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.