RNF10 attenuates age-related muscle atrophy by promoting p53 degradation and alleviating oxidative stress.

Evidence identifies proteostasis imbalance and oxidative stress serve as fundamental pathological hallmarks of muscular atrophy, yet ring finger protein 10 (RNF10), a novel E3 ubiquitin ligase, in age-related muscular atrophy remains poorly characterized. Employing a natural aging mouse model and D-galactose-induced senescent C2C12 myotubes, we performed loss- and gain-of-function approaches for RNF10 with the aim of elucidating its downstream regulatory mechanisms. Aged mice showed significant declines in skeletal muscle mass and exercise capacity. Histological analysis revealed a significant reduction in gastrocnemius muscle (GAS) fiber cross-sectional area (CSA). Both in vivo and in vitro experiments showed elevated aging markers, increased inflammatory factors, decreased protein synthesis, enhanced proteolysis, and upregulated muscle atrophy indicators accompanied by nearly 50% reduction of RNF10 expression. AAV-mediated restoration of RNF10 in aged mice improved skeletal muscle mass and function, while reducing inflammatory levels and enhancing systemic antioxidant capacity. Mechanistically, RNF10 directly interacted with p53 to promote its ubiquitin-dependent degradation, which in turn reduced oxidative stress and improved mitochondrial function. In senescent myotubes, RNF10 deficiency elevated mitochondrial oxidative stress and disrupted proteostasis, effects that were rescued by p53 inhibition. TIGAR expression increased upon p53 degradation, and TIGAR silencing abolished the protective effects against myotube atrophy and oxidative stress, indicating that TIGAR is required for these beneficial outcomes. Our findings demonstrate that promoting RNF10-mediated p53 degradation represents a promising therapeutic strategy for sarcopenia intervention.