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. Footnotes Abbreviations used in this paper: AMPK AMP-activated protein kinase CK creatine kinase CSA cross-sectional area EMSA electrophoretic mobility shift assay GA gastrocnemius GAPDH glyceraldehyde 3-phosphate dehydrogenase H&E hematoxylin and eosin IKK I κB kinase IRES internal ribosome entry site JNK c-Jun N-terminal kinase LLC Lewis lung carcinoma MCK muscle CK MEF mouse embryonic fibroblast MyHC myosin heavy chain nNOS neuronal nitric oxide synthase QRT-PCR quantitative real-time PCR STZ streptozotocin TA tibial anterior TRAF TNF receptor–associated factor TWEAK TNF-like weak inducer of apoptosis Submitted: 16 June 2010 Accepted: 19 November 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
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Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice
Paul, Pradyut K.; Gupta, Sanjay K.; Bhatnagar, Shephali; Panguluri, Siva K.; Darnay, Bryant G.; Choi, Yongwon; Kumar, Ashok
Follow The Journal of Cell Biology
, Volume 191 (7): 1395
Rockefeller University Press – Dec 27, 2010
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