The TWEAK–Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice

Mittal, Ashwani; Bhatnagar, Shephali; Kumar, Akhilesh; Lach-Trifilieff, Estelle; Wauters, Sandrine; Li, Hong; Makonchuk, Denys Y.; Glass, David J.; Kumar, Ashok

doi:10.1083/jcb.200909117

Cited by 211 publications

(360 citation statements)

References 56 publications

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“…For each muscle, the distribution of fiber cross-sectional area (CSA) was calculated by analyzing 200 to 250 myofibers as described. 21,22 Amount of fibrosis in TA muscle sections was determined using Sirius red staining kit following a protocol suggested by manufacturer (American Master Tech).…”

Section: Indirect Immunofluorescence and Histomorphometric Assaysmentioning

confidence: 99%

“…20,22 Briefly, RNA was extracted from homogenized TA muscle using TRIzol reagent (Invitrogen) and an RNeasy Mini Kit (Qiagen Inc., Valencia, CA) according to the manufacturer's protocol. The quantification of mRNA expression was carried out using the SYBR Green dye method on 7300 Sequence Detection system (Applied Biosystems, Foster City, CA).…”

Section: Rna Isolation and Quantitative Real-time Pcrmentioning

confidence: 99%

“…21 More importantly, we have recently demonstrated that TWEAK-Fn14 dyad hasten the loss of skeletal muscle mass and function in response to denervation. 22 While insufficient myofiber regeneration contributes significantly to skeletal muscle wasting, the role and the mechanisms of action of TWEAK during muscle regeneration in vivo remain unknown.…”

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confidence: 99%

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Genetic Ablation of TWEAK Augments Regeneration and Post-Injury Growth of Skeletal Muscle in Mice

Mittal

Bhatnagar

Kumar

et al. 2010

The American Journal of Pathology

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Impairment in the regeneration process is a critical determinant for skeletal muscle wasting in chronic diseases and degenerative muscle disorders. Inflammatory cytokines are known to cause significant muscle wasting , however, their role in myofiber regeneration is less clear. In this study we have investigated the role of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in skeletal muscle regeneration in vivo. Our results show that expression levels of TWEAK and its receptor Fn14 are significantly increased in skeletal muscles of mice after injury. Genetic deletion of TWEAK increased the fiber crosssectional area and levels of embryonic isoform of myosin heavy chain in regenerating tibial anterior muscle. Conversely , muscle-specific transgenic overexpression of TWEAK reduced the fiber cross-sectional area and levels of the embryonic myosin heavy chain in regenerating muscle. TWEAK induced the expression of several inflammatory molecules and increased interstitial fibrosis in regenerating muscle. Genetic ablation of TWEAK suppressed, whereas overexpression of TWEAK increased, the activation of nuclear factor-kappa B without affecting the activation of Akt or p38 kinase in regenerating myofibers. Primary myoblasts from TWEAK-null mice showed enhanced differentiation in vitro, whereas myoblasts from TWEAK-Tg mice showed reduced differentiation compared with wild-type mice. Collectively, our study suggests that TWEAK negatively regulates muscle regeneration and that TWEAK is a potential therapeutic target to enhance skeletal muscle regeneration in vivo. (Am J

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Section: Indirect Immunofluorescence and Histomorphometric Assaysmentioning

confidence: 99%

Section: Rna Isolation and Quantitative Real-time Pcrmentioning

confidence: 99%

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Genetic Ablation of TWEAK Augments Regeneration and Post-Injury Growth of Skeletal Muscle in Mice

Mittal

Bhatnagar

Kumar

et al. 2010

The American Journal of Pathology

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“…Nevertheless, it appears that the TWEAK-Fn14 system is active in processes related to growth and remodeling of tissue and organs during development and tissue repair. In accordance with this, animal studies implicated the TWEAK-Fn14 system in liver progenitor cell proliferation (6,7), regulation of muscle development and muscle regeneration (8)(9)(10)(11), tumor-associated angiogenesis (12), and in various inflammationrelated pathologies including graft-versus-host disease, systemic lupus erythematosus-related nephritis (13), 2,4,6-trinitrobenzene sulfonic acid-induced colitis (14), renal and cerebral ischemia (15)(16)(17)(18), and collagen-induced arthritis (19,20).…”

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confidence: 93%

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

Salzmann

Lang

Rosenthal

et al. 2013

The Journal of Immunology

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We found recently that TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor–inducible-14 (Fn14) by virtue of their strong capability to reduce the freely available cytoplasmic pool of TNFR-associated factor (TRAF)2 and cellular inhibitors of apoptosis (cIAPs) antagonize the functions of these molecules in TNFR1 signaling, resulting in sensitization for apoptosis and inhibition of classical NF-κB signaling. In this study, we demonstrate that priming of cells with TWEAK also interferes with activation of the classical NF-κB pathway by CD40. Likewise, there was strong inhibition of CD40 ligand (CD40L)–induced activation of MAPKs in TWEAK-primed cells. FACS analysis and CD40L binding studies revealed unchanged CD40 expression and normal CD40L–CD40 interaction in TWEAK-primed cells. CD40L immunoprecipitates, however, showed severely reduced amounts of CD40 and CD40-associated proteins, indicating impaired formation or reduced stability of CD40L–CD40 signaling complexes. The previously described inhibitory effect of TWEAK on TNFR1 signaling has been traced back to reduced activity of the TNFR1-associated TRAF2–cIAP1/2 ubiquitinase complex and did not affect the stability of the immunoprecipitable TNFR1 receptor complex. Thus, the inhibitory effect of TWEAK on CD40 signaling must be based at least partly on other mechanisms. In line with this, signaling by the CD40-related TRAF2-interacting receptor TNFR2 was also attenuated but still immunoprecipitable in TWEAK-primed cells. Collectively, we show that Fn14 activation by soluble TWEAK impairs CD40L–CD40 signaling complex formation and inhibits CD40 signaling and thus identify the Fn14-TWEAK system as a potential novel regulator of CD40-related cellular functions.

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“…During chronic inflammatory conditions, TWEAK has been shown to mediate proliferation of precursor cells while prohibiting their terminal differentiation 171. Furthermore, a critical role for TWEAK/Fn14 in fostering muscle atrophy has been proposed 172, 173. Therefore, disbalance of the TWEAK/Fn14 axis may, similarly to what has been reported for TNF‐ α and IL‐1 β , block myogenic differentiation through NF κ b‐signalling174, 175 and, additionally, promote progressive muscle wasting and atrophy during IBM.…”

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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The TWEAK–Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice

Abstract: The TNF-related cytokine TWEAK promotes skeletal muscle atrophy that is associated with classical disuse syndromes.

Cited by 211 publications

References 56 publications

Genetic Ablation of TWEAK Augments Regeneration and Post-Injury Growth of Skeletal Muscle in Mice

Genetic Ablation of TWEAK Augments Regeneration and Post-Injury Growth of Skeletal Muscle in Mice

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

Immune and myodegenerative pathomechanisms in inclusion body myositis

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