Journal
JOURNAL OF CELL SCIENCE
Volume 127, Issue 3, Pages 599-608Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.136648
Keywords
TGF-beta; Fibrosis; Regeneration; Skeletal muscle; Degeneration; Myofibroblast
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Funding
- MOE Academic Research Fund [T13-0802-P28]
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Sharp-1 is a basic helix-loop-helix (bHLH) transcriptional repressor that is involved in a number of cellular processes. Our previous studies have demonstrated that Sharp-1 is a negative regulator of skeletal myogenesis and it blocks differentiation of muscle precursor cells by modulating the activity of MyoD. In order to understand its role in pre- and post-natal myogenesis, we assessed skeletal muscle development and freeze-injury-induced regeneration in Sharp-1-deficient mice. We show that embryonic skeletal muscle development is not impaired in the absence of Sharp-1; however, post-natally, the regenerative capacity is compromised. Although the initial phases of injury-induced regeneration proceed normally in Sharp-1(-/-) mice, during late stages, the mutant muscle exhibits necrotic fibers, calcium deposits and fibrosis. TGF-beta expression, as well as levels of phosphorylated Smad2 and Smad3, are sustained in the mutant tissue and treatment with decorin, which blocks TGF-beta signaling, improves the histopathology of Sharp-1(-/-) injured muscles. In vitro, Sharp-1 associates with Smad3, and its overexpression inhibits TGF-beta- and Smad3-mediated expression of extracellular matrix genes in myofibroblasts. These results demonstrate that Sharp-1 regulates muscle regenerative capacity, at least in part, by modulation of TGF-beta signaling.
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