Aging-Associated CD55⁺ Fibroblasts Promote Chronic Inflammation and ECM Dysregulation in Sarcopenia

Xianfei Xie,1,2,* Jiawen Zhao,3,* Tong Wu,3,* Yi Yang,3,* Yuan Zong,3 Lei Li,4 Yiming Gao,3 Liting Jiang,3 Yuelong Cao,5 Linhui Shen6 1Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Department of Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Characteristic Diagnosis and Treatment Technology Research Institution, Shanghai Institute of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 6Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuelong Cao, Characteristic Diagnosis and Treatment Technology Research Institution, Shanghai Institute of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Email [email protected] Linhui Shen, Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email [email protected]: Sarcopenia, defined as the progressive loss of muscle mass and function with aging, is a major contributor to frailty and disability in the elderly. Fibroblasts, traditionally considered passive extracellular matrix (ECM) producers, are increasingly recognized for their active roles in inflammation, fibrosis, and immune modulation. However, the heterogeneity and specific functions of fibroblast subtypes in sarcopenic muscle remain poorly understood.Methods: We employed an integrative multi-omics and multi-modal approach combining single-nucleus RNA sequencing (snRNA-seq), untargeted metabolomics, and histological analyses to systematically characterize fibroblast populations in human skeletal muscle.Results: Several distinct fibroblast subtypes were identified, among which a CD55⁺ fibroblast subpopulation (FB_4) emerged as a major contributor to the pro-inflammatory and fibrotic microenvironment of aged and sarcopenic muscle. FB_4 demonstrated activation of NF-κB signaling, glycolytic metabolism, and oxidative stress pathways. Histological validation confirmed increased expression of inflammatory and fibrotic markers such as TGF-β 1 and TLR4. Moreover, FB_4 activity correlated with senescence-associated secretory phenotype (SASP) expression and enhanced immune cell infiltration.Conclusion: Our findings reveal CD55⁺ FB_4 as a critical driver of chronic inflammation and ECM remodeling in aging muscle. Targeting fibroblast-mediated inflammation and fibrosis may represent a promising therapeutic strategy for sarcopenia. The integration of transcriptomic, metabolic, and histological data provides new insights into fibroblast heterogeneity and offers a framework for future interventions in age-related muscle degeneration.Keywords: senescence-associated secretory phenotype, extracellular matrix remodeling, skeletal muscle aging, fibroblast heterogeneity