Introduction and Objective: The type 2 diabetes susceptibility gene GPSM1 is linked to impaired muscle function in patients, though its molecular mechanisms remain unknown. This study explores how GPSM1 regulates skeletal muscle metabolism and motor performance. Methods: Skeletal muscle-specific GPSM1 knockout (GPSM1 MKO) mice were generated and maintained on either a standard chow or high-fat diet (HFD), with body weight and composition monitored. Metabolic and motor phenotypes were assessed through glucose and insulin tolerance tests, grip strength and treadmill assays, respectively. Primary myotubes were cultured to investigate mitochondrial and molecular mechanisms, with mitochondrial respiration assessed by Seahorse assays and key pathways analyzed through RNA-seq, qPCR, and western blotting. Results: GPSM1 MKO mice exhibited impaired systemic metabolism and motor function in both feeding patterns, manifesting as reduced insulin sensitivity, glucose intolerance, decreased grip strength, and reduced exercise endurance, without affecting body weight. In cultured primary myotubes, GPSM1 KO impaired mitochondrial respiration, while GPSM1 overexpression enhanced mitochondrial function. Mechanistically, GPSM1 regulated mitochondrial biogenesis through the cAMP/PKA/ YAP/TAZ axis by suppressing PKA phosphorylation to activate YAP/TAZ, which subsequently stimulated the AMPK/PGC-1α pathway. Conclusion: Our study identifies GPSM1 as a key regulator of skeletal muscle mitochondrial content, thereby affecting metabolic and motor function and offering a potential therapeutic target for metabolic disorders. Disclosure L. You: None. L. Yao: None. X. Lyu: None. R. Qi: None. X. Ji: None. J. Yan: None. C. Hu: None. Funding Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0549400)
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