Chronic hypoxia induces skeletal muscle atrophy in mice: Potential roles of antioxidant imbalance and FOXO1.

Abstract

Skeletal muscle atrophy, characterized by progressive loss of muscle mass and strength, severely impairs quality of life. Chronic hypoxia is a well-recognized inducer of this condition, but its potential pathophysiological mechanisms remain unclear. This study aims to investigate the effects of chronic hypoxia on skeletal muscle atrophy and to elucidate the key molecular mechanisms involved. C57BL/6 J mice were subjected to continuous hypobaric hypoxia (simulating an altitude of 5000 m) for 36 days to establish a chronic hypoxia model. Western blot was used to detect oxidative stress regulator, muscle atrophy/growth markers, and associated proteins; H&E staining to evaluate muscle fiber morphology; and Sirius Red to assess the degree of muscle fibrosis. Complementary in vitro experiments were conducted using C2C12 mouse myoblasts. Results showed that chronic hypoxia induced gastrocnemius muscle atrophy in mice, as evidenced by a significant reduction in the muscle fibers cross-sectional area and increased fibrosis. In C2C12 cells, chronic hypoxia downregulated the protein levels of NF-κB, SOD1 and NOX4. In the in vivo mouse model, chronic hypoxia upregulated FOXO1 and Trim63 expression while inhibiting MyoD1. Collectively, this study demonstrates that chronic hypoxia drives skeletal muscle atrophy by simultaneously suppressing the cellular antioxidant defense system and activating the FOXO1-mediated proteolytic signaling.