Transforming Growth Factor-β–Induced Inhibition of Myogenesis Is Mediated Through Smad Pathway and Is Modulated by Microtubule Dynamic Stability

• Published in: Circulation research Vol. 94; no. 5; pp. 617 - 625
• Main Authors: Zhu, Shoukang, Goldschmidt-Clermont, Pascal J, Dong, Chunming
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 19.03.2004; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Biological and medical sciences; Cell Differentiation - drug effects; Cells, Cultured - drug effects; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - pharmacology; DNA-Binding Proteins - physiology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; MEF2 Transcription Factors; Microtubules - drug effects; Microtubules - physiology; Microtubules - ultrastructure; Muscle Development - genetics; Myoblasts - cytology; Myoblasts - drug effects; Myogenic Regulatory Factors; Myogenin - biosynthesis; Myogenin - genetics; Nocodazole - pharmacology; Paclitaxel - pharmacology; Recombinant Fusion Proteins - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Smad2 Protein; Smad3 Protein; Smad7 Protein; Striated muscle. Tendons; Trans-Activators - antagonists & inhibitors; Trans-Activators - genetics; Trans-Activators - pharmacology; Trans-Activators - physiology; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription, Genetic - drug effects; Transfection; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta - physiology; Transforming Growth Factor beta1; Vertebrates: osteoarticular system, musculoskeletal system; Transforming growth factor β; Rodentia; Striated muscle; Myogenesis; Signal transduction; Vertebrata; Cell line; Mammalia; Mouse; Myoblast; Cytoskeleton; Inhibition; Microtubule
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000118599.25944.D5

ABSTRACT—The expression of muscle-specific genes associated with myogenesis is controlled by several myogenic transcription factors, including myogenin and MEF2D. Transforming growth factor-β (TGF-β) has been shown to inhibit myogenesis, yet the molecular mechanisms underlying such inhibition are not known. In the present study, TGF-β 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-β/Smad signaling, restored the capacity of these cells to differentiate in the presence of TGF-β 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-β, 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-β/Smad signaling. Our results indicate that TGF-β 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.