TWEAK and TRAF6 regulate skeletal muscle atrophy

Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Current opinion in clinical nutrition and metabolic care 02/2012; 15(3):233-9. DOI: 10.1097/MCO.0b013e328351c3fc
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To discuss the roles and mechanisms of action of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and tumor necrosis factor receptor-associated factor 6 (TRAF6) in skeletal muscle atrophy.
Proinflammatory cytokines are known to mediate muscle atrophy in many chronic disease states. However, their role in the loss of skeletal muscle mass in disuse conditions has just begun to be elucidated. Further, the initial signaling events leading to the activation of various catabolic pathways in skeletal muscle under different atrophic conditions are also less well understood. The TWEAK-Fn14 system has now been identified as a novel inducer of skeletal muscle wasting. Adult skeletal muscles express minimal levels of Fn14, the bona fide TWEAK receptor. Specific conditions of atrophy such as denervation, immobilization, or unloading rapidly induce the expression of Fn14 leading to TWEAK-induced activation of various proteolytic pathways in skeletal muscle. Recent studies have also demonstrated that the expression and activity of TRAF6 are increased in distinct models of muscle atrophy. Muscle-specific ablation of TRAF6 inhibits the induction of atrophy program in response to starvation, denervation, or cancer cachexia. Moreover, TWEAK also appears to activate some catabolic signaling through TRAF6-dependent mechanisms.
Recent findings have uncovered TWEAK and TRAF6 as novel regulators of skeletal muscle atrophy. These proteins should potentially be used as molecular targets for prevention and/or treatment of muscular atrophy in future therapies.

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Available from: Pradyut Paul, Jan 11, 2014
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    • "Indeed, MuRF1 belongs to the RING finger E3 ligase family (the most numerous) that does not possess any catalytic activity and relies on E2 enzymes for targeting the proteins to be degraded. Other RING (Really Interesting New Genes) E3 ligases like Trim32 or TRAF6 may have a role in the atrophying program and also need specific E2s for correctly targeting substrates for degradation (Kudryashova et al., 2005; Hishiya et al., 2006; Kumar et al., 2012). E2 enzymes determine the type of chain built on the substrate and thus whether the ubiquitination of the target protein is dedicated to degradation or to other fates (signaling, modulation of activity, etc.). "
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    ABSTRACT: The Ubiquitin Proteasome System (UPS) is a major actor of muscle wasting during various physio-pathological situations. In the past 15 years, increasing amounts of data have depicted a picture, although incomplete, of the mechanisms implicated in myofibrillar protein degradation, from the discovery of muscle-specific E3 ligases to the identification of the signaling pathways involved. The targeting specificity of the UPS relies on the capacity of the system to first recognize and then label the proteins to be degraded with a poly-ubiquitin (Ub) chain. It is fairly assumed that the recognition of the substrate is accomplished by the numerous E3 ligases present in mammalian cells. However, most E3s do not possess any catalytic activity and E2 enzymes may be more than simple Ub-providers for E3s since they are probably important actors in the ubiquitination machinery. Surprisingly, most authors have tried to characterize E3 substrates, but the exact role of E2s in muscle protein degradation is largely unknown. A very limited number of the 35 E2s described in humans have been studied in muscle protein breakdown experiments and the vast majority of studies were only descriptive. We review here the role of E2 enzymes in skeletal muscle and the difficulties linked to their study and provide future directions for the identification of muscle E2s responsible for the ubiquitination of contractile proteins.
