient improvement in anabolic signaling and attenuation of inflammatory signaling. ispartof: Physiological Research vol:69 issue:5 pages:847-859 ispartof: location:Czech Republic status: published

Acute environmental hypoxia may potentiate muscle hypertrophy in response to resistance training but the mechanisms are still unknown. To this end, twenty subjects performed a 1-leg knee extension session (8 sets of 8 repetitions at 80% 1 repetition maximum, 2-min rest between sets) in normoxic or normobaric hypoxic conditions (FiO2 14%). Muscle biopsies were taken 15 min and 4 hours after exercise in the vastus lateralis of the exercised and the non-exercised legs. Blood samples were taken immediately, 2h and 4h after exercise. In vivo, hypoxic exercise fostered acute inflammation mediated by the TNFα/NF-κB/IL-6/STAT3 (+333%, +194%, + 163% and +50% respectively) pathway, which has been shown to contribute to satellite cells myogenesis. Inflammation activation was followed by skeletal muscle invasion by CD68 (+63%) and CD197 (+152%) positive immune cells, both known to regulate muscle regeneration. The role of hypoxia-induced activation of inflammation in myogenesis was confirmed in vitro. Acute hypoxia promoted myogenesis through increased Myf5 (+300%), MyoD (+88%), myogenin (+1816%) and MRF4 (+489%) mRNA levels in primary myotubes and this response was blunted by siRNA targeting STAT3. In conclusion, our results suggest that hypoxia could improve muscle hypertrophic response following resistance exercise through IL-6/STAT3-dependent myogenesis and immune cells-dependent muscle regeneration.

Skeletal muscle mass is critical for sport performance and in many pathological conditions. The combination of protein intake and resistance exercise is the most efficient strategy to promote skeletal muscle hypertrophy and remodeling. However, to be really efficient, certain conditions need to be considered. The amount, type and source of proteins do all matter as well as the timing of ingestion and spreading over the whole day. Optimizing those conditions favor a positive net protein balance, which in the long term, may result in muscle mass accretion. Last but not least, it is also essential to take the nutritional status and the exercise training load into consideration when looking for maintenance or gain of skeletal muscle mass.

Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types including pancreas cancer. We have previously reported that myoferlin controls mitochondrial structure and function, and demonstrated that myoferlin depletion disturbs the mitochondrial dynamics culminating in a mitochondrial fission. In order to unravel the mechanism underlying this observation, we explored the myoferlin localization in pancreatic cancer cells and showed a colocalization with the mitochondrial dynamic machinery element: mitofusin. This colocalization was confirmed in several pancreas cancer cell lines and in normal cell lines as well. Moreover, in pancreas cancer cell lines, it appeared that myoferlin interacted with mitofusin. These discoveries open-up new research avenues aiming at modulating mitofusin function in pancreas cancer.

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.

Purpose This study aimed to test whether environmental hypoxia could potentiate the effects of exercise training on glucose metabolism and insulin sensitivity. Methods Fourteen adolescents with obesity were assigned to 6 wk of exercise training either in normoxic or in hypoxic conditions (FiO2 15%). Adolescents trained three times per week for 50-60 min, including endurance and resistance exercises. Oral glucose tolerance test, blood and morphological analyses, and physical performance tests were performed before and after the training period. Results After training, hypoxia, but not normoxia, decreased the area under the curve of plasma insulin (-49%; P = 0.001) and glucose levels (-14%; P = 0.005) during oral glucose tolerance test. Decreased plasma triglycerides levels (P = 0.03) and increased maximal aerobic power (P = 0.002), work capacity at 160 bpm (P = 0.002), and carbohydrate consumption during exercise (P = 0.03) were measured only in the hypoxic group. Conclusions Hypoxic exercise training was particularly efficient at improving glucose tolerance and insulin response to a glucose challenge in adolescents with obesity. These results suggest that exercise training in hypoxia could be an interesting strategy against insulin resistance and type 2 diabetes development in adolescents with obesity.

The aim of the study was to determine the effect of α-actinin-3 (ACTN3) deficiency (XX) on muscle damage induced by an eccentric exercise bout. In this purpose, 4 RR and 4 XX individuals performed an intensive eccentric knee flexion exercise on an isokinetic dynamometer. Muscle biopsies, blood and pain scores were taken before and after the exercise to determine the extent of the exercise-induced damage and the effect of the ACTN3 R577X polymorphism. Maximal isometric strength of the quadriceps and single fibre properties were compared before and after the exercise. The drop in maximal isometric strength of the quadriceps at 45° knee flexion following the eccentric exercise bout was on average 37% 24 h post-exercise. The decrease in force was also apparent in isolated type IIa fibres (8%; P = 0.02), but not in type I fibres (P = 0.88). Creatine kinase and myoglobin plasma levels increased in all participants at least by 55% and 87%, respectively (P

