Tumor Necrosis Factor-related Weak Inducer of Apoptosis Augments Matrix Metalloproteinase 9 (MMP-9) Production in Skeletal Muscle through the Activation of Nuclear Factor-κB-inducing Kinase and p38 Mitogen-activated Protein Kinase

Abstract

Destruction of skeletal muscle extracellular matrix is an important pathological consequence of many diseases involving muscle wasting. However, the underlying mechanisms leading to extracellular matrix breakdown in skeletal muscle tissues remain unknown. Using a microarray approach, we investigated the effect of tumor necrosis factor-related weak inducer of apoptosis (TWEAK), a recently identified muscle-wasting cytokine, on the expression of extracellular proteases in skeletal muscle. Among several other matrix metalloproteinases (MMPs), we found that the expression of MMP-9, a type IV collagenase, was drastically increased in myotubes in response to TWEAK. The level of MMP-9 was also higher in myofibers of TWEAK transgenic mice. TWEAK increased the activation of both classical and alternative nuclear factor-κB (NF-κB) signaling pathways. Inhibition of NF-κB activity blocked the TWEAK-induced production of MMP-9 in myotubes. TWEAK also increased the activation of AP-1, and its inhibition attenuated the TWEAK-induced MMP-9 production. Overexpression of a kinase-dead mutant of NF-κB-inducing kinase or IκB kinase-β but not IκB kinase-α significantly inhibited the TWEAK-induced activation of MMP-9 promoter. The activation of MMP-9 also involved upstream recruitment of TRAF2 and cIAP2 proteins. TWEAK increased the activity of ERK1/2, JNK1, and p38 MAPK. However, the inhibition of only p38 MAPK blocked the TWEAK-induced expression of MMP-9 in myotubes. Furthermore the loss of body and skeletal muscle weights, inflammation, fiber necrosis, and degradation of basement membrane around muscle fibers were significantly attenuated in Mmp9 knock-out mice on chronic administration of TWEAK protein. The study unveils a novel mechanism of skeletal muscle tissue destruction in pathological conditions. Destruction of skeletal muscle extracellular matrix is an important pathological consequence of many diseases involving muscle wasting. However, the underlying mechanisms leading to extracellular matrix breakdown in skeletal muscle tissues remain unknown. Using a microarray approach, we investigated the effect of tumor necrosis factor-related weak inducer of apoptosis (TWEAK), a recently identified muscle-wasting cytokine, on the expression of extracellular proteases in skeletal muscle. Among several other matrix metalloproteinases (MMPs), we found that the expression of MMP-9, a type IV collagenase, was drastically increased in myotubes in response to TWEAK. The level of MMP-9 was also higher in myofibers of TWEAK transgenic mice. TWEAK increased the activation of both classical and alternative nuclear factor-κB (NF-κB) signaling pathways. Inhibition of NF-κB activity blocked the TWEAK-induced production of MMP-9 in myotubes. TWEAK also increased the activation of AP-1, and its inhibition attenuated the TWEAK-induced MMP-9 production. Overexpression of a kinase-dead mutant of NF-κB-inducing kinase or IκB kinase-β but not IκB kinase-α significantly inhibited the TWEAK-induced activation of MMP-9 promoter. The activation of MMP-9 also involved upstream recruitment of TRAF2 and cIAP2 proteins. TWEAK increased the activity of ERK1/2, JNK1, and p38 MAPK. However, the inhibition of only p38 MAPK blocked the TWEAK-induced expression of MMP-9 in myotubes. Furthermore the loss of body and skeletal muscle weights, inflammation, fiber necrosis, and degradation of basement membrane around muscle fibers were significantly attenuated in Mmp9 knock-out mice on chronic administration of TWEAK protein. The study unveils a novel mechanism of skeletal muscle tissue destruction in pathological conditions. Skeletal muscle atrophy/wasting has highly complex physiology that involves not only intracellular protein degradation but also several extracellular alterations including the breakdown of skeletal muscle basement membrane and intramuscular connective tissues (1Kanagawa M. Toda T. J. Hum. Genet. 2006; 51: 915-926Crossref PubMed Scopus (105) Google Scholar, 2Shiao T. Fond A. Deng B. Wehling-Henricks M. Adams M.E. Froehner S.C. Tidball J.G. Hum. Mol. Genet. 