Role of PGC-1-alpha-associated Mitochondrial Biogenesis in Statin-induced Myotoxicity

Methods: We used three mouse models: mice with muscle PGC-1α knockout (MKO), mice overexpressing PGC-1α (MCK), and wild-type (WT) mice. Mice were treated for 3 weeks with water or simvastatin (5 mg/kg/d) by oral gavage. We determined exercise capacity, muscle function and the function of muscle mitochondria from glycolytic gastrocnemius and soleus oxidative muscles. Results: Simvastatin showed muscular impairments in WT mice, manifested by decreased exercise capacity, grip strength and mitochondrial respiration in the glycolytic muscle, coupled with increased H2O2 production. Moreover, MKO mice treated with simvastatin exacerbated these muscular dysfunctions and showed impaired mitochondrial respiration in oxidative and glycolytic muscle types. However, MCK mice showed no impairments in exercise capacity and muscle function.