Hypoxia sensitizes skeletal muscle to fasting-induced muscle atrophy; role of AMPK activation

Background: Severe COPD exacerbations are often associated with hypoxemia and reduced dietary intake, which may contribute to impaired protein turnover and muscle wasting in these patients. Aim: Investigate whether hypoxia sensitizes skeletal muscle to fasting-induced muscle atrophy. Method: Mice were kept under hypoxic (H) (8% oxygen) or normoxic conditions (21% oxygen), or pair-fed to the hypoxia group (NC) for 12 days and then fasted for 24 hrs prior to analysis. Results: Weight loss of the gastrocnemius muscle in response to fasting was greater in the hypoxic (H) than the normoxic or pair-fed (NC) groups. Conversely, fasting-induced increase in expression of Ub 26S-proteasome E3 ligases ( Murf1 , Atrogin-1 ) and autophagy-lysosomal degradation related genes ( Bnip3, Map1lc3 B) was attenuated in the H-group compared to the NC-group. Under normoxic conditions mTORC1 activity was reduced by fasting, whereas under hypoxic conditions fasting resulted in sustained mTORC1 activity as phosphorylation levels of RBS6 and 4E-BP1 were maintained. Fasting-induced inhibition of mTORC1 was accompanied by reduced Akt/TSC2/mTOR phosphorylation in the NC-group. Under hypoxia Akt/TSC2/mTOR phosphorylation levels were already decreased but did not match sustained RPS6 and 4E-BP1 phosphorylation levels. Fasting-induced inhibition of mTORC1 by AMPK/TSC2 pathway was observed in the NC-group but absent in the H-group and matched RPS6 and 4E-BP1 phosphorylation levels. Conclusion: Fasting-induced AMPK signaling is impaired by hypoxia and is associated with sustained mTORC1 activity, which may sensitize skeletal muscle to fasting-induced muscle atrophy. Supported by the Dutch Top Institute Pharma (project # T1-201).