Inflammaging-induced TRAF3 degradation impairs AMP biosynthesis to drive sarcopenia

Inflammaging-induced TRAF3 degradation impairs AMP biosynthesis to drive sarcopenia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Inflammaging-induced TRAF3 degradation impairs AMP biosynthesis to drive sarcopenia Jinbo Li, Yaning Xing, Jinxiao Fan, Xing Li, Tian Jin, Congcong Zhang, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8857997/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version 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. Biological sciences/Cell biology/Mechanisms of disease Health sciences/Anatomy/Musculoskeletal system/Muscle/Skeletal muscle Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Suppl.Figures01252026.pdf Dataset 1, 2, 3, 4, 5, 6 and 7. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8857997","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":607773574,"identity":"308f76bc-2927-4426-a7de-25d23c6516ca","order_by":0,"name":"Jinbo 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