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. 2010 Sep 10;316(15):2487-503.
doi: 10.1016/j.yexcr.2010.04.031. Epub 2010 May 13.

TGF-beta receptors, in a Smad-independent manner, are required for terminal skeletal muscle differentiation

Rebeca Droguett  1 , Claudio Cabello-Verrugio, Cristian Santander, Enrique Brandan
Affiliations

TGF-beta receptors, in a Smad-independent manner, are required for terminal skeletal muscle differentiation

Rebeca Droguett et al. Exp Cell Res. .

Abstract

Skeletal muscle differentiation is strongly inhibited by transforming growth factor type beta (TGF-beta), although muscle formation as well as regeneration normally occurs in an environment rich in this growth factor. In this study, we evaluated the role of intracellular regulatory Smads proteins as well as TGF-beta-receptors (TGF-beta-Rs) during skeletal muscle differentiation. We found a decrease of TGF-beta signaling during differentiation. This phenomenon is explained by a decline in the levels of the regulatory proteins Smad-2, -3, and -4, a decrease in the phosphorylation of Smad-2 and lost of nuclear translocation of Smad-3 and -4 in response to TGF-beta. No change in the levels and inhibitory function of Smad-7 was observed. In contrast, we found that TGF-beta-R type I (TGF-beta-RI) and type II (TGF-beta-RII) increased on the cell surface during skeletal muscle differentiation. To analyze the direct role of the serine/threonine kinase activities of TGF-beta-Rs, we used the specific inhibitor SB 431542 and the dominant-negative form of TGF-beta-RII lacking the cytoplasmic domain. The TGF-beta-Rs were important for successful muscle formation, determined by the induction of myogenin, creatine kinase activity, and myosin. Silencing of Smad-2/3 expression by specific siRNA treatments accelerated myogenin, myosin expression, and myotube formation; although when SB 431542 was present inhibition in myosin induction and myotube formation was observed, suggesting that these last steps of skeletal muscle differentiation require active TGF-beta-Rs. These results suggest that both down-regulation of Smad regulatory proteins and cell signaling through the TGF-beta receptors independent of Smad proteins are essential for skeletal muscle differentiation.

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