GW8510 alleviated muscle atrophy and skeletal muscle dysfunction in mice through AMPK/PGC1a signaling

Preventing and restoring muscle loss and function is essential for elderly individuals. In this study, we expect to investigate the protective effect of GW8510 on muscle atrophy. We established mouse models of muscle atrophy induced by denervation, dexamethasone, and glycerol. We assessed the muscle weight-to-body weight ratio, the cross-sectional area of various muscles, grip strength, fatigue tasks, and serum analysis. In vitro, we created dexamethasone-induced C2C12 myotube atrophy and evaluated mitochondrial function. Additionally, we utilized real-time polymerase chain reaction, immunoblotting, and siRNA transfection to explore the potential molecular mechanisms following treatment with GW8510. Results showed that Treatment with GW8510 resulted in a significant increase in the gastrocnemius and soleus muscle ratios in denervation mice (7% and 3%, respectively, P < 0.001), alongside an increase in cross-sectional area. Moreover, GW8510 notably improved grip strength and superoxide dismutase (SOD) activity (P < 0.0001), with similar protective effects observed in dexamethasone and glycerol-induced muscle atrophy and injury models. Furthermore, GW8510 reduced reactive oxygen species production (P < 0.01), increased mitochondrial DNA copy number (P < 0.01), maintained mitochondrial dynamics, and enhanced antioxidant activity in C2C12 myotubes. Mechanistically, GW8510 significantly inhibited the expression of atrophy-related markers Fbxo32 and Trim63 (P < 0.01) while activating AMPK (P < 0.01). The knockdown of small interfering RNA targeting Pgc1a negated the effects of GW8510. Overall, GW8510 mitigated muscle atrophy through the activation of the AMPK/ PGC1a pathway. Our findings suggest that GW8510 could serve as a novel therapeutic agent for the prevention of muscle atrophy. Overall design: Gene expression profiling analysis of RNA-seq data from C2C12 myotubes stimulated with dexamethasone (10 µM) or vehicle, followed by treatment with GW8510 (2 µM) or vehicle for 24 hours in triplicate.