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Exercise modulates the circulating levels of the endocannabinoids ligands N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and possibly the levels of their receptors and downstream signaling in skeletal muscle. The aim of the present study was to investigate the regulation of the endocannabinoid system by several exercise paradigms in human skeletal muscle. A second aim was to compare endocannabinoid regulation in healthy and prediabetic people in response to an acute endurance exercise. Blood and muscle samples were taken before and after resistance and endurance exercise in normoxia and hypoxia to measure plasma endocannabinoid levels as well as muscle protein expression of CB1, CB2, and downstream signaling. We found that: 1) an acute resistance exercise session decreased plasma 2-AG and N-palmitoylethanolamine (PEA) levels in normoxia; 2) 4 wk resistance training decreased plasma AEA, PEA, and N-oleoylethanolamine (OEA) levels in both normoxia and hypoxia; 3) an acute moderate-intensity endurance exercise increased plasma OEA levels in the healthy and prediabetic groups in normoxia and hypoxia, whereas plasma 2-AG levels increased in the healthy group and AEA in the prediabetic group only in normoxia. The expression of the cannabinoid receptors was only marginally regulated by acute exercise, hypoxia, and prediabetes and downstream signaling did not follow the changes detected in the endocannabinoid ligands. Altogether, our results suggest that resistance and endurance exercise regulate the levels of the endocannabinoid ligands and CB1 expression in opposite ways. The physiological impact of the changes observed in the endocannabinoid ligands in human skeletal muscle after exercise needs further investigation. NEW & NOTEWORTHY We are the first to analyze both endocannabinoids ligands and receptors in response to endurance and resistance exercise. In addition, no study before has compared both exercise paradigms regarding endocannabinoid tone, which is of interest as endocannabinoids regulate energy metabolism, and these are different between endurance and resistance exercise. Furthermore, we investigated whether the endocannabinoid tone was differently regulated in response to acute endurance exercise in prediabetic people. Linking exercise, endocannabinoids and (pre)diabetic people has never been done before.

Muscle stem cells (MuSCs) are involved in muscle maintenance and regeneration. Mechanically loaded MuSCs within their native niche undergo tensile and shear deformations, but how MuSCs sense mechanical stimuli and translate these into biochemical signals regulating function and fate is still poorly understood. We aimed to investigate whether the glycocalyx is involved in the MuSC mechanoresponse, and whether MuSC morphology affects mechanical loading-induced pressure, shear stress, and fluid velocity distribution. FSS-induced deformation of active proliferating MuSCs (myoblasts) with intact or degraded glycocalyx was assessed by live-cell imaging. Glycocalyx-degradation did not significantly affect nitric oxide production, but reduced FSS-induced myoblast deformation and modulated gene expression. Finite-element analysis revealed that the distribution of FSS-induced pressure, shear stress, and fluid velocity on myoblasts was non-uniform, and the magnitude depended on myoblast morphology and apex-height. In conclusion, our results suggest that the glycocalyx does not play a role in NO production in myoblasts but might impact mechanotransduction and gene expression, which needs further investigation. Future studies will unravel the underlying mechanism by which the glycocalyx affects FSS-induced myoblast deformation, which might be related to increased drag forces. Moreover, MuSCs with varying apex-height experience different levels of FSS-induced pressure, shear stress, and fluid velocity, suggesting differential responsiveness to fluid shear forces. ispartof: EXPERIMENTAL CELL RESEARCH vol:417 issue:1 ispartof: location:United States status: published

Malnutrition is a highly prevalent condition in older adults. It is associated with low muscle mass and function and increased occurrence of health problems. Maintaining an adequate nutritional status as well as a sufficient nutrient intake in older people is therefore essential to address this public health problem. For this purpose, protein supplementation is known to prevent the loss of muscle mass during aging, and the consumption of various pomegranate extracts induces numerous health benefits, mainly through their antioxidant properties. However, to our knowledge, no study has to date investigated the impact of their combination on the level of malnutrition in older people. The objective of this preliminary study was thus to evaluate the safety of a combination of protein and a pomegranate extract in healthy subjects aged 65 years or more during a 21-day supplementation period. Thirty older participants were randomly assigned to receive protein and a pomegranate extract (Test group) or protein and maltodextrin (Control group) during a 21-day intervention period. The primary outcomes were the safety and tolerability of the supplementation defined as the occurrence of adverse events, and additional secondary outcomes included physical examination and hematological and biochemical parameters. No serious adverse events were reported in any group. Changes in physical, hematological, and biochemical parameters between the initial screening and the end of the study were equivalent in both groups, except for glutamate-pyruvate transaminase (GPT) and prealbumin, for which a decrease was observed only in the Test group. Our initial findings support the safety of the combination of protein and a pomegranate extract in healthy elderly people. Future clinical trials on a larger sample and a longer period are needed to determine the efficacy of this combination.

