1. Depletion of skeletal muscle satellite cells attenuates pathology in muscular dystrophy.
- Author
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Boyer, Justin G., Huo, Jiuzhou, Han, Sarah, Havens, Julian R., Prasad, Vikram, Lin, Brian L., Kass, David A., Song, Taejeong, Sadayappan, Sakthivel, Khairallah, Ramzi J., Ward, Christopher W., and Molkentin, Jeffery D.
- Subjects
SATELLITE cells ,MUSCULAR dystrophy ,MUSCLE cells ,CHRONIC wasting disease ,FACIOSCAPULOHUMERAL muscular dystrophy ,SKELETAL muscle ,PLASMA instabilities - Abstract
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. Boyer et al. created genetic mouse models of muscular dystrophy in which satellite cells were selectively depleted. The depletion of satellite cells at select times was protective. Myofibers no longer had plasma membrane instability leading to tissue wasting in the muscular dystrophies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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