Hypoxia‐induced muscle atrophy involves direct and indirect signaling towards protein turnover regulation

Background As COPD patients may experience hypoxemic episodes, we hypothesized that subsequent tissue hypoxia is a trigger of COPD‐associated skeletal muscle atrophy. Methods Mice were kept under normoxia or hypoxia. Oxygen levels were reduced stepwise to 8% during 48h, and maintained for 21 days. Food intake was monitored and mice were sacrificed at days 4 and 21. To discern direct and indirect effects of hypoxia, fully differentiated C2C12 myotube cultures were exposed to hypoxia (4% O 2 ). Results Hypoxia induced hypoxemia, acidosis, erythremia. Gastrocnemius muscle weight decreased, which was only in part attributable to hypophagia. Comparing hypoxia with pair‐fed, expression of ER‐stress markers Atf4 and Gadd34 , were increased as a direct effects of hypoxia and at day 4 partially by hypophagia. Protein synthesis was induced evidenced by reduced p‐eIF2α levels and increased mTOR signaling. Foxo‐1 activity and expression were directly induced by hypoxia and at day 4 by hypophagia. Gene expression associated with autophagy and ubiquitin 26S proteasomal degradation was induced and at day 4 partially attributable to hypophagia. As opposed to MuRF1 , Atrogin‐1 and LC3B , Bnip3 expression was directly regulated by hypoxia. Conclusion : Hypoxia‐induced muscle atrophy is characterized by signaling suggestive of increased muscle protein turnover. Supported by the Dutch Top Institute Pharma (project # T1‐201).