Enhancement of Hypoxia-Induced Autophagy via the HIF-1apha/BNIP3 Pathway Promotes Proliferation and Myogenic Differentiation of Aged Skeletal Muscle Satellite Cells

Aged skeletal muscle satellite cells (MuSCs) exhibit impaired autophagy-related activity, reduced proliferative capacity, and compromised myogenic differentiation, which collectively contribute to defective muscle regeneration during aging. However, whether hypoxia-driven modulation of autophagy-related activity can improve aged MuSC function and the underlying molecular mechanisms remain incompletely understood. In this study, aged MuSCs were divided into three groups: normoxia, hypoxia, and hypoxia combined with an Autophagy inhibitor. Aged MuSCs exhibited a decreased LC3B-II/LC3B-I ratio and Beclin-1 expression, together with elevated p62 levels, indicating altered autophagy-related activity. Hypoxic culture was associated with enhanced autophagy-related activity in aged MuSCs, accompanied by HIF-1α stabilization, BNIP3 upregulation, and reduced p62 accumulation. Functionally, hypoxia significantly promoted the proliferation and myogenic differentiation of aged MuSCs. Pharmacological inhibition of Autophagy using 3-methyladenine, as well as BNIP3 suppression, markedly attenuated these hypoxia-induced functional improvements. Collectively, these findings suggest that hypoxia is associated with improved proliferative and myogenic capacities of aged MuSCs, potentially involving autophagy-related activity regulated by the HIF-1α/BNIP3 pathway. This study provides insight into the relationship between hypoxic signaling and Autophagy in aged MuSCs and may inform future strategies aimed at improving muscle regeneration during aging.