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J. Biol. Chem., Vol. 282, Issue 20, 15000-15010, May 18, 2007

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Fibroblast Growth Factor Inducible 14 (Fn14) Is Required for the Expression of Myogenic Regulatory Factors and Differentiation of Myoblasts into Myotubes

EVIDENCE FOR TWEAK-INDEPENDENT FUNCTIONS OF Fn14 DURING MYOGENESIS^*

Charu Dogra, Susan L. Hall, Nia Wedhas, Thomas A. Linkhart, and Ashok Kumar¹

From the Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California 92357 and the Loma Linda University School of Medicine, Loma Linda, California 92350

Fibroblast growth factor-inducible 14 (Fn14), distantly related to tumor necrosis factor receptor superfamily and a receptor for TWEAK cytokine, has been implicated in several biological responses. In this study, we have investigated the role of Fn14 in skeletal muscle formation in vitro. Flow cytometric and Western blot analysis revealed that Fn14 is highly expressed on myoblastic cell line C2C12 and mouse primary myoblasts. The expression of Fn14 was decreased upon differentiation of myoblasts into myotubes. Suppression of Fn14 expression using RNA interference inhibited the myotube formation in both C2C12 and primary myoblast cultures. Fn14 was required for the transactivation of skeletal -actin promoter and the expression of specific muscle proteins such as myosin heavy chain fast type and creatine kinase. RNA interference-mediated knockdown of Fn14 receptor in C2C12 myoblasts decreased the levels of myogenic regulatory factors MyoD and myogenin upon induction of differentiation. Conversely, overexpression of MyoD increased differentiation in Fn14-knockdown C2C12 cultures. Suppression of Fn14 expression in C2C12 myoblasts also inhibited the differentiation-associated increase in the activity of serum response factor and RhoA GTPase. In addition, our data suggest that the role of Fn14 during myogenic differentiation could be independent of TWEAK cytokine. Collectively, our study suggests that the Fn14 receptor is required for the expression of myogenic regulatory factors and differentiation of myoblasts into myotubes.

Received for publication, September 7, 2006 , and in revised form, March 21, 2007.

^* This work was supported by National Institutes of Health Grant RO1 AG129623 and a research grant from the Muscular Dystrophy Association (to A. K.). 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 To whom correspondence should be addressed: Laboratory for Skeletal Muscle Physiology and Neurobiology, Jerry L. Pettis Memorial VA Medical Center, 11201 Benton St., Loma Linda, CA 92357. Tel.: 909-825-7084 (ext. 1704); Fax: 909-796-1680; E-mail: ashok.kumar2{at}va.gov.

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