    Frontiers in Physiology 03/2015; 6:59. DOI:10.3389/fphys.2015.00059 · 3.53 Impact Factor
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    • "The TWEAK cytokine and its receptor, Fn14, are identified as critical regulators of skeletal muscle mass [9,16]. It has been proposed that TWEAK causes Fn14 trimerization and subsequent activation of several signaling proteins including TRAF6, transforming growth factor-β activated kinase 1, I kappa B kinase, and MAPK leading to the activation of various transcription factors followed by gene expression [9,32-34]. Moreover, Mittal et al. reported that TWEAK could suppress the regeneration and growth of myofibers after injury and that the expression of both TWEAK and Fn14 were increased in skeletal muscle after injury caused by intramuscular injections of cardiotoxin [35]. "
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    ABSTRACT: The aim of this study was to investigate the expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) in patients with polymyositis (PM) and dermatomyositis (DM), and their relation to clinical manifestations . Serum levels of TWEAK were detected in 98 PM/DM patients and 37 healthy controls by using the ELISA method. Total RNA isolated from fresh-frozen muscle tissue samples of 36 PM/DM patients and 10 healthy controls were used for analyzing the mRNA levels of TWEAK and Fn14 by quantitative reverse transcription polymerase chain reaction (RT-PCR). Immunofluorescence staining of TWEAK and Fn14 was conducted on muscle biopsy specimens from 23 PM/DM patients and seven healthy controls. Serum levels of TWEAK were significantly decreased in the PM/DM patients compared to those in the healthy controls (P < 0.001), and serum TWEAK levels negatively correlated with serum CD163 levels in PM/DM patients (r = -0.49, P < 0.001). The expression of Fn14 mRNA was significantly increased in the muscle tissue of PM/DM patients than in the muscle tissue of healthy controls (P < 0.01), whereas the expression of TWEAK mRNA in PM/DM patients was not statistically different from that of the healthy controls (P > 0.05). Fn14 mRNA levels in muscle tissue positively correlated with muscle disease activity (r = 0.512, P < 0.01). Patients with oropharyngeal dysphagia had significantly higher Fn14 mRNA levels than patients without oropharyngeal dysphagia (P < 0.05). The results of immunofluorescence staining showed that 19 out of 23 PM/DM patients were TWEAK-positive, and 20 out of 23 PM/DM patients were Fn14-positive. No detectable expressions of TWEAK or Fn14 were observed in the healthy controls. TWEAK-Fn14 axis may be involved in the pathogenesis of PM/DM. Further understanding of TWEAK-Fn14 function in PM/DM may help to define therapeutic targets for PM/DM.
    Arthritis research & therapy 01/2014; 16(1):R26. DOI:10.1186/ar4454 · 3.75 Impact Factor
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    • "TWEAK-Fn14 signaling mediates unique and context-dependent pleiotropic effects [40]. TWEAK has been recently identified to be a key mediator that causes skeletal muscle loss that occurs in response to denervation, immobilization, and starvation [21,41,42]. Moreover, TWEAK-transgenic mice overexpressing physiological levels of TWEAK in skeletal muscle showed a higher proportion of fast-type fibers (glycolytic) in soleus and extensor digitorum longus (EDL) muscle [41] indicating that elevated levels of TWEAK cause a slow-to-fast type fiber switch. "
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    ABSTRACT: Proinflammatory cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 are the major regulators of skeletal muscle mass in many catabolic conditions. However, their role in muscle metabolism remains largely unknown. In the present study, we investigated the role of TWEAK on exercise capacity and skeletal muscle mitochondrial content and oxidative metabolism. We employed wild-type and TWEAK-knockout (KO) mice and primary myotube cultures and performed biochemical, bioenergetics, and morphometric assays to evaluate the effects of TWEAK on exercise tolerance and muscle mitochondrial function and angiogenesis. TWEAK-KO mice showed improved exercise tolerance compared to wild-type mice. Electron microscopy analysis showed that the abundance of subsarcolemmal and intermyofibrillar mitochondria is significantly increased in skeletal muscle of TWEAK-KO mice compared to wild-type mice. Furthermore, age-related loss in skeletal muscle oxidative capacity was rescued in TWEAK-KO mice. Expression of a key transcriptional regulator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) and several other molecules involved in oxidative metabolism were significantly higher in skeletal muscle of TWEAK-KO mice. Moreover, treatment of primary myotubes with soluble TWEAK inhibited the expression of PGC-1alpha and mitochondrial genes and decreased mitochondrial respiratory capacity. Deletion of TWEAK also improved angiogenesis and transcript levels of vascular endothelial growth factor in skeletal muscle of mice. These results demonstrate that TWEAK decreases mitochondrial content and oxidative phosphorylation and inhibits angiogenesis in skeletal muscle. Neutralization of TWEAK is a potential approach for improving exercise capacity and oxidative metabolism in skeletal muscle.
    Skeletal Muscle 07/2013; 3(1):18. DOI:10.1186/2044-5040-3-18
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