title: Sharp-1 regulates TGF-β signaling and skeletal muscle regeneration.
abstract: 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-β expression, as well as levels of phosphorylated Smad2 and Smad3, are sustained in the mutant tissue and treatment with decorin, which blocks TGF-β signaling, improves the histopathology of Sharp-1(-/-) injured muscles. In vitro, Sharp-1 associates with Smad3, and its overexpression inhibits TGF-β- 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-β signaling.
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Acharjee
authors.forename: Teng-Kai
authors.initials: TK
authors.lastname: Chung
authors.forename: Suma
authors.initials: S
authors.lastname: Gopinadhan
authors.forename: Shilpa Rani
authors.initials: SR
authors.lastname: Shankar
authors.forename: Yaju
authors.initials: Y
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Cecile
authors.initials: C
authors.lastname: Vercherat
authors.forename: Neriman Tuba
authors.initials: NT
authors.lastname: Gulbagci
authors.forename: Moritz
authors.initials: M
authors.lastname: Rossner
authors.forename: Reshma
authors.initials: R
authors.lastname: Taneja
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004622:Embryo, Mammalian; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D015398:Signal Transduction; D051900:Smad3 Protein; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C470968:Bhlhb3 protein, mouse; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta
keywords: Degeneration; Fibrosis; Myofibroblast; Regeneration; Skeletal muscle; TGF-β