Physical exertion exacerbates decline in the musculature of an animal model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a genetic disorder caused by loss of the protein dystrophin. In humans, DMD has early onset, causes developmental delays, muscle necrosis, loss of ambulation, and death. Current animal models have been challenged by their inability to model the early onset and se...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 9; pp. 3508 - 3517
Main Authors:	Hughes, K. J., Rodriguez, A., Flatt, K. M., Ray, S., Schuler, A., Rodemoyer, B., Veerappan, V., Cuciarone, K., Kullman, A., Lim, C., Gutta, N., Vemuri, S., Andriulis, V., Niswonger, D., Barickman, L., Stein, W., Singhvi, A., Schroeder, N. E., Vidal-Gade, A. G.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 26-02-2019
Series:	PNAS Plus
Subjects:	Animal models Animals Biological Sciences Caenorhabditis elegans - genetics Caenorhabditis elegans - physiology Caenorhabditis elegans Proteins - genetics Calcium Calcium-binding protein Calmodulin Disease Models, Animal Duchenne's muscular dystrophy Dystrophin Dystrophy Genetic disorders Humans Lethality Locomotion Machinery and equipment Mice Mice, Inbred mdx Mitochondria Muscle contraction Muscle Contraction - physiology Muscle, Skeletal - growth & development Muscle, Skeletal - physiopathology Muscles Muscular dystrophy Muscular Dystrophy, Animal - genetics Muscular Dystrophy, Animal - physiopathology Muscular Dystrophy, Animal - therapy Muscular Dystrophy, Duchenne - genetics Muscular Dystrophy, Duchenne - physiopathology Muscular Dystrophy, Duchenne - therapy Necrosis Pathogenesis Phenotypes Physical activity Physical Conditioning, Animal Physical Exertion - genetics Physical Exertion - physiology PNAS Plus Proteins Signs and symptoms Structural damage Therapeutic applications exercise C. elegans muscular dystrophy hypertrophy degeneration
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Summary:	Duchenne muscular dystrophy (DMD) is a genetic disorder caused by loss of the protein dystrophin. In humans, DMD has early onset, causes developmental delays, muscle necrosis, loss of ambulation, and death. Current animal models have been challenged by their inability to model the early onset and severity of the disease. It remains unresolved whether increased sarcoplasmic calcium observed in dystrophic muscles follows or leads the mechanical insults caused by the muscle’s disrupted contractile machinery. This knowledge has important implications for patients, as potential physiotherapeutic treatments may either help or exacerbate symptoms, depending on how dystrophic muscles differ from healthy ones. Recently we showed how burrowing dystrophic (dys-1) C. elegans recapitulate many salient phenotypes of DMD, including loss of mobility and muscle necrosis. Here, we report that dys-1 worms display early pathogenesis, including dysregulated sarcoplasmic calcium and increased lethality. Sarcoplasmic calcium dysregulation in dys-1 worms precedes overt structural phenotypes (e.g., mitochondrial, and contractile machinery damage) and can be mitigated by reducing calmodulin expression. To learn how dystrophic musculature responds to altered physical activity, we cultivated dys-1 animals in environments requiring high intensity or high frequency of muscle exertion during locomotion. We find that several muscular parameters (e.g., size) improve with increased activity. However, longevity in dystrophic animals was negatively associated with muscular exertion, regardless of effort duration. The high degree of phenotypic conservation between dystrophic worms and humans provides a unique opportunity to gain insight into the pathology of the disease as well as the initial assessment of potential treatment strategies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Iva Greenwald, Columbia University, New York, NY, and approved January 9, 2019 (received for review July 6, 2018) Author contributions: K.J.H., A.R., K.M.F., S.R., A. Singhvi, N.E.S., and A.G.V.-G. designed research; K.J.H., A.R., K.M.F., S.R., A. Schuler, B.R., K.C., A.K., C.L., N.G., S.V., V.A., L.B., and A.G.V.-G. performed research; A. Singhvi, N.E.S., and A.G.V.-G. contributed new reagents/analytic tools; K.J.H., A.R., K.M.F., A. Schuler, B.R., V.V., C.L., N.G., S.V., V.A., D.N., W.S., N.E.S., and A.G.V.-G. analyzed data; and K.J.H., W.S., and A.G.V.-G. wrote the paper. 1Present address: Program in Neuroscience, University of Washington, Seattle, WA 98195.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1811379116