Researchers at NIH found that aged muscle stem cells (MuSCs) autonomously drive fibrosis by secreting IL-6 and osteopontin (Spp1), which stimulate mesenchymal progenitors called fibro-adipogenic progenitors (FAPs) to proliferate and become fibrogenic. The mechanism involves age-related loss of the repressive histone mark H3K27me3 at the Nfkb1 gene, activating NF-κB and its downstream targets IL6 and Spp1. Using both an Ezh2-knockout mouse model that mimics epigenetic aging and naturally aged mice, the team showed that pharmacologically blocking IL-6 and Spp1 signaling reduced FAP expansion and muscle fibrosis. These findings illuminate a key epigenetic pathway linking MuSC dysfunction to sarcopenia-associated fibrosis.
