Abstract
INTRODUCTION: Skeletal muscle function is profoundly challenged under high-altitude environments, where hypobaric hypoxia disrupts structural integrity and impairs physiological function. However, few animal studies have examined the impact of hypobaric hypoxia on skeletal muscle and molecular basis. While exercise training holds promise for alleviating hypoxia-induced muscle dysfunction, the understanding of its protective mechanisms remains limited. OBJECTIVES: We aimed to investigate chronic hypobaric hypoxia-induced myotube atrophy and mitochondrial dysfunction in mouse models and C2C12 cells, and develop a combined exercise strategy (preconditioning and hypoxic training) to mitigate hypoxia-related muscle pathology. METHODS: A mouse chronic hypobaric hypoxia model (45-day exposure, 6,000 m equivalent) combined with in vitro C2C12 myotube hypoxia simulations was employed. Muscle atrophy, mitochondrial ultrastructure, and molecular pathways were analyzed via histology, proteomics, and functional assays. Exercise interventions included preconditioning (9-week treadmill training) followed by voluntary wheel running under hypobaric hypoxia. RESULTS: Chronic hypobaric hypoxia induced pronounced skeletal muscle dysfunction and mitochondrial structural disorganization. However, exercise preconditioning combined with hypoxic training attenuated these hypoxia-induced impairments. Both hypoxic skeletal muscles in vivo and C2C12 cells in vitro exhibited significant Sirt1 downregulation. Notably, overexpression of Sirt1 or treatment with exercise mimetics partially reversed hypoxia-induced myotube atrophy and mitochondrial dysfunction through the PGC-1α/FoxO3a signaling pathway-a mechanism shared with exercise interventions. CONCLUSION: This study uncovers exercise as a potent inducer of hypoxia resilience through Sirt1-dependent mitochondrial repair and multicellular crosstalk (vascular-endothelial-satellite cell axis). Our "train-before-you-climb" approach could transform how we prepare for high-altitude living, offering a drug-free way to keep muscles strong where the air is thin.