Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice

Molecular Therapy: Methods & Clinical Development

David A. Brown¹  Shelby E. Hamm²  Ryan P. McMillan²  Katherine E. Bukovec²  Daniel D. Fathalikhani²  Justin B. Perry²  Haiyan Zhang²  Adele K. Addington²  Carl A. Morris²  Suresh N. Kumar³  Mark A. Vanden Avond⁴  Mariah J. Prom⁴  Michael W. Lawlor⁴  David L. Mack⁵  Kirsten E. Coleman⁶  Robert W. Grange⁷  J. Patrick Gonzalez⁷  J.B. Dupont⁸ 

[1] Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98107, USA;Department of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USA;Department of Pathology and Laboratory Medicine and Children’s Hospital of Wisconsin Research Institute Imaging Core, Milwaukee, WI 53226, USA;Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;Department of Rehabilitation Medicine, University of Washington, Seattle, WA 98104, USA;Powell Gene Therapy Center Toxicology Core, University of Florida, Gainesville, FL 32610, USA;Solid Biosciences, Inc., Cambridge, MA 02139, USA;Translational Gene Therapy for Genetic Diseases, INSERM UMR1089, IRS2 Nantes Biotech, Université de Nantes, Nantes 44200, France;

关键词: duchenne muscular dystrophy;    muscle physiology;    muscle pathology;    dystrophic grade;    voluntary exercise;    endurance;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown