title: Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice.
abstract: Skeletal muscle wasting is a major human morbidity, and contributes to mortality in a variety of clinical settings, including denervation and cancer cachexia. In this study, we demonstrate that the expression level and autoubiquitination of tumor necrosis factor (α) receptor adaptor protein 6 (TRAF6), a protein involved in receptor-mediated activation of several signaling pathways, is enhanced in skeletal muscle during atrophy. Skeletal muscle-restricted depletion of TRAF6 rescues myofibril degradation and preserves muscle fiber size and strength upon denervation. TRAF6 mediates the activation of JNK1/2, p38 mitogen-activated protein kinase, adenosine monophosphate-activated protein kinase, and nuclear factor κB, and induces the expression of muscle-specific E3 ubiquitin ligases and autophagy-related molecules in skeletal muscle upon denervation. Inhibition of TRAF6 also preserves the orderly pattern of intermyofibrillar and subsarcolemmal mitochondria in denervated muscle. Moreover, depletion of TRAF6 prevents cancer cachexia in an experimental mouse model. This study unveils a novel mechanism of skeletal muscle atrophy and suggests that TRAF6 is an important therapeutic target to prevent skeletal muscle wasting.
authors.affiliation: Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Pradyut K
authors.initials: PK
authors.lastname: Paul
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Shephali
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Siva K
authors.initials: SK
authors.lastname: Panguluri
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics; D002100:Cachexia / Q000150:complications / Q000473:pathology; D000074049:Cytokine TWEAK; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009121:Muscle Denervation / Q000009:adverse effects; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D057149:Ubiquitinated Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000074049:Cytokine TWEAK; D009124:Muscle Proteins; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D057149:Ubiquitinated Proteins; D044767:Ubiquitin-Protein Ligases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D018995:Myosin Heavy Chains