title: Transforming growth factor-beta-induced inhibition of myogenesis is mediated through Smad pathway and is modulated by microtubule dynamic stability.
abstract: The expression of muscle-specific genes associated with myogenesis is controlled by several myogenic transcription factors, including myogenin and MEF2D. Transforming growth factor-beta (TGF-beta) has been shown to inhibit myogenesis, yet the molecular mechanisms underlying such inhibition are not known. In the present study, TGF-beta was shown to inhibit myogenin and MEF2D expression and myotube formation in C2C12 myoblasts cultured in differentiation medium in a cell density-dependent manner. Transfection of C2C12 cells with Smad7, an antagonist for TGF-beta/Smad signaling, restored the capacity of these cells to differentiate in the presence of TGF-beta or when cultured in growth medium at low confluence, conditions that hinder muscle differentiation. Moreover, nocodazole, a microtubule-destabilizing agent, enhanced the inhibition of myogenesis exerted by TGF-beta, an effect that could be restored by tubulin-polymerizing agent taxol, both of which have been shown to affect Smad-microtubule interaction and regulate TGF-beta/Smad signaling. Our results indicate that TGF-beta inhibits myogenesis, at least in part, via Smad pathway, and provide evidence that low-dose pharmacological agents taxol and nocodazole can be used as a means to modulate myogenesis without affecting cell survival.
authors.affiliation: Division of Cardiology, Duke University Medical Center, 406 Sands Building, Research Drive, Durham, NC 27710, USA.
authors.forename: Shoukang
authors.initials: S
authors.lastname: Zhu
authors.forename: Pascal J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
authors.forename: Chunming
authors.initials: C
authors.lastname: Dong
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D064326:MEF2 Transcription Factors; D008870:Microtubules / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D024510:Muscle Development / Q000235:genetics*; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects*; D018006:Myogenic Regulatory Factors; D018008:Myogenin / Q000096:biosynthesis* / Q000235:genetics; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1
chemical_list: D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D011993:Recombinant Fusion Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017239:Paclitaxel; D015739:Nocodazole