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

Dogra, Charu; Changotra, Harish; Mohan, Subburaman; Kumar, Ashok

doi:10.1074/jbc.m511131200

Cited by 147 publications

(207 citation statements)

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“…Although the exact mechanisms of action of TWEAK in skeletal muscle remain unknown, TWEAK has been found to inhibit the differentiation of myoblasts into myotubes (14). TWEAK also augments the degradation of specific muscle proteins such as MyoD and myosin heavy chain fast type in cultured muscle cells (13,15). Furthermore TWEAK-induced muscle atrophy in vivo is accompanied with significant extracellular matrix abnormalities (13).…”

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confidence: 99%

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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

Mittal

Paul

et al. 2009

Journal of Biological Chemistry

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107

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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-B (NF-B) signaling pathways. Inhibition of NF-B 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-B-inducing kinase or IB kinase-␤ but not IB kinase-␣ 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.

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confidence: 99%

“…In addition, we have also 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).…”

mentioning

confidence: 99%

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

Mittal

Paul

et al. 2009

Journal of Biological Chemistry

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107

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“…In particular, TWEAK induced NF-kB activation has been directly implicated in mesangial cell chemokine secretion, 26 glioma cell survival 23 and myoblast differentiation. 15 However, as suggested above, it appears that TWEAK can also elicit pro-death signalling in some cell types. In this regard TWEAK induced activation of c-Jun N-terminal kinase signalling in HT29 cells and RAW264.7 macrophages has been observed.…”

Section: The Involvement Of Tweak and Fn14 In Cell Deathmentioning

confidence: 83%

“…14 Similarly, myoblasts in skeletal muscle, that are critical for muscle growth and repair, are stimulated by TWEAK and induced to proliferate, with a concomitant decrease in differentiation into myotubes. 15 Hence, FGF2, a known inhibitor of myoblast differentiation and wound response mediator, may work through induction of the TWEAK/FN14 signalling system. In support of this notion it has been observed that TWEAK can synergize with FGF2 in promoting endothelial cell proliferation, migration and microvessel formation.…”

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confidence: 99%

TWEAK shall inherit the earth

Vince

Silke

2006

Cell Death Differ

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Sometimes size really does not matter: recent papers on the tumour necrosis factor (TNF)-like ligand, TWEAK (tumour necrosis factor-like weak inducer of apoptosis), and its diminutive 129 amino-acid receptor, FN14 (fibroblast growth factor (FGF) -inducible 14 kDa protein), describe an impressive and potent range of biological effects. The TNF superfamily (TNSF) receptor FN14 has a small cytoplasmic domain, and the limited similarity of its extracellular domain to the cysteine-rich domains of the TNFSF receptors was only appreciated retrospectively when it was discovered that it bound TWEAK. 1 Recent work has demonstrated that TWEAK knockout animals have an activated immune system that is skewed by elevated numbers of natural killer (NK) cells and responds lethally to bacterial endotoxins, but also shows a powerful ability to prevent tumour growth. 2 Other topical papers show that TWEAK and FN14 work to promote liver regeneration following injury and prevent the differentiation of a diverse range of cell types. The role of TWEAK and FN14 in cancer has yet to be conclusively established, but several groups have observed high expression of FN14 in cancerous tissues, and demonstrated that it can promote cellular functions important for tumorigenesis, including cytokine production, cellular proliferation, survival, migration and angiogenesis. 3 TWEAK is a type II transmembrane protein (extracellular C-terminus) that can undergo proteolysis to produce an active soluble homotrimer, 4,5 whereas FN14 is a type Ia transmembrane protein. 6 In some respects the potent effects of the ligand TWEAK are reminiscent to those of TNFa: both factors appear to play roles in inflammation, and both have the capacity to induce cell death, although usually in conjunction with another stimulus. Responses to TNFSF ligands can be complex because several ligands often bind to the same receptor and vice versa. For example, both the human ligands TNFa and LTa bind the receptors TNFR1 and TNFR2, whereas LTa also binds HVEM. In fact, more than half of the TNSF ligands bind to at least two receptors. 7 One of the amazing things about the TWEAK/FN14 system is that it is a simple, single ligand, single receptor system 7 in which the intracellular signalling domain of FN14 is only 28 amino acids. It remains possible that another TWEAK receptor exists 8 which might help to explain the diverse range of effects that TWEAK produces, but this is yet to be conclusively established.

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“…The proinflammatory cytokine signals through binding to its receptor Fn14 and activates NF κ b in a TGF β ‐activated kinase 1‐(TAK1‐) dependent manner 162. TWEAK is expressed in a wide variety of cell types including monocytes and macrophages, dendritic cells and T cells163, 164, 165, 166, 167 and its implications in controlling muscle tissue repair and regeneration have reaffirmed its role as a key regulator of myogenesis 164, 168. As opposed to DM, PM and healthy mesoangioblasts, IBM mesoangioblasts fail to fully differentiate into skeletal myotubes 169.…”

Section: Pathomechanisms In Ibmmentioning

confidence: 99%

Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.

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

Cited by 147 publications

References 75 publications

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

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

TWEAK shall inherit the earth

Immune and myodegenerative pathomechanisms in inclusion body myositis

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