Metformin increases peroxisome proliferator-activated receptor γ Co-activator-1α and utrophin a expression in dystrophic skeletal muscle.
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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 C2 C12 muscle cells and mdx mouse skeletal muscle. Expression of potent phenotypic modifiers was assessed, including peroxisome proliferator-activated receptor (PPAR)γ coactivator-1α (PGC-1α), PPARδ, and receptor-interacting protein 140 (RIP140), as well as that of the dystrophin-homolog, utrophin A. RESULTS: In C2 C12 cells, MET augmented expression of PGC-1α, PPARδ, and utrophin A, whereas RIP140 content was reciprocally downregulated. MET treatment of mdx mice increased PGC-1α 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.
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