Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050121000395 |
| _version_ | 1819103657977708544 |
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| author | Shelby E. Hamm Daniel D. Fathalikhani Katherine E. Bukovec Adele K. Addington Haiyan Zhang Justin B. Perry Ryan P. McMillan Michael W. Lawlor Mariah J. Prom Mark A. Vanden Avond Suresh N. Kumar Kirsten E. Coleman J.B. Dupont David L. Mack David A. Brown Carl A. Morris J. Patrick Gonzalez Robert W. Grange |
| author_facet | Shelby E. Hamm Daniel D. Fathalikhani Katherine E. Bukovec Adele K. Addington Haiyan Zhang Justin B. Perry Ryan P. McMillan Michael W. Lawlor Mariah J. Prom Mark A. Vanden Avond Suresh N. Kumar Kirsten E. Coleman J.B. Dupont David L. Mack David A. Brown Carl A. Morris J. Patrick Gonzalez Robert W. Grange |
| author_sort | Shelby E. Hamm |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T01:53:57Z |
| format | Article |
| id | doaj.art-d1cbb7f0e57f48a4854b84e1f8896a3a |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-22T01:53:57Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
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| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-d1cbb7f0e57f48a4854b84e1f8896a3a2022-12-21T18:42:51ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012021-06-0121144160Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx miceShelby E. Hamm0Daniel D. Fathalikhani1Katherine E. Bukovec2Adele K. Addington3Haiyan Zhang4Justin B. Perry5Ryan P. McMillan6Michael W. Lawlor7Mariah J. Prom8Mark A. Vanden Avond9Suresh N. Kumar10Kirsten E. Coleman11J.B. Dupont12David L. Mack13David A. Brown14Carl A. Morris15J. Patrick Gonzalez16Robert W. Grange17Department of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USADepartment of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USADepartment of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USADepartment of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USADepartment of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USADepartment of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USADepartment of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USADepartment of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Pathology and Laboratory Medicine and Children’s Hospital of Wisconsin Research Institute Imaging Core, Milwaukee, WI 53226, USAPowell Gene Therapy Center Toxicology Core, University of Florida, Gainesville, FL 32610, USATranslational Gene Therapy for Genetic Diseases, INSERM UMR1089, IRS2 Nantes Biotech, Université de Nantes, Nantes 44200, FranceDepartment of Rehabilitation Medicine, University of Washington, Seattle, WA 98104, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98107, USADepartment of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USASolid Biosciences, Inc., Cambridge, MA 02139, USASolid Biosciences, Inc., Cambridge, MA 02139, USADepartment of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USA; Corresponding author: Robert W. Grange, Department of Human Nutrition, Foods, and Exercise and Metabolism Core, Virginia Tech, Blacksburg, VA 24060, USA.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.http://www.sciencedirect.com/science/article/pii/S2329050121000395duchenne muscular dystrophymuscle physiologymuscle pathologydystrophic gradevoluntary exerciseendurance |
| spellingShingle | Shelby E. Hamm Daniel D. Fathalikhani Katherine E. Bukovec Adele K. Addington Haiyan Zhang Justin B. Perry Ryan P. McMillan Michael W. Lawlor Mariah J. Prom Mark A. Vanden Avond Suresh N. Kumar Kirsten E. Coleman J.B. Dupont David L. Mack David A. Brown Carl A. Morris J. Patrick Gonzalez Robert W. Grange Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice Molecular Therapy: Methods & Clinical Development duchenne muscular dystrophy muscle physiology muscle pathology dystrophic grade voluntary exercise endurance |
| title | Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice |
| title_full | Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice |
| title_fullStr | Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice |
| title_full_unstemmed | Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice |
| title_short | Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice |
| title_sort | voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice |
| topic | duchenne muscular dystrophy muscle physiology muscle pathology dystrophic grade voluntary exercise endurance |
| url | http://www.sciencedirect.com/science/article/pii/S2329050121000395 |
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