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J. Cell Biol. 191 (7): 1395-1411

Copyright © 2010 by the Rockefeller University Press.


Article

Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice

Pradyut K. Paul1, Sanjay K. Gupta1, Shephali Bhatnagar1, Siva K. Panguluri1, Bryant G. Darnay2, Yongwon Choi3, , and Ashok Kumar1

1 Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202
2 Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030
3 Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Correspondence to Ashok Kumar: ashok.kumar{at}louisville.edu

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 ({alpha}) 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 {kappa}B, 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.


Abbreviations: 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 {kappa}B 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



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