Supplemental Digital Content is available in the text., Objectives: As the catabolic state induced by septic shock together with the physical inactivity of patients lead to the rapid loss of muscle mass and impaired function, the purpose of this study was to test whether an early physical therapy during the onset of septic shock regulates catabolic signals and preserves skeletal muscle mass. Design: Randomized controlled trial. Setting: Tertiary mixed ICU. Patients: Adult patients admitted for septic shock within the first 72 hours. Interventions: Patients were assigned randomly into two groups. The control group benefited from manual mobilization once a day. The intervention group had twice daily sessions of both manual mobilization and 30-minute passive/active cycling therapy. Measurements and Main Results: Skeletal muscle biopsies and electrophysiology testing were performed at day 1 and day 7. Muscle biopsies were analyzed for histology and molecular components of signaling pathways regulating protein synthesis and degradation as well as inflammation markers. Hemodynamic values and patient perception were collected during each session. Twenty-one patients were included. Three died before the second muscle biopsy. Ten patients in the control and eight in the intervention group were analyzed. Markers of the catabolic ubiquitin-proteasome pathway, muscle atrophy F-box and muscle ring finger-1 messenger RNA, were reduced at day 7 only in the intervention group, but without difference between groups (muscle atrophy F-box: –7.3% ± 138.4% in control vs –56.4% ± 37.4% in intervention group; p = 0.23 and muscle ring finger-1: –30.8% ± 66.9% in control vs –62.7% ± 45.5% in intervention group; p = 0.15). Muscle fiber cross-sectional area (µm2) was preserved by exercise (–25.8% ± 21.6% in control vs 12.4% ± 22.5% in intervention group; p = 0.005). Molecular regulations suggest that the excessive activation of autophagy due to septic shock was lower in the intervention group, without being suppressed. Markers of anabolism and inflammation were not modified by the intervention, which was well tolerated by the patients. Conclusions: Early physical therapy during the first week of septic shock is safe and preserves muscle fiber cross-sectional area.

In this study, we investigate adaptations in muscle oxidative capacity, fiber size and oxygen supply capacity in team-sport athletes after six repeated-sprint sessions in normobaric hypoxia or normoxia combined with 14 days of chronic normobaric hypoxic exposure. Lowland elite field hockey players resided at simulated altitude (≥14 h/day at 2,800–3,000 m) and performed regular training plus six repeated-sprint sessions in normobaric hypoxia (3,000 m; LHTLH; n = 6) or normoxia (0 m; LHTL; n = 6) or lived at sea level with regular training only (LLTL; n = 6). Muscle biopsies were obtained from the m. vastus lateralis before (pre), immediately after (post-1), and 3 wk after the intervention (post-2). Changes over time between groups were compared, including likelihood of the effect size (ES). Succinate dehydrogenase activity in LHTLH largely increased from pre to post-1 (~35%), likely more than LHTL and LLTL (ESs = large-very large), and remained elevated in LHTLH at post-2 (~12%) vs. LHTL (ESs = moderate-large). Fiber cross-sectional area remained fairly similar in LHTLH from pre to post-1 and post-2 but was increased at post-1 and post-2 in LHTL and LLTL (ES = moderate-large). A unique observation was that LHTLH and LHTL, but not LLTL, improved their combination of fiber size and oxidative capacity. Small-to-moderate differences in oxygen supply capacity (i.e., myoglobin and capillarization) were observed between groups. In conclusion, elite team-sport athletes substantially increased their skeletal muscle oxidative capacity, while maintaining fiber size, after only 14 days of chronic hypoxic residence combined with six repeated-sprint training sessions in hypoxia. NEW & NOTEWORTHY Our novel findings show that elite team-sport athletes were able to substantially increase the skeletal muscle oxidative capacity in type I and II fibers (+37 and +32%, respectively), while maintaining fiber size after only 14 days of chronic hypoxic residence combined with six repeated-sprint sessions in hypoxia. This increase in oxidative capacity was superior to groups performing chronic hypoxic residence with repeated sprints in normoxia and residence at sea level with regular training only.

To examine the effects of a moderate dose of caffeine in elite male volleyball players on countermovement-jump (CMJ) performance, as well as temporal concentric- and eccentric-phase effects.Ten elite male volleyball players took part in 2 experimental days via a randomized crossover trial 1 wk apart in which they ingested either 5 mg/kg of caffeine or a placebo in double-blind fashion. Heart rate and blood pressure were measured at rest and 60 min postingestion. Afterward, subjects also performed 3 CMJ trials 60 min postingestion, of which the average was used for further analysis. They filled out a questionnaire on possible side effects 24 h posttrial.Caffeine intake, compared with placebo, increased CMJ peak concentric force (6.5% ± 6.4%; P = .01), peak power (16.2% ± 8.3%; P .01), flight time (5.3% ± 3.4%; P .01), velocity at peak power (10.6% ± 8.0%; P .01), peak displacement (10.8% ± 6.5%; P .01), peak velocity (12.6% ± 7.4%; P .01), peak acceleration (13.5% ± 8.5%; P .01), and the force developed at peak power (6.0% ± 4.0%; P .01) and reduced the time between peak power and peak force (16.7% ± 21.6%, P = .04). Caffeine increased diastolic blood pressure by 13.0% ± 8.9% (P .05), whereas no adverse side effects were found.The ingestion of 5 mg/kg of anhydrous caffeine improves overall CMJ performance without inducing side effects.

