4.8 Article

Depletion of skeletal muscle satellite cells attenuates pathology in muscular dystrophy

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-30619-7

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  1. National Institutes of Health
  2. Muscular Dystrophy Association

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Satellite cells play a crucial role in the progression of muscular dystrophy, and their depletion can improve the pathology and muscle performance in dystrophic mouse models. Mechanistically, satellite cells initiate the expression of MyoD, which induces the re-expression of fetal genes in myofibers, leading to sarcolemmal destabilization. These findings suggest that satellite cell activation and the fetal gene program are maladaptive in chronic muscular dystrophy.
Skeletal muscle can repair and regenerate due to resident stem cells known as satellite cells. The muscular dystrophies are progressive muscle wasting diseases underscored by chronic muscle damage that is continually repaired by satellite cell-driven regeneration. Here we generate a genetic strategy to mediate satellite cell ablation in dystrophic mouse models to investigate how satellite cells impact disease trajectory. Unexpectedly, we observe that depletion of satellite cells reduces dystrophic disease features, with improved histopathology, enhanced sarcolemmal stability and augmented muscle performance. Mechanistically, we demonstrate that satellite cells initiate expression of the myogenic transcription factor MyoD, which then induces re-expression of fetal genes in the myofibers that destabilize the sarcolemma. Indeed, MyoD re-expression in wildtype adult skeletal muscle reduces membrane stability and promotes histopathology, while MyoD inhibition in a mouse model of muscular dystrophy improved membrane stability. Taken together these observations suggest that satellite cell activation and the fetal gene program is maladaptive in chronic dystrophic skeletal muscle.

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