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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cell Differentiation / drug effects
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Cells, Cultured / drug effects
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / pharmacology
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DNA-Binding Proteins / physiology*
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Gene Expression Regulation / drug effects
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MEF2 Transcription Factors
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Microtubules / drug effects
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Microtubules / physiology*
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Microtubules / ultrastructure
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Muscle Development / genetics*
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Myoblasts / cytology
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Myoblasts / drug effects*
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Myogenic Regulatory Factors
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Myogenin / biosynthesis*
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Myogenin / genetics
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Nocodazole / pharmacology
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Paclitaxel / pharmacology
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Recombinant Fusion Proteins / physiology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Smad2 Protein
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Smad3 Protein
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Smad7 Protein
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics
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Trans-Activators / pharmacology
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Trans-Activators / physiology*
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Transcription, Genetic / drug effects
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Transfection
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta / physiology*
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Transforming Growth Factor beta1
Substances
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DNA-Binding Proteins
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MEF2 Transcription Factors
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Myogenic Regulatory Factors
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Myogenin
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Recombinant Fusion Proteins
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Smad2 Protein
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Smad3 Protein
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Smad7 Protein
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Paclitaxel
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Nocodazole