METFORMIN INCREASES PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR γ CO-ACTIVATOR-1α AND UTROPHIN A EXPRESSION IN DYSTROPHIC SKELETAL MUSCLE

Introduction: Metformin (MET) stimulates skeletal muscle AMP-activated protein kinase (AMPK), a key phenotype remodeling protein with emerging therapeutic relevance for Duchenne muscular dystrophy (DMD). Our aim was to identify the mechanism of impact of MET on dystrophic muscle. Methods: We investigated the effects of MET in cultured C2C12 muscle cells and mdx mouse skeletal muscle. Expression of potent phenotypic modifiers was assessed, including peroxisome proliferator-activated receptor (PPAR)gamma coactivator-1 alpha (PGC-1 alpha), PPAR delta, and receptor-interacting protein 140 (RIP140), as well as that of the dystrophin-homolog, utrophin A. Results: In C2C12 cells, MET augmented expression of PGC-1 alpha, PPAR delta, and utrophin A, whereas RIP140 content was reciprocally downregulated. MET treatment of mdx mice increased PGC-1 alpha and utrophin A and normalized RIP140 levels. Conclusions: In this study we identify the impact of MET on skeletal muscle and underscore the timeliness and importance of investigating MET and other AMPK activators as relevant therapeutics for DMD.