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

Area of Science:

• Cell Biology
• Aging Research
• Muscle Physiology

Background:

• Sarcopenia, characterized by age-related muscle mass and function loss, significantly contributes to elderly frailty and disability.
• Fibroblasts, beyond ECM production, play active roles in inflammation, fibrosis, and immune responses.
• The specific functions and heterogeneity of fibroblast subtypes in sarcopenic muscle are not well understood.

Purpose of the Study:

• To systematically characterize fibroblast populations in human skeletal muscle.
• To elucidate the role of fibroblast heterogeneity in age-related muscle degeneration and sarcopenia.

Main Methods:

• Utilized an integrative multi-omics approach combining single-nucleus RNA sequencing (snRNA-seq).
• Incorporated untargeted metabolomics and histological analyses for comprehensive characterization.
• Focused on identifying distinct fibroblast subtypes and their functional characteristics in skeletal muscle.

Main Results:

• Identified several distinct fibroblast subtypes, with CD55⁺ fibroblasts (FB_4) being a major contributor to the pro-inflammatory and fibrotic microenvironment in aged muscle.
• FB_4 cells showed activated NF-κB signaling, enhanced glycolytic metabolism, and increased oxidative stress.
• FB_4 activity correlated with senescence-associated secretory phenotype (SASP) and heightened immune cell infiltration, alongside increased TGF-β1 and TLR4 expression.

Conclusions:

• CD55⁺ FB_4 cells are identified as critical drivers of chronic inflammation and extracellular matrix remodeling in aging muscle.
• Targeting fibroblast-mediated inflammation and fibrosis presents a potential therapeutic strategy for sarcopenia.
• This multi-omics approach provides novel insights into fibroblast heterogeneity and a framework for future interventions in age-related muscle diseases.