Published online before print January 22, 2004, doi: 10.1161/01.RES.0000118599.25944.D5
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Submitted on January 31, 2003
Revised on January 13, 2004
Accepted on January 15, 2004
Transforming Growth Factor-
-Induced Inhibition of Myogenesis Is Mediated Through Smad Pathway and Is Modulated by Microtubule Dynamic Stability
Shoukang Zhu ;
From the Division of Cardiology, Department of Internal Medicine, Duke University Medical Center, Durham, NC 27710
* To whom correspondence should be addressed. E-mail: dong0005{at}mc.duke.edu.
The expression of muscle-specific genes associated with myogenesis is controlled by several myogenic transcription factors, including myogenin and MEF2D. Transforming growth factor-
(TGF-) has been shown to inhibit myogenesis, yet the molecular mechanisms underlying such inhibition are not known. In the present study, TGF- 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-/Smad signaling, restored the capacity of these cells to differentiate in the presence of TGF- 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-, 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-/Smad signaling. Our results indicate that TGF- 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.
Key words: myogenesis • transforming growth factor-
•
Smad •
signal transduction •
microtubules
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