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J. Biol. Chem., Vol. 281, Issue 22, 15249-15257, June 2, 2006

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Fine Regulation of RhoA and Rock Is Required for Skeletal Muscle Differentiation^*

Loriana Castellani¹, Erica Salvati¹², Stefano Alemà³, and Germana Falcone⁴

From the Istituto di Biologia Cellulare, Consiglio Nazionale delle Ricerche, 00016 Monterotondo Scalo (RM), Italy and Dipartimento di Scienze Motorie e della Salute, Università di Cassino, 03043 Cassino (FR), Italy

The RhoA GTPase controls a variety of cell functions such as cell motility, cell growth, and gene expression. Previous studies suggested that RhoA mediates signaling inputs that promote skeletal myogenic differentiation. We show here that levels and activity of RhoA protein are down-regulated in both primary avian myoblasts and mouse satellite cells undergoing differentiation, suggesting that a fine regulation of this GTPase is required. In addition, ectopic expression of activated RhoA in primary quail myocytes, but not in mouse myocytes, inhibits accumulation of muscle-specific proteins and cell fusion. By disrupting RhoA signaling with specific inhibitors, we have shown that this GTPase, although required for cell identity in proliferating myoblasts, is not essential for commitment to terminal differentiation and muscle gene expression. Ectopic expression of an activated form of its downstream effector, Rock, impairs differentiation of both avian and mouse myoblasts. Conversely, Rock inhibition with specific inhibitors and small interfering RNA-mediated gene silencing leads to accelerated progression in the lineage and enhanced cell fusion, underscoring a negative regulatory function of Rock in myogenesis. Finally, we have reported that Rock acts independently from RhoA in preventing myoblast exit from the cell cycle and commitment to differentiation and may receive signaling inputs from Raf-1 kinase.

Received for publication, February 14, 2006

^* This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (to S. A.), Fondo Investimenti Ricerca di Base (to G. F. and S. A.), and Fondi Ateneo Ricerca, Università di Cassino (to L. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Present address: Istituto Regina Elena, 00158 Rome, Italy.

³ To whom correspondence may be addressed: Istituto di Biologia Cellulare, CNR, Via Ramarini 32, 00016 Monterotondo, Italy. Tel.: 39-06-90091324; Fax: 39-06-90091259; E-mail: alema{at}ibc.cnr.it. ⁴ To whom correspondence may be addressed: Istituto di Biologia Cellulare, CNR, Via Ramarini 32, 00016 Monterotondo, Italy. Tel.: 39-06-90091324; Fax: 39-06-90091259; E-mail: gfalcone{at}ibc.cnr.it.

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