Related Experiment Video
Updated: Jun 14, 2026
Tibial Nerve Transection - A Standardized Model for Denervation-induced Skeletal Muscle Atrophy in Mice
Published on: November 3, 2013
The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice
Ashwani Mittal1, Shephali Bhatnagar, Akhilesh Kumar
1Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
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 kappaB, 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.
Insights
TNF-like weak inducer of apoptosis (TWEAK) causes skeletal muscle atrophy following denervation. Inhibiting TWEAK protects muscle mass and strength, revealing TWEAK as a key target for preventing muscle wasting.
Area of Science:
- Muscle physiology
- Molecular biology
- Cell signaling
Background:
- Skeletal muscle atrophy is linked to cachexia, disuse, and denervation.
- The role of cytokines in denervation-induced muscle loss is not well understood.
Purpose of the Study:
- To investigate the role of TNF-like weak inducer of apoptosis (TWEAK) in denervation-induced skeletal muscle atrophy.
- To elucidate the signaling pathway involved in TWEAK-mediated muscle loss.
Main Methods:
- Transgenic expression of TWEAK in mice.
- Genetic ablation of TWEAK in mice.
- Analysis of muscle protein degradation, fiber type, cross-sectional area, mass, and strength after denervation.
- Measurement of TWEAK receptor Fn14 expression and nuclear factor kappaB activation.
Main Results:
- TWEAK expression induces skeletal muscle atrophy, fibrosis, fiber-type switching, and protein degradation.
- Genetic deletion of TWEAK mitigates muscle protein loss, preserves fiber size, mass, and strength post-denervation.
- Denervation up-regulates the TWEAK receptor Fn14, initiating an inside-out signaling cascade.
- TWEAK-Fn14 signaling activates nuclear factor kappaB, increasing E3 ubiquitin ligase MuRF1 expression.
Conclusions:
- TWEAK is a critical mediator of skeletal muscle atrophy in denervation.
- The TWEAK-Fn14 signaling pathway is a novel mechanism driving muscle wasting.
- Targeting the TWEAK-Fn14 system offers a potential therapeutic strategy for preventing muscle atrophy.
