title: Myostatin-null mice exhibit delayed skin wound healing through the blockade of transforming growth factor-β signaling by decorin.
abstract: Myostatin (Mstn) is a secreted growth and differentiation factor that belongs to the transforming growth factor-β (TGF-β) superfamily. Mstn has been well characterized as a regulator of myogenesis and has been shown to play a critical role in postnatal muscle regeneration. Herein, we report for the first time that Mstn is expressed in both epidermis and dermis of murine and human skin and that Mstn-null mice exhibited delayed skin wound healing attributable to a combination of effects resulting from delayed epidermal reepithelialization and dermal contraction. In epidermis, reduced keratinocyte migration and protracted keratinocyte proliferation were observed, which subsequently led to delayed recovery of epidermal thickness and slower reepithelialization. Furthermore, primary keratinocytes derived from Mstn-null mice displayed reduced migration capacity and increased proliferation rate as assessed through in vitro migration and adhesion assays, as well as bromodeoxyuridine incorporation and Western blot analysis. Moreover, in dermis, both fibroblast-to-myofibroblast transformation and collagen deposition were concomitantly reduced, resulting in a delayed dermal wound contraction. These decreases are due to the inhibition of TGF-β signaling. In agreement, the expression of decorin, a naturally occurring TGF-β suppressor, was elevated in Mstn-null mice; moreover, topical treatment with TGF-β1 protein rescued the impaired skin wound healing observed in Mstn-null mice. These observations highlight the interplay between TGF-β and Mstn signaling pathways, specifically through Mstn regulation of decorin levels during the skin wound healing process. Thus we propose that Mstn agonists might be beneficial for skin wound repair.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Chek Kun
authors.initials: CK
authors.lastname: Tan
authors.forename: Craig
authors.initials: C
authors.lastname: McFarlane
authors.forename: Mridula
authors.initials: M
authors.lastname: Sharma
authors.forename: Nguan Soon
authors.initials: NS
authors.lastname: Tan
authors.forename: Ravi
authors.initials: R
authors.lastname: Kambadur
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D058575:Decorin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018859:Hair Follicle / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics / Q000502:physiology; D058628:Myofibroblasts / Q000378:metabolism / Q000502:physiology; D055435:Myostatin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D058575:Decorin; D055435:Myostatin; D053773:Transforming Growth Factor beta1; D003094:Collagen