Ambient hypoxia enhances the muscle‐mass loss after extensive injury

Abstract

The aim of this study was to examine the effect of ambient hypoxia on the main intracellular pathways involved in muscle regeneration. Left soleus muscles of female rats were degenerated by notexin injection before exposure to either normoxia (N) or ambient hypoxia (H) (10% O2) during 3, 7, 14 and 28 days (d). The expected muscle-mass loss of injured muscles was higher in H than in N rats at d3 and d7, whereas the recovery of muscle mass was similar in H and N rats at d28. The mammalian target of rapamycin (mTOR) activity, assessed from both eIF-4E binding protein (4E-BP1) and P70S6K phosphorylation, was markedly increased during the early period of regeneration, but remained two-fold lower in H than in N groups at d3. The hypoxia-induced alteration of mTOR activity, independently of Akt, was associated with an activation of AMP-activated kinase (AMPK) at d3. In contrast, REDD1, another negative regulator of mTOR, was markedly activated by H at d14 and d28 in intact muscles, but was blunted during the first days of regeneration (d3–7), independently of H. Taken together, we show for the first 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, without detectable effect of REDD1. This work was supported by the Association Française contre les Myopathies (AFM).