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J. Cell Biol. 188 (6): 833-849

Copyright © 2010 by the Rockefeller University Press.


Article

The TWEAK–Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice

Ashwani Mittal1, Shephali Bhatnagar1, Akhilesh Kumar1, Estelle Lach-Trifilieff2, Sandrine Wauters2, Hong Li1, Denys Y. Makonchuk1, David J. Glass2, , and Ashok Kumar1

1 Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202
2 Novartis Institutes for BioMedical Research, Inc., Cambridge, MA 02139

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

Abstract: Skeletal muscle atrophy occurs in a variety of clinical settings, including cachexia, disuse, and denervation. Inflammatory cytokines have been shown to be mediators of cancer cachexia; however, the role of cytokines in denervation- and immobilization-induced skeletal muscle loss remains unknown. In this study, we demonstrate that a single cytokine, TNF-like weak inducer of apoptosis (TWEAK), mediates skeletal muscle atrophy that occurs under denervation conditions. Transgenic expression of TWEAK induces atrophy, fibrosis, fiber-type switching, and the degradation of muscle proteins. Importantly, genetic ablation of TWEAK decreases the loss of muscle proteins and spared fiber cross-sectional area, muscle mass, and strength after denervation. Expression of the TWEAK receptor Fn14 (fibroblast growth factor–inducible receptor 14) and not the cytokine is significantly increased in muscle upon denervation, demonstrating an unexpected inside-out signaling pathway; the receptor up-regulation allows for TWEAK activation of nuclear factor {kappa}B, causing an increase in the expression of the E3 ubiquitin ligase MuRF1. This study reveals a novel mediator of skeletal muscle atrophy and indicates that the TWEAK–Fn14 system is an important target for preventing skeletal muscle wasting.


Abbreviations: CK, creatine kinase • CSA, cross-sectional area • EDL, extensor digitorum longus • EMSA, electrophoretic mobility shift assay • GA, gastrocnemius • mTOR, mammalian target of rapamycin • MyHC, myosin heavy chain • NF-{kappa}B, nuclear factor {kappa}B • nNOS, neuronal nitric oxide synthase • QRT-PCR, quantitative real-time PCR • TA, tibialis anterior • TWEAK, TNF-like weak inducer of apoptosis • TWEAK-KO, TWEAK knockout • TWEAK-Tg, TWEAK transgenic



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