# Inflammaging-induced TRAF3 degradation impairs AMP biosynthesis to drive sarcopenia

## TL;DR

This study shows how inflammation in aging leads to muscle loss by degrading TRAF3, a protein important for energy production in muscles.

## Contribution

The study identifies TRAF3 degradation as a novel mechanism linking inflammaging to sarcopenia through impaired AMP biosynthesis.

## Key findings

- TRAF3 levels decrease in aging muscle cells and contribute to sarcopenia.
- TRAF3 stabilizes ADSL to maintain ATP production in muscle cells.
- Restoring TRAF3 or supplementing AMP rescues sarcopenic phenotypes in mice.

## Abstract

Inflammaging is a recognized driver of age-related pathologies, yet its specific mechanistic link to sarcopenia remains poorly understood. Here, we identified a significant reduction of TNF receptor-associated factor 3 (TRAF3) in myoblasts exposed to aged serum and in skeletal muscles from both aging mice and humans. Genetic deletion of TRAF3 in myocytes or satellite cells induced early-onset sarcopenia and impaired regeneration, independent of non-canonical NF-κB signaling. Mechanistically, TRAF3 maintains energy homeostasis by stabilizing the key metabolic enzyme, adenylosuccinate lyase (ADSL), and its loss impairs AMP biosynthesis and ATP production. Muscle-specific TRAF3 restoration or AMP supplementation rescued sarcopenic phenotypes in TRAF3-deficient mice. Notably, neutrophil-derived transforming growth factor β1 (TGFβ1) caused IAP-mediated ubiquitination and degradation of TRAF3 in aged mice—a process reversible by the IAP inhibitor SM-164. Inducible neutrophil-specific TGFβ1 deletion prevented age-related sarcopenia. Our study establishes that TRAF3 is a key protective factor in muscle aging, and its loss mechanistically links inflammaging to bioenergetic deficits, suggesting new strategies to prevent age-related muscle wasting.