Chronic hypoxia impairs skeletal muscle repair via HIF‐2α stabilization

Abstract Background Chronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio‐pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions. Methods Experimental mice were exposed to prolonged normobaric hypoxic air (15% pO2, 1 atm, 2 weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia‐inducible factors HIF‐1α and HIF‐2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin‐induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC‐specific HIF‐2α knockout mice, and mice treated with HIF‐2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia‐ and HIF‐2α‐dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann–Whitney U tests. Results Chronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P