Chronic metformin treatment induces beneficial adaptations in dystrophic skeletal muscle

DMD is the most severe inherited neuromuscular disorder for which there is no effective treatment. Our pre‐clinical studies in mdx mice demonstrated that pharmacological activation of PPARβ/γ or AMPK elicits a fiber type shift towards the slower, more oxidative (SO) phenotype together with utrophin A upregulation thereby attenuating the dystrophic pathology (HMG, 18:2640, 2009; HMG, 20:3478, 2011; AJP Cell 302:C110, 2012). The challenge now is to identify agonists of these pathways that have more immediate clinical relevance. The purpose of this study was to investigate whether AMPK stimulation via metformin (MET), a front‐line drug in the treatment of type 2 diabetes, induces beneficial muscle remodeling. In C2C12 cells, MET augmented expression of PGC‐1α, a master regulator of the SO myogenic program, as well as utrophin A levels. MET treatment of mdx mice for 6 weeks resulted in an increase in PGC‐1α in fast skeletal muscle with a concomitant reduction of the transcriptional corepressor RIP140. Expression of utrophin A was also augmented after MET administration in vivo. The data clearly suggest that MET‐induced reciprocal changes in PGC‐1α and RIP140 expression are linked to elevations in utrophin A content. As these adaptations are expected to be highly beneficial to dystrophic fibers, we propose that MET represents a novel and promising therapeutic avenue for DMD. Supported by MDA, CIHR, and Jesse's Journey.