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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

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.

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.

We analysed the effects of resistance exercise upon the phosphorylation state of proteins associated with adaptive processes from the Akt/PKB (protein kinase B) and the mitogen-activated protein kinase (MAPK) pathways. Nine healthy young men (21.7 +/- 0.55 year) performed 10 sets of 10 leg extensions at 80% of their 1-RM (repetition maximum). Muscle biopsies were taken from the vastus lateralis at rest, within the first 30 s after exercise and at 24 h post-exercise. Immediately post exercise, the phosphorylation states of Akt/PKB on Thr308 and Ser473 and 4E-BP1 on Thr37/46 (eukaryotic initiation factor 4E-binding protein 1) were decreased (-60 to -90%, P < 0.05). Conversely, the phosphorylation of p70(s6k) (p70 ribosomal S6 kinase) on Thr421/Ser424 was increased more than 20-fold (P < 0.05), and this was associated with a 10- to 50-fold increase in the phosphorylation of p38 and ERK1/2 (extracellular signal-regulated kinase) (P < 0.05). Twenty-four hours post-exercise the phosphorylation state of Akt/PKB on Thr308 was depressed, whereas the phosphorylation of p70(s6k) on Thr421/Ser424 and sarcoplasmic ERK1/2 were elevated. The present results indicate that high-intensity resistance exercise in the fasted state inhibits Akt/PKB and 4E-BP1 whilst concomitantly augmenting MAPK signalling and p70(s6k) on Thr421/Ser424. ispartof: European journal of applied physiology vol:104 issue:1 pages:57-65 ispartof: location:Germany status: published

Resistance exercise disturbs skeletal muscle homeostasis leading to activation of catabolic and anabolic processes within the muscle cell. A current challenge of exercise biology is to describe the molecular mechanisms of regulation by which contractile activity stimulates net protein breakdown during exercise and net protein synthesis during recovery. Muscle growth is optimized by combining exercise and appropriate nutritional strategies, such as amino acid (AA) and carbohydrate ingestion. The effects are integrated at the level of one central regulatory protein, mTOR (mammalian target of rapamycin). mTOR is a complex protein integrating signals of the energetic status of the cell and environmental stimuli to control protein synthesis, protein breakdown and therefore cell growth. mTOR is known to be activated by insulin, and the mechanisms involved are well documented. The ways by which exercise and AA lead to mTOR activation remain partially unclear. Exercise and AA use different signalling pathways upstream of mTOR. Exercise seems to recruit partially the same pathway as insulin, whereas AA could act more directly on mTOR. During resistance exercise, the activity of mTOR could be acutely blunted by AMP-activated protein kinase (AMPK), thus inhibiting protein synthesis and enhancing AA availability for energy metabolism. During recovery, the inhibition of mTOR by AMPK is suppressed, and its activation is maximized by the presence of AA. There appears to be a requirement for a minimal concentration of plasma insulin to stimulate muscle protein synthesis in response to resistance exercise and AA ingestion. ispartof: European journal of applied physiology vol:94 issue:1 pages:1-10 ispartof: location:Germany status: published