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

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 wasmore » 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.« less

Authors:
; ;  [1];  [1]
  1. Centro de Regulacion Celular y Patologia, Centro de Regeneracion y Envejecimiento (CARE), Departamento de Biologia Celular y Molecular, MIFAB, Pontificia Universidad Catolica de Chile, Santiago (Chile)
Publication Date:
OSTI Identifier:
22209899
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 316; Journal Issue: 15; Other Information: Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CATTLE; CREATINE; GENE REGULATION; GROWTH FACTORS; INHIBITION; LIPOPROTEINS; MUSCLES; MYOSIN; PHOSPHORYLATION; RECEPTORS; RNA; SERINE; THREONINE

Citation Formats

Droguett, Rebeca, Cabello-Verrugio, Claudio, Santander, Cristian, and Brandan, Enrique, E-mail: ebrandan@bio.puc.cl. TGF-{beta} receptors, in a Smad-independent manner, are required for terminal skeletal muscle differentiation. United States: N. p., 2010. Web. doi:10.1016/J.YEXCR.2010.04.031.
Droguett, Rebeca, Cabello-Verrugio, Claudio, Santander, Cristian, & Brandan, Enrique, E-mail: ebrandan@bio.puc.cl. TGF-{beta} receptors, in a Smad-independent manner, are required for terminal skeletal muscle differentiation. United States. doi:10.1016/J.YEXCR.2010.04.031.
Droguett, Rebeca, Cabello-Verrugio, Claudio, Santander, Cristian, and Brandan, Enrique, E-mail: ebrandan@bio.puc.cl. Fri . "TGF-{beta} receptors, in a Smad-independent manner, are required for terminal skeletal muscle differentiation". United States. doi:10.1016/J.YEXCR.2010.04.031.
@article{osti_22209899,
title = {TGF-{beta} receptors, in a Smad-independent manner, are required for terminal skeletal muscle differentiation},
author = {Droguett, Rebeca and Cabello-Verrugio, Claudio and Santander, Cristian and Brandan, Enrique, E-mail: ebrandan@bio.puc.cl},
abstractNote = {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.},
doi = {10.1016/J.YEXCR.2010.04.031},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 15,
volume = 316,
place = {United States},
year = {2010},
month = {9}
}