Résumé :
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A therapeutic approach for Duchenne muscular dystrophy (DMD) is to upregulate utrophin levels in skeletal muscle in an effort to compensate for the lack of dystrophin. We have previously hypothesized that promotion of the slow, oxidative myogenic program, which triggers utrophin upregulation, can attenuate the dystrophic pathology in mdx animals, the murine model of DMD. Indeed, treatment of mdx mice with the PPAR_ activator GW501516 shifted muscle phenotype and ameliorated the disease pathology (Miura et al. Hum Mol Genet. 18:4640-49, 2009). Treatment of healthy mice with the AMPK activator AICAR enhances oxidative capacity and triggers a fast-toslow fiber-type transition. Our purpose was to evaluate the effects of chronic AICAR administration on muscle gene expression and the dystrophic pathology in mdx mice. AICAR mitigated muscle pseudo-hypertrophy and attenuated central nucleation. Furthermore, we observed an elevation in mitochondrial enzyme activity, an increase in myosin heavy chain IIa-positive fibers, and slower twitch contraction kinetics in the fast, glycolytic extensor digitorum longus muscle. Total utrophin protein content, as well as utrophin localization beyond the neuromuscular junction, was augmented in response to chronic AMPK stimulation. Moreover, _-dystroglycan expression was also partially restored along the sarcolemma. These molecular adaptations at the muscle cell membrane were accompanied by an increase in sarcolemmal integrity and stability at rest, and during intense eccentric muscle contractions ex vivo. Muscle PGC-1_ protein content was augmented in response to AICAR, concomitant with a reduction in RIP140, suggesting mechanisms underlying the AICAR-induced phenotypic changes. Notably, acute muscle contractile activity in vivo increased utrophin A, PGC-1_, and PPAR_ mRNAs in mdx animals. This effect was attenuated after chronic AICAR treatment which further highlights the phenotype-shifting capabilities of AMPK activation in dystrophic muscle. Our data suggest that AICAR-evoked muscle plasticity elicits the slow, oxidative myogenic program and results in beneficial phenotypic adaptations in mdx mice.Supported by MDA (USA), CIHR and NSERC.
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