Both oxidative stress and telomere transcription are up-regulated by acute endurance exercise in human skeletal muscle. Whether and how life-long exercise training influences the antioxidant system response at transcriptional level and TERRA expression is unknown, especially during aging. Response to acute endurance exercise was investigated in muscle biopsies of 3 male subjects after 45 min of cycling. MCP-1 and SOD1 mRNA levels increased up to, 15-fold and 63%, respectively, after the cycling session while the mRNA levels of SOD2 were downregulated by 25%. The effects of chronic endurance exercise and aging were tested in the blood and muscle of 34 male subjects divided into four groups: young (YU) or old (OU) untrained, young (YT) or old (OT) trained cyclists. Long-term endurance training limited the age-dependent elevation in SOD1 (OT vs OU, −26%, P = 0.03) and the decline in SOD2 mRNA levels (OU vs YU, −41%, P = 0.04). A high endurance training status alleviated the age-related increase in the aging biological marker MCP-1 in plasma (OU vs YU, +48%, P = 0.005). Similar results were observed for telomeric transcription as the age-associated increase in 16p TERRA levels (OU vs YU, +39%, P = 0.001) was counteracted by a high endurance training status (OT vs OU, −63%, P = 0.0005). In conclusion, as MCP-1, we propose that the age-related TERRA accumulation might represent a novel biological marker of aging. Those aging-related increase expression might be alleviated by a high endurance training status. Whether those biological markers of aging are linked to an elevation of oxidative stress is still an open question. Therefore, whether the positive adaptations provided by endurance training indeed reduce oxidative stress, including at telomeres, and whether TERRA plays any role in this, need to be further investigated.

Activating transcription factor (ATF) 3 regulates chemokine expression in various cell types and tissues. Herein, we studied this regulation in contracting muscle cells in vitro , and in skeletal muscle after muscle-damaging exercise in vivo . C 2 C 12 myotubes with normal or low ATF3 levels (atf3_siRNA) were electrically stimulated (EPS). Also, ATF3-knockout (ATF3-KO) and control mice ran downhill until exhaustion, and muscles were analyzed post-exercise. EPS increased ATF3 levels in myotubes ( P ccl ) 2 mRNA increased post-EPS, but atf3_siRNA attenuated the response ( P ccl6 basal mRNA, and down-regulated ccl9 and chemokine C-X-C motif ligand ( cxcl ) 1 basal mRNAs. Post-exercise, ATF3-KO mice showed exacerbated mRNA levels of ccl6 and ccl9 in soleus ( P ccl2 and interleukin ( il ) 1β ( P il6 mRNA level increased only in ATF3-KO ( P cxcl1 mRNA showed a similar trend ( P = 0.082). Cluster of differentiation-68 ( cd68 ) mRNA, a macrophage marker, increased in quadriceps and soleus independently of genotype ( P in vitro and skeletal muscle in vivo , but the regulation differs in each model. Cells other than myofibers may thus participate in the response observed in skeletal muscle. Our results also indicate that ATF3-independent mechanisms would regulate macrophage infiltration upon muscle-damaging exercise. The implications of chemokine regulation in skeletal muscle remain to be determined.

This study aimed to determine whether fission and mitophagy are activated by acute endurance exercise in human skeletal muscle and to investigate if this activation is dependent upon the nutritional state. Trained athletes (n = 7) cycled for 2 h at 70% V˙O2peak in a fed or fasted state. Vastus lateralis muscle biopsies were obtained at baseline, before, immediately after, and 1 h after exercise. Protein and mRNA markers for mitophagy, mitochondrial biogenesis, fission, and fusion were analyzed using quantitative real-time polymerase chain reaction and Western blot. Fission, assessed by phospho-DRP1 in the mitochondrial fraction, increased postexercise and 1 h postexercise only in the fed state. LC3bII and p62/SQSTM1 in the mitochondrial fraction were unchanged, whereas the LC3bII/LC3bI ratio was decreased only postexercise in the fasted state (P = 0.019), indicating a reduced mitophagy. Genes implicated in fission and mitophagy, such as Drp1, Bnip3, and Bnip3L, and proteins involved in fission (Fis1) or mitophagy (BNIP3) were all more expressed after exercise in the fed state (P < 0.05). As expected, the mRNA levels of PGC1α, Tfam, and Hsp60, all markers of mitogenesis, were increased after endurance exercise, but to a larger extent in the fed than that in the fasted state. The present study provides the very first evidence that mitophagy is not activated during and early after high-intensity endurance exercise in human, whatever the nutritional state, despite a selective activation of fission in the fed state. However, when nutrient availability is optimal, muscle cells seem capable of preparing mitochondria for lysosomal degradation. Thus, we may not exclude an activation of mitophagy at a later stage after exercise.

