Résumé :
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IntroductionSkeletal muscle is susceptible to injury after either direct trauma, prolonged physical exercise including eccentric contractions, or resulting from indirect causessuch as neuromuscular diseases. A delay in the muscle regeneration process may lead to muscle atrophy, locomotive deficiency, and even to lethality. The maturationof regenerating fibers is influenced by external factors, such as mechanical load, and/or by endogenous factors such as metabolic perturbations. Hypoxia exposure wasidentified to alter the muscle growth rate (1). To date, the molecular pathways involved in muscle regeneration are poorly documented. Thus, we aimed at determiningthe effect of ambient hypoxia on the main intracellular pathways involved in muscle regeneration.MethodsLeft soleus muscles of female rats were degenerated by notexininjection before exposure to either normoxia (N) or ambient hypoxia (H) (10% O2) during 3, 7, 14 and 28 days (d). We measured muscle mass and studied by western-blotthe Akt/mammalian target of rapamycin (mTOR) pathway [AktThr308, p70S6KThr389 and eIF-4E binding protein 1 (4E-BP1Thr70)], and two negative regulators of mTOR[AMP-activated kinase (AMPKThr172) and regulated in development and DNA damage response 1 (REDD1)].ResultsThe expected muscle-mass loss of injured muscleswas increased by hypoxia at d3 and d7, whereas the recovery of muscle mass remained similar in H and N rats at d28 (Fig.1). The mTOR activity, assessed fromboth 4E-BP1 and P70S6K phosphorylation, was markedly increased during the early period of regeneration, but remained 2-fold lower in H than in N groups at d3.The hypoxia-induced decrease of mTOR activity was not related to specific alteration of Akt, but was associated with AMPK activation at d3. REDD1 expression wasmarkedly increased by H at d14 and d28 in intact muscles, but was blunted during the first days of regeneration (d3-7), independently of H. ConclusionWe show for thefirst time, that hypoxia enhances the muscle-mass loss after extensive injury. This could be due to a specific impairment of mTOR activation during muscle regeneration,independently of Akt, at least partly related to AMPK activation. The involvement of hypoxia in the REDD1-induced inhibition of mTOR (1) appears to be uncertain.REDD1 expression could be more likely modulated by muscle growth-related signals than by hypoxia. References1. Favier FB et al. (2010) This work was supported by the Association Franse contre les Myopathies
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