Hamm SE, Fathalikhani DD, Bukovec KE, Addington AK, Zhang H, Perry JB, McMillan RP, Lawlor MW, Prom MJ, Vanden Avond MA, Kumar SN, Coleman KE, Dupont JB, Mack DL, Brown DA, Morris CA, Gonzalez JP, and Grange RW
We tested the hypothesis that voluntary wheel running would complement microdystrophin gene therapy to improve muscle function in young mdx mice, a model of Duchenne muscular dystrophy. mdx mice injected with a single dose of AAV9-CK8-microdystrophin or vehicle at age 7 weeks were assigned to three groups: mdxRGT (run, gene therapy), mdxGT (no run, gene therapy), or mdx (no run, no gene therapy). Wild-type (WT) mice were assigned to WTR (run) and WT (no run) groups. WTR and mdxRGT performed voluntary wheel running for 21 weeks; remaining groups were cage active. Robust expression of microdystrophin occurred in heart and limb muscles of treated mice. mdxRGT versus mdxGT mice showed increased microdystrophin in quadriceps but decreased levels in diaphragm. mdx final treadmill fatigue time was depressed compared to all groups, improved in mdxGT, and highest in mdxRGT. Both weekly running distance (km) and final treadmill fatigue time for mdxRGT and WTR were similar. Remarkably, mdxRGT diaphragm power was only rescued to 60% of WT, suggesting a negative impact of running. However, potential changes in fiber type distribution in mdxRGT diaphragms could indicate an adaptation to trade power for endurance. Post-treatment in vivo maximal plantar flexor torque relative to baseline values was greater for mdxGT and mdxRGT versus all other groups. Mitochondrial respiration rates from red quadriceps fibers were significantly improved in mdxGT animals, but the greatest bioenergetic benefit was observed in the mdxRGT group. Additional assessments revealed partial to full functional restoration in mdxGT and mdxRGT muscles relative to WT. These data demonstrate that voluntary wheel running combined with microdystrophin gene therapy in young mdx mice improved whole-body performance, affected muscle function differentially, mitigated energetic deficits, but also revealed some detrimental effects of exercise. With microdystrophin gene therapy currently in clinical trials, these data may help us understand the potential impact of exercise in treated patients., Competing Interests: Research funding for R.W.G. was provided by Solid Biosciences, Inc.; R.W.G. is a consultant for Lion Therapeutics, Inc., Cytokinetics, Inc., Prothelia Inc., and Anagenesis Biotechnologies, Inc. Research funding for M.W.L. was provided by Solid Biosciences, Audentes Therapeutics, Taysha Therapeutics, and Prothelia. M.W.L. was a board member for Solid Biosciences and Audentes Therapeutics during the period when studies were performed. M.W.L. is a consultant for Audentes Therapeutics, AGADA Biosciences, Encoded Therapeutics, Kate Therapeutics, Lacerta Therapeutics, Affinia Therapeutics, Modis Therapeutics, Dynacure, and Biomarin. Research funding and D.L.M. was provided by Audentes Therapeutics and Cytokinetics. D.L.M. is a consultant for Audentes Therapeutics, Kate Therapeutics, and Affinia Therapeutics. Research funding for K.E.C. was provided by Solid Biosciences, Inc.; no other remuneration was received. J.P.G. and C.A.M. are employees of Solid Biosciences, Inc. All other authors declare no competing interests., (© 2021 The Author(s).)