As the world demographic structure is getting older, highlighting strategies to counteract age-related diseases is a major public health concern. Telomeres are nucleoprotein structures that serve as guardians of genome stability by ensuring protection against both cell death and senescence. A hallmark of biological aging, telomere health is determined throughout the lifespan by a combination of both genetic and non-genetic influences. This review summarizes data from recently published studies looking at the effect of lifestyle variables such as nutrition and physical activity on telomere dynamics.

BACKGROUND Blood is a life-saving product for many people worldwide. Voluntary blood donation serves the demand for blood but there are concerns among potential donors about the impact of blood loss on exercise performance. This systematic review aimed to collect the best available evidence of the effect of a standard whole blood donation on aerobic exercise performance. STUDY DESIGN AND METHODS Studies from six databases dealing with a standard whole blood donation (400-500 mL) followed by (sub)maximal exercise were retained. The outcomes included exercise-related blood variables (hemoglobin [Hb] concentration, hematocrit, and red blood cell count) and endurance exercise variables ((sub)maximal oxygen uptake, peak work rate, and time to exhaustion). Overall effects at different time points postdonation were investigated by performing meta-analyses and calculating mean differences (and 95% confidence intervals). The GRADE methodology (Grades of Recommendation, Assessment, Development, and Evaluation) was used to assess the quality of evidence. RESULTS We identified 6237 references and finally included 18 before–after studies of low quality. Twenty-four to 48 hours after a blood donation, 1) Hb concentration was reduced (7% decrease) until 14 days after the blood donation (4% decrease), 2) maximal oxygen uptake (VO2max) was lower (7% decrease), and 3) a reduction in maximal exercise capacity (10% decrease) was present. CONCLUSION The best available evidence indicates that a standard whole blood donation (400-500 mL) leads to small but potentially physiologically important reductions in Hb levels, VO2max, and maximal exercise capacity in the first 2 days after the blood donation.

The purpose of this article is to collect the most recent data regarding the safety of well-known or emerging dietary supplements used by athletes.From January 2014 to April 2016, about 30 articles have been published in the field. New data show that 90% of sports supplements contain trace of estrogenic endocrine disruptors, with 25% of them having a higher estrogenic activity than acceptable. About 50% of the supplements are contaminated by melamine, a source of nonprotein nitrogen. Additional data accumulate toward the safety of nitrate ingestion. In the last 2 years, the safety of emerging supplements such as higenamine, potentially interesting to lose weight, creatine nitrate and guanidinoacetic acid has been evaluated but still needs further investigation.The consumption of over-the-counter supplements is very popular in athletes. Although most supplements may be considered as safe when taking at the recommended doses, athletes should be aware of the potential risks linked to the consumption of supplements. In addition to the risks linked to overdosage and cross-effects when combining different supplements at the same time, inadvertent or deliberate contamination with stimulants, estrogenic compounds, diuretics or anabolic agents may occur.

Anabolic resistance reflects the inability of skeletal muscle to maintain protein mass by appropriate stimulation of protein synthesis. We hypothesized that endoplasmic reticulum (ER) stress contributes to anabolic resistance in skeletal muscle with aging. Muscles were isolated from adult (8 mo) and old (26 mo) mice and weighed. ER stress markers in each muscle were quantified, and the anabolic response to leucine was assessed by measuring the phosphorylation state of S6K1 in soleus and EDL using an ex vivo muscle model. Aging reduced the muscle-to-body weight ratio in soleus, gastrocnemius, and plantaris, but not in EDL and tibialis anterior. Compared to adult mice, the expression of ER stress markers BiP and IRE1α was higher in EDL, and phospho-eIF2α was higher in soleus and EDL of old mice. S6K1 response to leucine was impaired in soleus, but not in EDL, suggesting that anabolic resistance contributes to soleus weight loss in old mice. Pre-incubation with ER stress inducer tunicamycin before leucine stimulation increased S6K1 phosphorylation beyond the level reached by leucine alone. Since tunicamycin did not impair leucine-induced S6K1 response, and based on the different ER stress marker regulation patterns, ER stress is probably not involved in anabolic resistance in skeletal muscle with aging. ispartof: Biochemical and Biophysical Research Communications vol:468 issue:4 pages:702-707 ispartof: location:United States status: published