This study aimed to investigate the modulation of circulating exosome-like extracellular vesicles (ELVs) after 6 wk of sprint interval training (SIT) at sea level and at 2000, 3000, and 4000 m.Thirty trained endurance male athletes (18-35 yr) participated in a 6-wk SIT program (30-s all-out sprint, 4-min 30-s recovery; 4-9 repetitions, 2 sessions per week) at sea level ( n = 8), 2000 m (fraction of inspired oxygen (F io2 ) 0.167, n = 8), 3000 m (F io2 0.145, n = 7), or 4000 m (F io2 0.13, n = 7). Venous blood samples were taken before and after the training period. Plasma ELVs were isolated by size exclusion chromatography, counted by nanoparticle tracking analysis, and characterized according to international standards. Candidate ELV microRNAs (miRNAs) were quantified by real-time polymerase chain reaction.When the three hypoxic groups were analyzed separately, only very minor differences could be detected in the levels of circulating particles, ELV markers, or miRNA. However, the levels of circulating particles increased (+262%) after training when the three hypoxic groups were pooled, and tended to increase at sea level (+65%), with no difference between these two groups. A trend to an increase was observed for the two ELV markers, TSG101 (+65%) and HSP60 (+441%), at sea level, but not in hypoxia. Training also seemed to decrease the abundance of miR-23a-3p and to increase the abundance of miR-21-5p in hypoxia but not at sea level.A 6-wk SIT program tended to increase the basal levels of circulating ELVs when performed at sea level but not in hypoxia. In contrast, ELV miRNA cargo seemed to be modulated in hypoxic conditions only. Further research should explore the potential differences in the origin of ELVs between normoxic and local and systemic hypoxic conditions.

Impaired metabolism is becoming one of the main causes of mortality and the identification of strategies to cure those diseases is a major public health concern. A number of therapies are being developed to treat type 2 diabetes mellitus (T2DM), but few of them focus on situations prior to diabetes. Obesity, aging and insulin resistance are all risk factors, which fortunately can be reversed to some extent. Non-drug interventions, such as exercise, are interesting strategies to prevent the onset of diabetes, but it remains to determine the optimal dose and conditions. In the search of optimizing the effects of physical exercise to prevent T2DM, hypoxic training has emerged as an interesting and original strategy. Several recent studies have chosen to look at the effects of hypoxic training in people at risk of developing T2DM. Therefore, the purpose of this narrative review is to give an overview of all original articles having tested the effects of a single exercise or exercise training in hypoxia on glucose metabolism and other health-related parameters in people at risk of developing T2DM. Taken together, the data on the effects of hypoxic training on glucose metabolism, insulin sensitivity and the health status of people at risk of T2DM are inconclusive. Some studies show that hypoxic training can improve glucose metabolism and the health status to a greater extent than normoxic training, while others do not corroborate the latter. When an additional benefit of hypoxic vs normoxic training is found, it still remains to determine which signaling pathways and molecular mechanisms are involved.

The aim of this study was to compare the potential additional effect of chia flour, whey protein, and a placebo juice to resistance training on fat-free mass (FFM) and strength gains in untrained young men. Eighteen healthy, untrained young men underwent an 8-week whole-body resistance training program, comprising three sessions per week. Subjects were randomized into three groups that after each training session consumed: (1) 30 g whey protein concentrate containing 23 g protein (WG), (2) 50 g chia flour containing 20 g protein (CG), or (3) a placebo not containing protein (PG). Strength tests (lower- and upper-limb one repetition maximum (1 RM) tests) and body composition analyses (dual-energy X-ray absorptiometry; DXA) were performed before (PRE) and after (POST) the intervention. Resistance training increased FFM and the 1 RM for each of the strength tests similarly in the three groups. FFM increased by 2.3% in WG (p = 0.04), by 3.6% in CG (p = 0.004), and by 3.0% in PG (p = 0.002)., and 1 RM increased in the different strength tests in the three groups (p < 0.05) with no difference between PG, CG, and WG. In conclusion, neither chia flour nor whey protein supplementation elicited an enhanced effect on FFM and strength gains after an 8-week resistance training program in healthy, untrained young men consuming a habitual high protein mixed diet (>1.2 g/kg/day).

