Emergent dilated cardiomyopathy caused by targeted repair of dystrophic skeletal muscle.
Duchenne muscular dystrophy (DMD) is a fatal disease characterized by deterioration of striated muscle, affecting skeletal and cardiac muscles. Recently, several therapeutic approaches have shown promise for repairing dystrophic skeletal muscles. However, these methods often leave the dystrophic heart untreated. Here we show that, in comparison to fully dystrophin-deficient animals, targeted transgenic repair of skeletal muscle, but not cardiac muscle, in otherwise dystrophin-deficient (mdx) mice paradoxically elicited a fivefold increase in cardiac injury and dilated cardiomyopathy in these animals in vivo. Skeletal muscle repair was shown to increase the voluntary activity of the mdx mice as quantified by voluntary running on the exercise wheel. Because the dystrophin-deficient heart is highly sensitive to increased stress, we hypothesize that increased activity (enabled by the repaired skeletal muscle) provided the stimulus for heightened cardiac injury and heart remodeling. In support of this hypothesis, the primary cellular compliance defect in dystrophin-deficient cardiac myocytes was found to be unchanged by skeletal muscle repair in the mdx mice. These findings provide new information on the evolution of cardiac disease in dystrophin-deficient animals and underscore the importance of implementing global striated muscle therapies for muscular dystrophy.
Townsend
DeWayne
D
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109-0622, USA. 48109-0622, USA. dtown@umich.edu
Yasuda
Soichiro
S
Li
Sheng
S
Chamberlain
Jeffrey S
JS
Metzger
Joseph M
JM
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016189:Dystrophin / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000628:therapy; D009206:Myocardium / Q000378:metabolism; D010805:Physical Conditioning, Animal
D016189:Dystrophin