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.

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.

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