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

Although the effects of high intensity interval training (HIIT) on health and sports performance are well documented, the effects of this training type on mucosal immune function remain unclear. The aim of this study was to assess the impact of an acute HIIT session on salivary immune and endocrine marker levels (immunoglobulin A (sIgA), alpha amylase (sAA), cortisol (C), and testosterone (T)) in male and female endurance athletes. Twenty subjects (ten males and ten females) underwent ten bouts of treadmill running using a 4 min:2 min work:rest ratio at ~90% of peak oxygen uptake (VO2peak). Saliva samples were collected 5 min before and 20 min post-exercise. During work intervals, female participants had a higher HR than male participants (+4.0 ± 5%; p = 0.008). Rating of perceived exertion (RPE) increased throughout the duration of the HIIT session in both males and females (main time effect: p < 0.001), but was higher in males than females (+17 ± 4%; time x gender main effect: p < 0.001). Lactate concentrations were similar in both males and females. Exercise increased the concentration of salivary IgA (males: +24 ± 6%, p = 0.004; females: +27 ± 3%, p = 0.03), salivary alpha-amylase (males: +44 ± 22%, p = 0.036; females: +71 ± 26%, p = 0.026) and salivary cortisol (males: +41 ± 24%, p = 0.015; females: +55 ± 24%, p = 0.005). Testosterone levels and the Testosterone/Cortisol ratio remained stable in both males and females. These findings suggest that the physiological stress produced by a HIIT session does not affect immune function and does not disturb the anabolic/catabolic balance.

mTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood. We show that loss of the prolyl hydroxylase domain isoform 1 oxygen sensor in mice (PHD1KO) reduces muscle mass. PHD1KO muscles show impaired mTORC1 activation in response to leucine whereas mTORC1 activation by growth factors or eccentric contractions was preserved. The ability of PHD1 to promote mTORC1 activity is independent of its hydroxylation activity but is caused by decreased protein content of the leucyl tRNA synthetase (LRS) leucine sensor. Mechanistically, PHD1 interacts with and stabilizes LRS. This interaction is promoted during oxygen and amino acid depletion and protects LRS from degradation. Finally, elderly subjects have lower PHD1 levels and LRS activity in muscle from aged versus young human subjects. In conclusion, PHD1 ensures an optimal mTORC1 response to leucine after episodes of metabolic scarcity., Nature Communications, 11, ISSN:2041-1723

The purpose of this study is to investigate exosome-like vesicle (ELV) plasma concentrations and markers of multivesicular body (MVB) biogenesis in skeletal muscle in response to acute exercise. Seventeen healthy [body mass index (BMI): 23.5 ± 0.5 kg·m−2] and 15 prediabetic (BMI: 27.3 ± 1.2 kg·m−2) men were randomly assigned to two groups performing an acute cycling bout in normoxia or hypoxia ([Formula: see text] 14.0%). Venous blood samples were taken before (T0), during (T30), and after (T60) exercise, and biopsies from m. vastus lateralis were collected before and after exercise. Plasma ELVs were isolated by size exclusion chromatography, counted by nanoparticle tracking analysis (NTA), and characterized according to international standards, followed by expression analyses of canonical ELV markers in skeletal muscle. In the healthy normoxic group, the total number of particles in the plasma increased during exercise from T0 to T30 (+313%) followed by a decrease from T30 to T60 (−53%). In the same group, an increase in TSG101, CD81, and HSP60 protein expression was measured after exercise in plasma ELVs; however, in the prediabetic group, the total number of particles in the plasma was not affected by exercise. The mRNA content of TSG101, ALIX, and CD9 was upregulated in skeletal muscle after exercise in normoxia, whereas CD9 and CD81 were downregulated in hypoxia. ELV plasma abundance increased in response to acute aerobic exercise in healthy subjects in normoxia, but not in prediabetic subjects, nor in hypoxia. Skeletal muscle analyses suggested that this tissue did not likely play a major role of the exercise-induced increase in circulating ELVs.

