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TWEAK/Fn14 system is a critical regulator of denervation‐induced skeletal muscle atrophy
Author(s) -
Kumar Ashok,
Bhatnagar Shephali,
Mittal Ashwani,
Glass David J
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.801.30
Subject(s) - denervation , atrophy , muscle atrophy , skeletal muscle , ubiquitin ligase , cachexia , medicine , wasting , protein degradation , endocrinology , ubiquitin , biology , microbiology and biotechnology , biochemistry , cancer , gene
Skeletal muscle atrophy occurs in a variety of clinical settings, including disuse atrophy and denervation. Inflammatory cytokines are important mediators of muscle‐wasting in settings such as cancer cachexia; however, their role in denervation remains unknown. We demonstrate the cytokine TWEAK mediates skeletal muscle atrophy in response to denervation. Transgenic expression of TWEAK induced atrophy, fibrosis, fiber‐type switching, and the degradation of muscle proteins. Conversely, genetic ablation of TWEAK decreased the loss of muscle proteins and spared fiber cross‐sectional area, muscle mass and strength after denervation. Expression of the TWEAK receptor Fn14 was significantly increased in muscle upon denervation, demonstrating an unexpected “inside‐out” signaling pathway leading to atrophy. TWEAK activates NF‐kappa B, causing an increase in the expression of the E3 ubiquitin ligase MuRF1. This study reveals a novel mechanism of skeletal muscle atrophy, and indicates that the TWEAK/Fn14 system is an important target for preventing skeletal muscle wasting. This work was supported by a National Institute of Health grant (RO1 AG129623) to AK.