Dystrophin Restoration after Adeno-Associated Virus U7-Mediated Dmd Exon Skipping Is Modulated by Muscular Exercise in the Severe D2-Mdx Duchenne Muscular Dystrophy Murine Model.

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease caused by Dmd mutations, resulting in the absence of dystrophin in skeletal muscle, with a greater susceptibility to damage during contraction (exercise). In this study, we evaluated whether voluntary exercise impacts a Dmd exon skipping approach and muscle physiology in a severe DMD murine model. We intramuscularly injected an adeno-associated virus (AAV) U7 snRNA that aimed to correct Dmd reading frame in D2-mdx mice, and they voluntary ran in a wheel for 1 month. Our results suggested that voluntary running did not induce muscle fiber regeneration, considering the percentage of centronucleated fibers, Myh3 and Myh4 expression, or maximal force production, and thus possibly not compromise a gene therapy approach. With the AAV-U7 injected just before exercise initiation, we reported that voluntary running did not impact the number of viral genomes and the expression of U7 and Dmd 1 month after injection of AAV-U7, but reduced the amount of dystrophin, from 80% to 65% of the muscle cross-sectional area with dystrophin-expressing fibers. In conclusion, voluntary running did not induce muscle damage and had no drastic detrimental effect on the AAV gene therapy exon skipping approach in a severe murine DMD model. Moreover, our results suggested that exercise should be an additional element to consider in the design and conception of future therapeutic approaches for DMD.