Mechanistic insights into the molecular events by which exercise enhances the skeletal muscle phenotype are lacking, particularly in the context of type 2 diabetes. Here, we unravel a fundamental role for exercise-responsive cytokines (exerkines) on skeletal muscle development and growth in individuals with normal glucose tolerance or type 2 diabetes. Acute exercise triggered an inflammatory response in skeletal muscle, concomitant with an infiltration of immune cells. These exercise effects were potentiated in type 2 diabetes. In response to contraction or hypoxia, cytokines were mainly produced by endothelial cells and macrophages. The chemokine CXCL12 was induced by hypoxia in endothelial cells, as well as by conditioned medium from contracted myotubes in macrophages. We found that CXCL12 was associated with skeletal muscle remodeling after exercise and differentiation of cultured muscle. Collectively, acute aerobic exercise mounts a noncanonical inflammatory response, with an atypical production of exerkines, which is potentiated in type 2 diabetes.

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.

Even though physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Here, we combine data for up to 674,980 individuals from 51 studies in a trans-ancestry meta-analysis of genome-wide association studies for self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA); leisure screen time (LST); sedentary commuting; and sedentary behavior at work. We identify 99 loci that associate with at least one trait. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. Molecular dynamics simulations suggest that the Glu to Ala substitution encoded by rs2229456 (ACTN3) – associated with more MVPA – disrupts salt bridge interactions and makes the alpha actinin 3 filaments more flexible. In isolated type IIA muscle fibers, the Ala-encoding allele is associated with lower maximal force and power during an isometric contraction, suggesting protection from exercise-induced muscle damage. Finally, Mendelian Randomization analyses show that the causal effect of LST on BMI is 2-3 times larger than the effect of body mass index (BMI) on LST, and that beneficial effects of LST and MVPA on several risk factors and diseases are mediated or confounded by BMI. Taken together, our results provide mechanistic insights into the regulation of MVPA and into the role of LST and MVPA in disease prevention. These insights may facilitate the development of tailored physical activity interventions.

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.

Despite the benefits of commercial exergames, in the practical application, players might not be spending sufficient time in physical activity levels compatible with health outcomes. We adopted a design-based exergame approach to build a bike exergame called Greedy Rabbit. The purpose of this study was to identify the impact of Greedy Rabbit on players' physical activity metrics and situational interest. : Sixty undergraduate students were assigned to two groups: an experimental group playing Greedy Rabbit (N = 41) and a control group playing a placebo version of Greedy Rabbit (N = 19). The physical activity metrics measured were maximum oxygen consumption, heart rate and cadence. : The experimental group reported higher scores for all physical activity metrics and for two dimensions of situational interest (instant enjoyment and attention demand). Furthermore, the physical activity metrics increased more during the exergame for the experimental group, reaching the standard guidelines for vigorous physical activity. : This study demonstrated that a design-based bike exergame might be a good option to enhance players' health-related physical activity outcomes and situational interest.

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.

Aging-associated muscle wasting and impaired regeneration are caused by deficiencies in muscle stem cell (MuSC) number and function. We postulated that aged MuSCs are intrinsically impaired in their responsiveness to omnipresent mechanical cues through alterations in MuSC morphology, mechanical properties, and number of integrins, culminating in impaired proliferative capacity. Here we show that aged MuSCs exhibited significantly lower growth rate and reduced integrin-α7 expression as well as lower number of phospho-paxillin clusters than young MuSCs. Moreover, aged MuSCs were less firmly attached to matrigel-coated glass substrates compared to young MuSCs, as 43% of the cells detached in response to pulsating fluid shear stress (1 Pa). YAP nuclear localization was 59% higher than in young MuSCs, yet YAP target genes Cyr61 and Ctgf were substantially downregulated. When subjected to pulsating fluid shear stress, aged MuSCs exhibited reduced upregulation of proliferation-related genes. Together these results indicate that aged MuSCs exhibit impaired mechanosensitivity and growth potential, accompanied by altered morphology and mechanical properties as well as reduced integrin-α7 expression. Aging-associated impaired muscle regenerative capacity and muscle wasting is likely due to aging-induced intrinsic MuSC alterations and dysfunctional mechanosensitivity. ispartof: AGING-US vol:14 issue:1 pages:28-53 ispartof: location:United States status: published

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.

