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-kappaB (NF-kappaB) signaling pathways. Inhibition of NF-kappaB 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-kappaB-inducing kinase or IkappaB kinase-beta but not IkappaB kinase-alpha 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.
Highlights
Destruction of skeletal muscle extracellular matrix is an important pathological consequence of many diseases involving muscle wasting
We have recently reported that tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK), a proinflammatory cytokine belonging to the TNF superfamily, is a potent skeletal muscle-wasting cytokine [13]
By chronic administration of tumor necrosis factor-related weak inducer of apoptosis (TWEAK) in control and Mmp9 knock-out mice, we investigated the role of matrix metalloproteinases (MMPs)-9 in TWEAK-induced body and skeletal muscle loss
Summary
We have reported that the TWEAK-induced degradation of muscle proteins (e.g. myosin heavy chain fast type and MyoD) involves the activation of nuclear factor-B (NF-B) transcription factor [13, 15]. The activation of either the classical or alternative NF-B signaling pathway can lead to skeletal muscle wasting in response to specific stimuli [22, 23], the upstream signaling mechanisms regulating NF-B activation and the genes that activated NF-B induces in skeletal muscle tissues remain largely unknown. Our study shows that NIK-, IKK-, and protein kinase 38 (p38) MAPK-dependent activation of NF-B is responsible for the increased expression of MMP-9 in cultured muscle cells. Our experiments demonstrate that compared with control mice TWEAK-induced myopathy is significantly attenuated in Mmp knock-out mice
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