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J. Biol. Chem., Vol. 282, Issue 48, 35113-35124, November 30, 2007

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Tumor Necrosis Factor- Augments Matrix Metalloproteinase-9 Production in Skeletal Muscle Cells through the Activation of Transforming Growth Factor-β-activated Kinase 1 (TAK1)-dependent Signaling Pathway^*

Apurva K. Srivastava, Xuezhong Qin, Nia Wedhas, Marc Arnush, Thomas A. Linkhart, Robert B. Chadwick, and Ashok Kumar^¶1

From the Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California 92357, Loma Linda University School of Medicine, Loma Linda, California 92350, and the ^¶Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky 40202

We have investigated the effect of tumor necrosis factor- (TNF-) on the production of extracellular matrix-degrading proteases in skeletal muscles. Using microarray, quantitative PCR, Western blotting, and zymography, we found that TNF- drastically increases the production of matrix metalloproteinase (MMP)-9 from C2C12 myotubes. In vivo administration of TNF- in mice increased the transcript level of MMP-9 in skeletal muscle tissues. Although TNF- activated all the three MAPKs (i.e. ERK1/2, JNK, and p38), inhibition of ERK1/2 or p38 but not JNK blunted the TNF--induced production of MMP-9 from myotubes. Inhibition of Akt also inhibited the TNF--induced production of MMP-9. TNF- increased the activation of transcription factors NF-B and AP-1 but not SP-1 in myotubes. Overexpression of a dominant negative inhibitor of NF-B or AP-1 blocked the TNF--induced expression of MMP-9 in myotubes. Similarly, point mutations in AP-1- or NF-B-binding sites in MMP-9 promoter inhibited the TNF--induced expression of a reporter gene. TNF- increased the activity of transforming growth factor-β-activating kinase-1 (TAK1). Furthermore, overexpression of a dominant negative mutant of TAK1 blocked the TNF--induced expression of MMP-9 and activation of NF-B and AP-1. Our results also suggest that TNF- induces MMP-9 expression in muscle cells through the recruitment of TRAF-2, Fas-associated protein with death domain, and TNF receptor-associated protein with death domain but not NIK or TRAF-6 proteins. We conclude that TAK1-mediated pathways are involved in TNF--induced MMP-9 production in skeletal muscle cells.

Received for publication, June 28, 2007 , and in revised form, September 4, 2007.

^* This work was supported by National Institute of Health Grant RO1 AG129623 (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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1S, Fig. 1S, and an additional reference.

¹ To whom correspondence should be addressed: Dept. of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, 500 S. Preston St., Louisville, KY 40202. Tel.: 502-852-1133; Fax: 502-852-6228; E-mail: ashok.kumar{at}louisville.edu.

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