Summary

Skeletal muscle regeneration depends on the function of fibro/adipogenic progenitors (FAPs). Here we show that aging impairs myogenic stem cells by disrupting the integration of extracellular matrix and immunomodulatory functions within the stem cell niche, thereby promoting fibro/fatty degeneration. We identify the FAP-secreted protein Periostin as a niche factor that is decreased in aged muscle and in circulation of aged humans with low-exercise lifestyle. Periostin controls FAP-expansion after injury and its depletion fate-regulates FAPs towards adipogenesis. This leads to delayed pro- to anti-inflammatory macrophage transition during regeneration. Transplantation of young FAPs with high Periostin secretion, but not Periostin-deficient FAPs, into aged muscle restores inflammation resolution and successful regeneration. Mechanistically, Periostin activates Focal adhesion kinase- and AKT-signaling in macrophages via integrins to promote an anti-inflammatory profile, which synchronizes matrix-derived mechanosensory signaling and immunomodulation. These results uncover a novel role of FAP-based regulation that orchestrates successful muscle regeneration and prevents fibro/fatty degeneration.