TWEAKing Muscle Atrophy

Science Signaling  30 Mar 2010:
Vol. 3, Issue 115, pp. ec94
DOI: 10.1126/scisignal.3115ec94

Skeletal muscle atrophy occurs in such conditions as cancer cachexia and also in response to denervation or disuse. Although inflammatory cytokines have been implicated in muscle wasting in cachexia, their role in atrophy from disuse has been unclear. Mittal et al., a group that previously identified TWEAK (tumor necrosis factor–like weak inducer of apoptosis) as a muscle-wasting cytokine, investigated its role in denervation-induced muscle atrophy. After determining that TWEAK overexpression in skeletal muscle led to skeletal muscle atrophy in transgenic mice (TWEAK-Tg mice), the authors looked for changes in its abundance under conditions leading to muscle atrophy or hypertrophy. Although they did not detect such changes in TWEAK, they found that abundance of the TWEAK receptor Fn14 (fibroblast growth factor–inducible receptor 14) and its encoding mRNA increased in denervated mouse muscle; similarly, muscles immobilized by a cast showed increased Fn14 mRNA. The effects of denervation on muscle mass were exacerbated in TWEAK-Tg mice and were attenuated in mice lacking TWEAK (TWEAK-KO mice) or mice treated with a TWEAK-neutralizing antibody. TWEAK-Tg mice showed an increase in DNA binding of the transcription factor nuclear factor κB (NF-κB, which has been implicated in muscle wasting) in denervated muscle compared with control mice, as well as increased activation of NF-κB target genes and increased abundance of the E3 ubiquitin ligase MuRF1. Conversely, denervation-induced increases in NF-κB signaling and MuRF1 abundance were reduced in TWEAK-KO mice. The authors thus conclude that TWEAK-Fn14 signaling through NF-κB plays a role in denervation-induced skeletal muscle atrophy through a mechanism that involves increased abundance of the receptor rather than the cytokine.

A. Mittal, S. Bhatnagar, A. Kumar, E. Lach-Trifilieff, S. Wauters, H. Li, D. Y. Makonchuk, D. J. Glass, A. Kumar, The TWEAK–Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice. J. Cell Biol. 188, 833–849 (2010). [Abstract] [Full Text]