Objective Hypoxia is a state of lowered oxygen tension in tissue that can be created by environmental or pathological conditions. Whatever the origin of hypoxia, different tissues will adapt acutely and/or chronically to deal with this reduction in oxygen availability. Hypoxia has recently emerged as a particularly efficient stimulus to stimulate muscle cell proliferation and accretion of muscle mass and hypoxic resistance training has become popular amongst athletes as it is thought to favor muscle accretion. However, the molecular mechanisms are largely unknown. Methods To determine those molecular mechanisms, 19 volunteers participated to 12 sessions of resistance training spread over 4 weeks whether in normoxia (n=9) or in hypoxia (n=10, FiO213.5% corresponding to 3500m altitude). Each session consisted in 6 sets of 10 repetitions of a one-leg extension exercise at 80% of one repetition maximum (1-RM). Blood and muscle samples in each leg were taken before and after the 4-week training period. Fiber types were determined by immunohistochemistry based on myosin heavy chain isotypes. Blood saturation (SpO2, pulsoximetry) and tissue saturation index (TSI, near-infrared spectroscopy) were monitored during the exercise sessions. Results Muscle thickness determined by ultrasound was increased by 7% in normoxia only (p=0.04). The 1-RM was increased in both groups but the increase was higher in hypoxia (+34%) than in normoxia (+24%) (p=0.02). In average, SpO2stayed around 98-99% in normoxia and around 93-94% in hypoxia during each set of contractions. No difference in TSI between normoxia and hypoxia was measured, which averaged 60% before starting muscle contractions and 40% during muscle contractions. A trend towards a shift in fiber type from type I to type IIa was observed in normoxia (p

During the course of life, muscle mass undergoes many changes in terms of quantity and quality. Skeletal muscle is a dynamic tissue able to hypertrophy or atrophy according to growth, ageing, physical activity, nutrition and health state. The purpose of the present review is to present the mechanisms by which exercise can induce changes in human skeletal muscle mass by modulating protein balance and regulating the fate of satellite cells. Exercise is known to exert transcriptional, translational and post-translational regulations as well as to induce epigenetic modifications and to control messenger RNA stability, which all contribute to the regulation of protein synthesis. Exercise also regulates the autophagy-lysosomal and the ubiquitin-proteasome pathways, the two main proteolytic systems in skeletal muscle, indicating that exercise participates to the regulation of the quality control mechanisms of cellular components and, therefore, to muscle health. Finally, activation, proliferation and differentiation of satellite cells can be enhanced by exercise to induce muscle remodelling and hypertrophy. Each of these mechanisms can potentially impact skeletal muscle mass, depending on the intensity, duration and frequency with which the signal appears.

To highlight recent evidence for the ability of polyphenols and their derivatives to reduce muscle wasting in different pathological states.From January 2016 to August 2017, four articles dealt with the effects of polyphenols on muscle wasting, which were all carried out in mice. The four studies found that polyphenols reduced muscle mass loss associated with cancer cachexia, acute inflammation or sciatic nerve section. One study even showed that muscle mass was totally preserved when rutin was added to the diet of mice undergoing cancer cachexia. The beneficial effects of polyphenols on muscle wasting were mainly due to a reduction in the activation of the nuclear factor-kappa B pathway, a lower oxidative stress level and a better mitochondrial function. In addition, urolithin B was found to have a testosterone-like effect and to favorably regulate muscle protein balance.During the last 20 months, additional data have been collected about the beneficial effects of rutin, curcumin, quercetin, ellagitanins and urolithin B to limit the loss of muscle mass associated with several pathological states. However, currently, scientific evidence lacks for their use as nutraceuticals in human.

This study aimed at determining the influence of the ACTN3 R577X polymorphism on muscle strength and muscle endurance in non-athletic young men.266 healthy young men were included in this study. Each subject performed maximal isometric, concentric and eccentric contractions of the knee extensor muscles on an isokinetic dynamometer. Force depression, force enhancement and the fatigue index were derived from these data. In addition, handgrip strength, squat jump (SJ) and counter movement jump (CMJ) height were obtained.Our group included 83 RR (31 %), 131 RX (49 %) and 52 XX (20 %) individuals. The muscle bone cross-sectional area of the thigh was 5 % higher in RR compared to XX individuals (P = 0.033). RR genotypes showed 6 % higher handgrip strength compared to the XX group (P = 0.047). They also jumped 5 % higher in both the SJ and CMJ tests (P = 0.029; P = 0.031). No differences were found in force depression, force enhancement, isometric or eccentric strength. The relative concentric knee torque at 200°/s and at 300°/s was 7 and 8 % higher in RR compared to XX genotypes, respectively (P = 0.049; P = 0.048). Also, the fatigue index was found to be 4 % lower in XX genotypes (P = 0.037).Our findings are in agreement with the higher prevalence of the RR genotype in power-oriented activities. The better fatigue index of XX genotypes may be beneficial in endurance-type activities.

