title: TWEAK and TRAF6 regulate skeletal muscle atrophy.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA. ashok.kumar@louisville.edu
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Shephali
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Pradyut K
authors.initials: PK
authors.lastname: Paul
mesh_terms: D000818:Animals; D002100:Cachexia / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D000074049:Cytokine TWEAK; D016207:Cytokines / Q000097:blood; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000378:metabolism* / Q000503:physiopathology; D032448:Myoblasts, Skeletal / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000074049:Cytokine TWEAK; D016207:Cytokines; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex