Résumé :
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Myostatin is a TGF-? family member that negatively regulates muscle growth. Studies in a mouse model of Duchenne and Becker muscular dystrophy (mdx) showed that deletion of myostatin gene or treatment with a postnatal inhibitor of myostatin significantly reduced muscle fibrosis, in addition to enhancing regeneration of muscle. The current study was designed to determine if the observed reduction in muscle fibrosis is directly regulated by myostatin or is secondary to increased myofiber regeneration. We found that muscle derived fibroblasts expressed myostatin and the putative receptor ActRIIB, suggesting fibroblast could be directly tageted either by autocrine or paracrine production of myostatin. Studies in primary cultured muscle fibroblast in vitro showed that myostatin significantly increased fibroblast proliferation and extracellular matrix protein production, which were determined by 3H-thymidine incorporation as well as expression of several fibroblast proteins. In vivo modulation of fibroblast growth by myostatin was demonstrated by injection of coated beads coated into mouse muscle yielding approximately 5 times more fibrosis surrounding myostatin coated beads than control. Collagen synthesis determined by incorporation of 3H-proline was increased in fibroblasts from Mdx mouse muscle compared to those from myostatin null Mdx mice, suggesting that myostatin can directly modulate muscle fibrosis in muscular dystrophies. These results expand our understanding of the role of myostatin in muscle tissue, beyond regulation of myocyte growth to that of control of the composition of the tissue as a whole. Myostatin may be a therapeutic target to reduce fibrosis in muscle disease.
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