BACKGROUND: Sarcopenia contributes to the decreased quality of life in the older person. While resistance exercise is an effective measure to increase muscle mass and strength, the hypertrophic response may be blunted in old age. OBJECTIVES: To determine 1) whether hypertrophy in the m. plantaris of old mice was blunted compared to adult and 2) whether this was related to a reduced satellite cell (SC) density and 3) how resveratrol affects hypertrophy in old mice. METHODS: In adult (7.5 months, n=11), old (23.5 months, n=10) and old-resveratrol-treated (n=10) male C57BL/6J mice, hypertrophy of the left m. plantaris was induced by denervation of its synergists. The contralateral leg served as control. RESULTS: After six weeks, overload-induced myofiber hypertrophy and IIB-IIA shift in myofiber type composition were less pronounced in old than adult mice (P=0.03), irrespective of resveratrol treatment. Muscles from old mice had a lower SC density than adult muscles (P=0.002). Overload-induced SC proliferation (P

To investigate how acute environmental hypoxia regulates blood glucose and downstream intramuscular insulin signaling after a meal in healthy humans.Fifteen subjects were exposed for 4 h to normoxia (NOR) or to normobaric hypoxia (HYP, FiO2 = 0.11) in a randomized order 40 min after consumption of a high glycemic meal. A muscle biopsy from m. vastus lateralis and a blood sample were taken before (T0), after 1 h (T60) and 4 h (T240) in NOR or HYP and blood glucose levels were measured before exposure and every 30 min.In HYP, blood glucose was reduced 100 min (110.1 ± 5.4 in NOR vs 89.5 ± 4.7 mg dl(-1) in HYP) and 130 min (98.7 ± 3.8 in NOR vs 85.6 ± 4.9 mg dl(-1) in HYP) after completion of a meal, which resulted in an 83 % lower AUC in HYP compared to NOR (p = 0.006). This coincided with 40 % lower GLUT4 protein in the cytosolic fraction (p = 0.013) and a tendency to increase in the crude membrane fraction (p = 0.070) in HYP compared to NOR. At T240, blood glucose concentration was similar between HYP and NOR, whereas plasma insulin as well as phosphorylation of muscle Akt and GSK-3 was ~2-fold higher in HYP compared to NOR (p 0.05). In contrast, Rac1 protein was less abundant in the membrane fraction in HYP compared to NOR (p = 0.003), reflecting lower activation.Acute environmental hypoxia initially reduced blood glucose response to a meal, possibly via an increase in GLUT4 abundance at the sarcolemmal membrane. Later on, whole body insulin intolerance developed independently of defects in conventional insulin signaling in skeletal muscle.

Aging reduces bone mass as well as the anabolic response of bone to mechanical stimuli, resulting in osteopenia. Endoplasmic reticulum (ER) stress impairs the response of myogenic cells to anabolic stimuli, and is involved in sarcopenia, but whether ER stress also contributes to osteopenia is unknown. Therefore, we tested whether ER stress exists in bones of aged mice, and whether this impairs the osteocyte response to mechanical stimulation. Primary osteocytes were obtained from long bones of adult (8 months) and old (24-26 months) mice, treated with or without the pharmacological ER stress inducer tunicamycin, and either or not subjected to mechanical loading by pulsating fluid flow (PFF). The osteocyte response to PFF was assessed by measuring cyclooxygenase-2 (Cox-2) mRNA levels and nitric oxide (NO) production. mRNA levels of ER stress markers were higher in old versus adult osteocytes (+40% for activating transcription factor-4, +120% for C/EBP homologous protein, and +120% for spliced X-box binding protein-1, p < 0.05). The Cox-2 response to PFF was fourfold decreased in cells from old bones (p < 0.001), while tunicamycin decreased PFF-induced Cox-2 expression by threefold in cells from adult bones (p < 0.01). PFF increased NO production by 50% at 60 min in osteocytes from old versus adult bones (p < 0.01). In conclusion, our data indicate that the expression of several ER stress markers was higher in osteocytes from bones of old compared to adult mice. Since ER stress altered the response of osteocytes to mechanical loading, it could be a novel factor contributing to osteopenia. ispartof: Calcified Tissue International vol:96 issue:2 pages:123-128 ispartof: location:United States status: published

Skeletal muscle mass reflects a dynamic turnover between net protein synthesis and degradation. In addition, satellite cell inclusion may contribute to increase muscle mass while fiber loss results in a reduction of muscle mass. Since 2010, a few studies looked at the involvement of the newly discovered Hippo pathway in the regulation of muscle mass. In line with its roles in other organs, it has been hypothesized that the Hippo pathway could play a role in different regulatory mechanisms in skeletal muscle as well, namely proliferation and renewal of satellite cells, differentiation, death, and growth of myogenic cells. While the Hippo components have been identified in skeletal muscle, their role in muscle mass regulation has been less investigated and conflicting results have been reported. Indeed, the first studies described both atrophic and hypertrophic roles of the Hippo pathway and its effectors Yap/Taz using different biochemical approaches. Further, investigation is therefore warranted to determine the role of the Hippo pathway in the regulation of skeletal muscle mass. New components of the pathway will probably emerge and unsuspected roles will likely be discovered due to its numerous interactions with different cellular processes. This mini-review aims to summarize the current literature concerning the roles of the Hippo pathway in the regulation of muscle mass and to develop the hypothesis that this pathway could contribute to muscle mass adaptation after exercise.

