TWEAK/Fn14 Regulates Denervation-Induced Skeletal Muscle Atrophy through an “Inside-Out” Signaling Pathway

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 is less understood. 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-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.