2004; 13: 1873-1884Crossref PubMed Scopus (47) Google Scholar). However, the identity of the molecules that cause extracellular matrix degradation in skeletal muscle during pathological conditions remains unknown. Matrix metalloproteinases (MMPs) 2The abbreviations used are: MMP, matrix metalloproteinase; AP-1, activator protein-1; cIAP, cellular inhibitor of apoptosis; DM, differentiation medium; DN, dominant negative; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal-regulated kinase; IκB, inhibitor of κB; IKK, IκB kinase; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; NIK, NF-κB-inducing kinase; SEAP, secreted alkaline phosphatase; TNF, tumor necrosis factor; TRAF, TNF receptor-associated factor; TIMP, tissue inhibitor of metalloproteases; TWEAK, TNF-related weak inducer of apoptosis; NDGA, nordihydroguaiaretic acid; siRNA, short interfering RNA; GST, glutathione S-transferase; TA, tibial anterior. are a family of extracellular matrix-degrading enzymes that are collectively capable of degrading all the components of the extracellular matrix (3Mott J.D. Werb Z. Curr. Opin. Cell Biol. 2004; 16: 558-564Crossref PubMed Scopus (874) Google Scholar, 4Vu T.H. Werb Z. Genes Dev. 2000; 14: 2123-2133Crossref PubMed Scopus (1052) Google Scholar). These proteases are synthesized as secreted or transmembrane proenzymes and processed to an active form by the removal of an amino-terminal propeptide (3Mott J.D. Werb Z. Curr. Opin. Cell Biol. 2004; 16: 558-564Crossref PubMed Scopus (874) Google Scholar, 4Vu T.H. Werb Z. Genes Dev. 2000; 14: 2123-2133Crossref PubMed Scopus (1052) Google Scholar, 5Nagase H. Woessner Jr., J.F. J. Biol. Chem. 1999; 274: 21491-21494Abstract Full Text Full Text PDF PubMed Scopus (3890) Google Scholar). MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are the two major MMPs that can several matrix including type IV an of the basement membrane (3Mott J.D. Werb Z. Curr. Opin. Cell Biol. 2004; 16: 558-564Crossref PubMed Scopus (874) Google Scholar, 4Vu T.H. Werb Z. Genes Dev. 2000; 14: 2123-2133Crossref PubMed Scopus (1052) Google Scholar, 5Nagase H. Woessner Jr., J.F. J. Biol. Chem. 1999; 274: 21491-21494Abstract Full Text Full Text PDF PubMed Scopus (3890) Google Scholar). production of MMP-2 and MMP-9 has found to tissue destruction in a of including and and J. Adams J. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Curr. 13: PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar, M. J. 2006; PubMed Scopus Google Scholar, S.C. J. Full Text Full Text PDF PubMed Scopus Google Scholar, B. A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). However, the and the mechanisms MMP-2 or MMP-9 expression during conditions not are as of the important of skeletal muscle in chronic diseases Curr. Opin. 2004; PubMed Scopus Google Scholar). recently that tumor necrosis weak inducer of apoptosis (TWEAK), a to the TNF is a skeletal muscle-wasting H. A. J. PubMed Scopus Google Scholar). the mechanisms of of TWEAK in skeletal muscle remain TWEAK has found to the differentiation of myotubes M. A. T. Mol. PubMed Scopus Google Scholar). TWEAK also the degradation of muscle as and type in muscle H. A. J. PubMed Scopus Google Scholar, H. A. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore TWEAK-induced muscle in is extracellular matrix H. A. J. PubMed Scopus Google Scholar). we also that the TWEAK-induced degradation of muscle type and involves the activation of nuclear factor-κB (NF-κB) H. A. J. PubMed Scopus Google Scholar, H. A. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). NF-κB is a major that the expression of a of involved in and H. A. J. Mol. PubMed Scopus Google Scholar, A. J. Mol. 2004; PubMed Google Scholar, Genes Dev. 2004; PubMed Scopus Google Scholar). that activation of NF-κB to skeletal muscle H. A. J. Mol. PubMed Scopus Google Scholar, J.D. Jr., J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). inhibition of NF-κB loss of skeletal muscle in response to as tumor and J.D. Jr., J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, S.C. J. 2004; PubMed Scopus Google Scholar). on the type of the activation of NF-κB can a or alternative Genes Dev. 2004; PubMed Scopus Google Scholar). The NF-κB signaling involves the upstream activation of of kinase-β and and degradation of IκB proteins. the other activation of the alternative NF-κB the upstream activation of NF-κB-inducing kinase and and the of A. J. Mol. 2004; PubMed Google Scholar, Genes Dev. 2004; PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar). the activation of the classical or alternative NF-κB signaling can to skeletal muscle in response to B. Tidball J.