Hypoxia-induced muscle atrophy and impaired regulation of protein turnover are partially dependent on muscle glucocorticoid receptor signaling

Abstract

Background: Tissue hypoxia may contribute to muscle wasting in COPD. Hypoxemia induces skeletal muscle atrophy in mice, which in part can be attributed to reduction of food intake. Increased glucocorticoid concentrations and glucocorticoid receptor (GR) signaling have been implicated in muscle atrophy. Aim: Investigate whether hypoxia-induced muscle atrophy is GR dependent. Method: Muscle-specific GR knockout (mGRKO) mice and control mice were subjected to normoxia, normobaric hypoxia (8% oxygen) or pair-fed to the hypoxia group for 4 days. Result: Hypoxia and reduced food-intake resulted in an elevated corticosterone plasma concentration and increased expression of the GR-dependent genes Klf15 , Glul and Foxo1 in the gastrocnemius muscle. GR deficiency prevented muscle atrophy in the pair-fed group but not in the hypoxic group. GR deficiency blunted the elevated expression of genes related to autophagy-lysosomal degradation ( Map1lc3B , Bnip3 ) in both hypoxic and pair-fed mice. Hypoxia-induced expression of the Ub 26S-proteasome E3 ligases ( Murf1 , Atrogin-1 ) was suppressed in the pair-fed group. Reduced food intake but not hypoxia led to an inhibition of mTORC1 signaling, resulting in reduced phosphorylation of 4E-BP1 and S6. This deregulation of mTORC1 by hypoxia was GR-dependent and did not involve the established Akt/TSC2/mTOR axis or alterations of Redd1 or Klf15 expression. Conclusion: Hypoxia-induced muscle atrophy is partially dependent on muscle GR signaling. GR signaling is responsible for the impaired regulation of mTORC1 under hypoxia in the absence of anabolic stimuli. Supported by the Dutch Top Institute Pharma (project # T1-201).