Activating transcription factor (ATF)3 regulates the expression of inflammation-related genes in several tissues under pathological contexts. In skeletal muscle, atf3 expression increases after exercise, but its target genes remain unknown. We aimed to identify those genes and to determine the influence of ATF3 on muscle adaptation to training. Skeletal muscles of ATF3-knockout (ATF3-KO) and control mice were analyzed at rest, after exercise, and after training. In resting muscles, there was no difference between genotypes in enzymatic activities or fiber type. After exercise, a microarray analysis in quadriceps revealed ATF3 affects genes modulating chemotaxis and chemokine/cytokine activity. Quantitative PCR showed that the mRNA levels of chemokine C-C motif ligand (ccl)8 and chemokine C-X-C motif ligand (cxcl)13 were higher in quadriceps of ATF3-KO mice than in control mice. The same was observed for ccl9 and cxcl13 in soleus. Also in soleus, ccl2, interleukin (il)6, il1β, and cluster of differentiation (cd)68 mRNA levels increased after exercise only in ATF3-KO mice. Endurance training increased the basal mRNA level of hexokinase-2, hormone sensitive lipase, glutathione peroxidase-1, and myosin heavy chain IIa in quadriceps of control mice but not in ATF3-KO mice. In summary, ATF3 attenuates the expression of inflammation-related genes after exercise and thus facilitates molecular adaptation to training.-Fernandez-Verdejo, R., Vanwynsberghe, A. M., Essaghir, A., Demoulin, J.-B., Hai, T., Deldicque, L., Francaux, M. Activating transcription factor 3 attenuates chemokine and cytokine expression in mouse skeletal muscle after exercise and facilitates molecular adaptation to endurance training.

Androgens have well-established anabolic actions on skeletal muscle, although the direct effects of the androgen receptor (AR) in muscle remain unclear. We generated satellite cell-specific AR-knockout (satARKO) mice in which the AR is selectively ablated in satellite cells, the muscle precursor cells. Total-limb maximal grip strength is decreased by 7% in satARKO mice, with soleus muscles containing ∼10% more type I fibers and 10% less type IIa fibers than the corresponding control littermates. The weight of the perineal levator ani muscle is markedly reduced (-52%). Thus, muscle AR is involved in fiber-type distribution and force production of the limb muscles, while it is a major determinant of the perineal muscle mass. Surprisingly, myostatin (Mstn), a strong inhibitor of skeletal muscle growth, is one of the most androgen-responsive genes (6-fold reduction in satARKO) through direct transcription activation by the AR. Consequently, muscle hypertrophy in response to androgens is augmented in Mstn-knockout mice. Our finding that androgens induce Mstn signaling to restrain their own anabolic actions has implications for the treatment of muscle wasting disorders.-Dubois, V., Laurent, M. R., Sinnesael, M., Cielen, N., Helsen, C., Clinckemalie, L., Spans, L., Gayan-Ramirez, G., Deldicque, L., Hespel, P., Carmeliet, G., Vanderschueren, D., and Claessens, F. A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.

We investigated whether dietary nitrate (NO(3)(-)) supplementation enhances the effect of training in hypoxia on endurance performance at sea level. Twenty-two healthy male volunteers performed high-intensity endurance training on a cycle ergometer (6 weeks, 5×30 min/week at 4-6 mmol/L blood lactate) in normobaric hypoxia (12.5% FiO(2)), while ingesting either beetroot juice [0.07 mmol NO(3)(-) /kg body weight (bw)/day; BR, n = 11] or a control drink (CON, n = 11). During the pretest and the posttest, the subjects performed a 30-min simulated time trial (TT) and an incremental VO(2max) test. Furthermore, a biopsy was taken from m. vastus lateralis before and after the TT. Power output during the training sessions in both groups increased by ∼6% from week 1 to week 6 (P

to the editor: We appreciate the numerous comments (see Ref. [4][1]) on our Viewpoint ([2][2]), which demonstrates the interest of muscle physiologists for the topic. A number of commentaries pointed toward the fact that our model did not sufficiently account for the high interindividual variability

UNLABELLED: Hypoxia-induced muscle wasting has been observed in several environmental and pathological conditions. However, the molecular mechanisms behind this loss of muscle mass are far from being completely elucidated, certainly in vivo. When studying the regulation of muscle mass by environmental hypoxia, many confounding factors have to be taken into account, such as decreased protein ingestion, sleep deprivation or reduced physical activity, which make difficult to know whether hypoxia per se causes a reduction in muscle mass. AIM: We hypothesized that acute exposure to normobaric hypoxia (11% O2 ) would repress the activation of the mTOR pathway usually observed after a meal and would activate the proteolytic pathways in skeletal muscle. METHODS: Fifteen subjects were exposed passively for 4 h to normoxic and hypoxic conditions in a random order after consumption of a light breakfast. A muscle biopsy and a blood sample were taken before, after 1 and 4 h of exposure. RESULTS: After 4 h, plasma insulin concentration and the phosphorylation state of PKB and S6K1 in skeletal muscle were higher in hypoxia than in normoxia (P

