MON-709 Fibro-inflammatory Stromal Cells Produce Atrophy-inducing Paracrine Factors in a Mouse model of Diabetes-associated Sarcopenia

Abstract Disclosure: S.K. Patterson: None. J.A. Syed: None. J. Yang: None. M. Woo: None. E.D. Buras: None. Introduction and objective: Sarcopenia—encompassing age-related declines in skeletal muscle mass and performance—strongly predicts negative health outcomes; quantitatively correlating with measures of mobility impairment, cardiovascular disease risk and overall mortality. Within the myofiber, sarcopenia drivers include activation of Stat3 signaling by interleukin (IL)6 and Smad2/3 signaling by transforming growth factor (TGF)β. Mesenchymal cells called fibro-adipogenic progenitors (FAPs) are important mediators of myofiber integrity; however, in contexts such as denervation, can promote atrophy through secretion of paracrine factors. Diabetes accelerates sarcopenia progression. While expansion pro-fibrotic FAP populations has been observed in limb muscles of human subjects with type 2 diabetes, the role of FAPs in diabetes-associated sarcopenia remains unclear. Methods: We modeled diabetes-associated sarcopenia by subjecting mice to a 12-month diet-induced obesity (DIO) protocol beginning at 2-months old—equivalent to obesity developing in adolescence and persisting to middle age—and analyzed muscle structure/ function parameters, while conducting scRNA-seq-based evaluation of mesenchymal cell profiles. We further evaluated the impact of FAP conditioned medium on C2C12 myoblasts and myotubes. Results: 12-month DIO mice developed limb muscle atrophy, as indicated by reduced muscle mass, cross-sectional area (CSA), contractile force, and myofiber size. scRNA-seq of gastrocnemius FAPs demonstrated increased advanced glycation end-product (AGE) signaling and emergence of “fibro-inflammatory” sub-populations enriched in transcripts encoding IL6 and thrombospondin-1 (THBS1), The latter is an obesity-induced matricellular protein that promotes TGFβ activation and has recently been linked to Smad2/3-dependent atrophy in mouse models of extreme aging. Conditioned medium from 12-month DIO FAPs impaired in vitro differentiation of C2C12 myoblasts and growth of C2C12 myotubes. Conclusion: These data suggest paracrine signaling from emergent fibro-inflammatory FAPs is a novel contributor to diabetic myoatrophy. Presentation: Monday, July 14, 2025