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.