Purpose: We investigated the effect of sprint interval training (SIT) in normoxia, vs. SIT in hypoxia alone or in conjunction with oral nitrate intake, on buffering capacity of homogenized muscle (βhm) and fiber type distribution, as well as on sprint and endurance performance. Methods: Twenty-seven moderately-trained participants were allocated to one of three experimental groups: SIT in normoxia (20.9% FiO2) + placebo (N), SIT in hypoxia (15% F +iO2) placebo (H), or SIT in hypoxia + nitrate supplementation (HN). All participated in 5 weeks of SIT on a cycle ergometer (30-s sprints interspersed by 4.5 min recovery-intervals, 3 weekly sessions, 4–6 sprints per session). Nitrate (6.45 mmol NaNO3) or placebo capsules were administered 3 h before each session. Before and after SIT participants performed an incremental VO2max-test, a 30-min simulated cycling time-trial, as well as a 30-s cycling sprint test. Muscle biopsies were taken from m. vastus lateralis. Results: SIT decreased the proportion of type IIx muscle fibers in all groups (P < 0.05). The relative number of type IIa fibers increased (P < 0.05) in HN (P < 0.05 vs. H), but not in the other groups. SIT had no significant effect on βhm. Compared with H, SIT tended to enhance 30-s sprint performance more in HN than in H (P = 0.085). VO2max and 30-min time-trial performance increased in all groups to a similar extent. Conclusion: SIT in hypoxia combined with nitrate supplementation increases the proportion of type IIa fibers in muscle, which may be associated with enhanced performance in short maximal exercise. Compared with normoxic training, hypoxic SIT does not alter βhm or endurance and sprinting exercise performance. ispartof: Frontiers in Physiology vol:7 issue:JUN ispartof: location:Switzerland status: published

Skeletal muscle wasting has been shown to be a mechanism by which humans are able to adapt to extreme altitude. Nonetheless, the literature is conflicting regarding the altitude or time point at which this phenomenon starts to occur. Using the metric recently suggested by Garvivan-Lewis et al. (8), we propose an hypoxic dose of 5000 km·h as the cut-off point above which hypoxia-induced muscle atrophy starts to develop. As such, we suggest that both elevation and hours of altitude exposure should be incorporated in future studies unraveling hypoxic regulation of muscle mass.

Gommaar D'Hulst,1 Alessandra Ferri,2,3 Damien Naslain,4 Luc Bertrand,5 Sandrine Horman,5 Marc Francaux,4 David J Bishop,2 Louise Deldicque1,41Department of Kinesiology, Exercise Physiology Research Group, FaBeR, KU Leuven, Leuven, Belgium; 2Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, Australia; 3Department of Health Sciences, University of Milano-Bicocca, Monza, Italy; 4Institute of Neuroscience, Université catholique de Louvain, Louvain-la-Neuve, 5Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, BelgiumAbstract: Chronic hypoxia leads to muscle atrophy. The molecular mechanisms responsible for this phenomenon are not well defined in vivo. We sought to determine how chronic hypoxia regulates molecular markers of protein synthesis and degradation in human skeletal muscle and whether these regulations were related to the regulation of the hypoxia-inducible factor (HIF) pathway. Eight young male subjects lived in a normobaric hypoxic hotel (FiO2 14.1%, 3,200 m) for 15 days in well-controlled conditions for nutrition and physical activity. Skeletal muscle biopsies were obtained in the musculus vastus lateralis before (PRE) and immediately after (POST) hypoxic exposure. Intramuscular hypoxia-inducible factor-1 alpha (HIF-1α) protein expression decreased (−49%, P=0.03), whereas hypoxia-inducible factor-2 alpha (HIF-2α) remained unaffected from PRE to POST hypoxic exposure. Also, downstream HIF-1α target genes VEGF-A (−66%, P=0.006) and BNIP3 (−24%, P=0.002) were downregulated, and a tendency was measured for neural precursor cell expressed, developmentally Nedd4 (−47%, P=0.07), suggesting lowered HIF-1α transcriptional activity after 15 days of exposure to environmental hypoxia. No difference was found on microtubule-associated protein 1 light chain 3 type II/I (LC3b-II/I) ratio, and P62 protein expression tended to increase (+45%, P=0.07) compared to PRE exposure levels, suggesting that autophagy was not modulated after chronic hypoxia. The mammalian target of rapamycin complex 1 pathway was not altered as Akt, mammalian target of rapamycin, S6 kinase 1, and 4E-binding protein 1 phosphorylation did not change between PRE and POST. Finally, myofiber cross-sectional area was unchanged between PRE and POST. In summary, our data indicate that moderate chronic hypoxia differentially regulates HIF-1α and HIF-2α, marginally affects markers of protein degradation, and does not modify markers of protein synthesis or myofiber cross-sectional area in human skeletal muscle.Keywords: HIF-1α, hypoxia, autophagy, mTORC1