Every day, blood banks worldwide face the challenge of ensuring an adequate blood supply. Iron deficiency is by far the most common cause of deferral of blood donors. The aim of the present study was to determine the effect of iron supplementation after repeated blood donation on iron status and physiological performance.Forty-four moderately trained and iron-replete subjects were randomly divided into a whole blood donation (n=36) and a placebo donation (n=8) group. One third of the donation group received no iron supplementation, whereas one third received 20 mg iron and one third received 80 mg iron daily for 28 days. The subjects were intended to make three donations 3 months apart, and recovery of endurance capacity, assessed by an incremental maximal cycling test, and haematological parameters was monitored up to 28 days after each donation.Negative effects of repeated blood donation were found for markers of iron storage, markers of functional iron and/or iron metabolism regulation, and physiological markers. Iron supplementation did not affect iron storage but did limit, at the highest dose of 80 mg, the effect of blood donations on functional iron and/or iron metabolism regulation, and at both 20 and 80 mg the negative effects on maximal power output and peak oxygen consumption.Iron supplementation limited the deleterious effects of repeated blood donation on endurance sport performance but not on decline in iron status in iron-replete young men. These results underline the importance of iron supplementation to minimise the deleterious effects of blood donation on physiological functions, and the necessity to optimise the supplementation strategy to preserve iron status.

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.

The aim of the present study was to determine if the training status decreases inflammation, slows down senescence, and preserves telomere health in skeletal muscle in older compared with younger subjects, with a specific focus on satellite cells. Analyses were conducted on skeletal muscle and cultured satellite cells from vastus lateralis biopsies ( n = 34) of male volunteers divided into four groups: young sedentary (YS), young trained cyclists (YT), old sedentary (OS), and old trained cyclists (OT). The senescence state and inflammatory profile were evaluated by telomere dysfunction-induced foci (TIF) quantification, senescence-associated β-galactosidase (SA-β-Gal) staining, and quantitative (q)RT-PCR. Independently of the endurance training status, TIF levels (+35%, P < 0.001) and the percentage of SA-β-Gal-positive cells (+30%, P < 0.05) were higher in cultured satellite cells of older compared with younger subjects. p16 (4- to 5-fold) and p21 (2-fold) mRNA levels in skeletal muscle were higher with age but unchanged by the training status. Aging induced higher CD68 mRNA levels in human skeletal muscle (+102%, P = 0.009). Independently of age, both trained groups had lower IL-8 mRNA levels (−70%, P = 0.011) and tended to have lower TNF-α mRNA levels (−40%, P = 0.10) compared with the sedentary subjects. All together, we found that the endurance training status did not slow down senescence in skeletal muscle and satellite cells in older compared with younger subjects despite reduced inflammation in skeletal muscle. These findings highlight that the link between senescence and inflammation can be disrupted in skeletal muscle.

Background: Benefits of sprint interval training performed in hypoxia (SIH) compared to normoxia (SIN) have been assessed by studies mostly conducted around 3000 m of simulated altitude. The present study aims to determine whether SIH at an altitude as high as 4000 m can elicit greater adaptations than the same training at 2000 m, 3000 m or sea-level. Methods: Thirty well-trained endurance male athletes (18&ndash, 35 years old) participated in a six-week repeated sprint interval training program (30 s all-out sprint, 4 min 30 s recovery, 4&ndash, 9 repetitions, 2 sessions/week) at sea-level (SL, n = 8), 2000 m (FiO2 16.7%, n = 8), 3000 m (FiO2 14.5%, n = 7) or 4000 m (FiO2 13.0%, n = 7). Aerobic and anaerobic exercise components were evaluated by an incremental exercise test, a 600 kJ time trial and a Wingate test before and after the training program. Results: After training, peak power output (PPO) during the incremental exercise test increased (~6%) without differences between groups. The lactate threshold assessed by Dmax increased at 2000 m (+14 &plusmn, 12 W) and 4000 m (+12 &plusmn, 11 W) but did not change at SL and 3000 m. Mean power during the Wingate test increased at SL, 2000 m and 4000 m, although peak power increased only at 4000 m (+38 &plusmn, 38 W). Conclusions: The present study indicates that SIH using 30 s sprints is as efficient as SIN for improving aerobic and anaerobic qualities. Additional benefits such as lactate-related adaptations were found only in SIH and Wingate peak power only increased at 4000 m. This finding is of particular interest for disciplines requiring high power output, such as in very explosive sports.