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. H. S.C. J. 16: PubMed Scopus Google the upstream signaling mechanisms NF-κB activation and the that NF-κB in skeletal muscle tissues remain unknown. that of the mechanisms by TWEAK is the increased production of extracellular proteases we a microarray and myotubes. that the expression and production of MMP-9 are drastically increased in myotubes. expression of MMP-9 was also in skeletal muscle tissues of TWEAK transgenic mice. study also that and protein kinase activation of NF-κB is the increased expression of MMP-9 in muscle that mice TWEAK-induced is significantly attenuated in Mmp9 knock-out mice. and were and and were and were was NF-κB and activator and were and and protein were Cell inhibitor of apoptosis and receptor-associated were TWEAK protein and MMP-9 protein were was and Mmp9 knock-out mice were The mice TWEAK the of muscle kinase H. A. J. 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Chem. 1999; 274: 21491-21494Abstract Full Text Full Text PDF PubMed Scopus (3890) Google was only increased Furthermore the increased of MMP-9 in skeletal muscle tissue of transgenic mice TWEAK in skeletal muscle and in administration of TWEAK in mice not that of the mechanisms by TWEAK is the increased production of MMP-9 other in the skeletal muscle in study that TWEAK-induced is significantly attenuated in Mmp9 knock-out mice The of MMP-9 is the of a upstream AP-1, NF-κB, and are in both and M. J. 2006; PubMed Scopus Google Scholar, J. H. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). that the activation of NF-κB is of the important signaling the expression of MMP-9 in response to M. A. T. Mol. 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Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). are of the important that are involved in activation of a of signaling pathways. that the of a and of TRAF2 and the TWEAK-induced activation of NF-κB in J. PubMed Scopus Google Scholar, T. M. H. H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). also that and cIAP2 TRAF2 protein the activation of NF-κB J. A. PubMed Scopus Google Scholar, M. M. M. T. M. J. Cell Biol. PubMed Scopus Google Scholar). B. M. J. J. Cell Biol. 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NF-κB, p38 MAPK as an important to the expression of muscle-wasting molecules in skeletal muscle. important of study was that the TWEAK-induced loss of body was significantly attenuated in Mmp9 knock-out mice to mice Furthermore muscle and muscle fiber were significantly higher in Mmp9 knock-out mice to mice that the increased production of MMP-9 to the TWEAK-induced muscle in Furthermore the of and fibers and in skeletal muscle tissues of Mmp9 knock-out mice that the increased of MMP-9 in muscle tissues to and fiber necrosis in skeletal muscle. of MMP-9 in skeletal muscle is not is MMP-9 is a of the and and tissue degradation in several J. Adams J. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Curr. 13: PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar, M. J. 2006; PubMed Scopus Google Scholar, S.C. J. Full Text Full Text PDF PubMed Scopus Google Scholar, B. A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). IV in skeletal muscle basement membrane is the important degradation of MMP-9, to MMP-9 can also and in skeletal muscle tissues or by the activation of other MMPs M. A. T. Mol. PubMed Scopus Google Scholar). Furthermore MMP-9 can and M. A. T. Mol. PubMed Scopus Google Scholar, M. T. A. Mol. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, Z. J. J. PubMed Scopus Google are all components of skeletal muscle extracellular also that an important of the complex on muscle is also of the important of MMP-9 B. J. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. T. 2006; PubMed Scopus Google Scholar). degradation of basement membrane around muscle fibers in Mmp9 knock-out mice to mice that MMP-9 is involved in the degradation of the components of extracellular matrix in skeletal muscle that to increased and fiber we the that TWEAK can MMP-9 production in skeletal muscle and that the increased production of MMP-9 to the loss of skeletal muscle in also the signaling mechanisms by TWEAK MMP-9 expression in muscle the cause and effect the production of MMP-9 and skeletal muscle has not in is that mechanisms involved in skeletal muscle tissue destruction in other conditions expression of MMP-9 is the in that of MMP-9 in skeletal muscle in in mice. and A. also important to the that MMP-9 in the skeletal muscle and and of MMP-9 can in and the of MMP-9 used in