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J. Biol. Chem., Vol. 281, Issue 15, 10327-10336, April 14, 2006

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Tumor Necrosis Factor-like Weak Inducer of Apoptosis Inhibits Skeletal Myogenesis through Sustained Activation of Nuclear Factor-B and Degradation of MyoD Protein^*

Charu Dogra, Harish Changotra, Subburaman Mohan^¶, and Ashok Kumar¹

From the Molecular Genetics Division, Musculoskeletal Disease Center, Jerry L. Pettis Veterans Administration Medical Center, Loma Linda, California 92357 and the Departments of Medicine and ^¶Biochemistry, Loma Linda University, Loma Linda, California 92350

In this study we have investigated the effect and the mechanisms by which tumor necrosis factor-like weak inducer of apoptosis (TWEAK) modulates myogenic differentiation. Treatment of C2C12 myoblasts with TWEAK inhibited their differentiation evident by a decrease in the expression of creatine kinase, myosin heavy chain-fast twitch, myogenin, and the formation of multinucleated myotubes. TWEAK also inhibited the differentiation of mouse primary myoblasts. Conversely, the proliferation of C2C12 myoblasts and the expression of a cell-cycle regulator cyclin D1 were increased in response to TWEAK treatment. Inhibition of cellular proliferation using hydroxyurea only partially reversed the inhibitory effect of TWEAK on myogenic differentiation. Treatment of C2C12 myoblasts with TWEAK resulted in the activation of nuclear factor-B (NF-B), the (IkappaB) IB kinase (IKK) complex, and the phosphorylation and degradation of IB protein. Inhibition of NF-B activity by overexpression of a dominant negative mutant of IB (IBN) significantly increased the myogenic differentiation in TWEAK-treated C2C12 cultures. Furthermore, overexpression of a dominant negative mutant of IKK (IKKK44A) but not IKK (IKKK44M) reversed the inhibitory effect of TWEAK on myogenesis. TWEAK inhibited the expression of myogenic regulatory factors MyoD and myogenin and also induced the degradation of MyoD protein. Finally, inhibition of NF-B activation through overexpression of IKKK44A prevented the degradation of MyoD protein. Overall, our data suggest that TWEAK inhibits myogenesis through the activation of NF-B signaling pathway and degradation of MyoD protein.

Received for publication, October 12, 2005 , and in revised form, December 23, 2005.

^* This work was supported by the Department of the Army Cooperative Agreement Number DAMD 17-97-2-7016. This study was also supported, in part, by a research grant from the Muscular Dystrophy Association (to A. K.). All the work was performed at facilities provided by the Jerry L. Pettis Memorial Veterans Administration Medical Center in Loma Linda, California. 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: Molecular Genetics Division, Musculoskeletal Disease Center, Jerry L. Pettis Veterans Administration Medical Center, 11201 Benton St. (151), Loma Linda, CA 92357. Tel.: 909-825-7084 (ext. 1704); Fax: 909-796-1680; E-mail: Ashok.Kumar2{at}med.va.gov.

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