| Summary: | p53 has been implicated in metabolic regulation, but its role in obesity-induced skeletal muscle insulin resistance remains incompletely understood. This study aimed to determine the functional contribution of skeletal muscle p53 to insulin resistance and mitochondrial dysfunction, particularly in the context of obesity. We demonstrate that inducible, skeletal muscle-specific deletion of p53 (iMp53 KO) significantly improves insulin sensitivity in high-fat diet (HFD)-induced obese mice, with no effect in chow-fed controls. This metabolic improvement was accompanied by enhanced mitochondrial respiration and membrane potential, as well as reduced mitochondrial calcium overload in palmitate-treated C2C12 myotubes. Electron microscopy and immunoblotting revealed a marked reduction in mitochondria-associated membrane (MAM) area and decreased levels of MAM components (IP3R, VDAC, GRP75) in iMp53 KO muscle. Co-immunoprecipitation assays demonstrated physical interactions between p53 and MAM proteins, supporting a role for p53 in promoting MAM formation under obese conditions. Consistently, skeletal muscle from patients with type 2 diabetes exhibited elevated expression of both p53 and MAM markers, with a positive correlation between them. These findings suggest that p53 plays an important role in modulating ER–mitochondrial contacts and mitochondrial homeostasis in skeletal muscle and suggest its contribution to obesity-induced insulin resistance. This study provides new mechanistic insight into the pathological role of p53 in muscle metabolism.
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