This study explores the impact of voluntary exercise on the effectiveness of a gene therapy approach for Duchenne muscular dystrophy (DMD) using the D2-mdx murine model. DMD is caused by mutations in the dystrophin gene, leading to muscle damage and impaired regeneration. The research utilizes adeno-associated virus (AAV)-mediated U7 snRNA to skip a mutation-containing exon and restore dystrophin production. D2-mdx mice were treated with AAV-U7 and allowed to run voluntarily for one month to assess whether exercise affects gene therapy outcomes.

Findings and Results

Voluntary exercise did not worsen muscle damage indicators, such as centronucleated fibers and extracellular matrix deposition. Interestingly, running improved specific maximal muscle force, showing adaptive benefits. However, the percentage of muscle area expressing dystrophin decreased from 80% to 65% in exercising mice. Despite this reduction, dystrophin levels remained relatively high, indicating that gene therapy was not severely compromised.

Furthermore, exercise did not reduce the number of viral genomes or the expression of the therapeutic transgene, suggesting that muscle fiber infection and gene expression remained stable. Researchers also found no increased muscle damage, such as a rise in regeneration markers or a decline in muscle function. These results indicate that short-term voluntary exercise may be integrated into DMD therapeutic strategies without significantly affecting gene therapy outcomes.

Clinical Implications and Future Directions

Overall, this study underscores the potential of combining exercise with genetic approaches to optimize treatment for DMD. However, further research is needed to understand the long-term effects and to explore whether similar results occur in male D2-mdx mice or other DMD models.