Aging impairs muscle regeneration by desynchronizing matrix mechano-signaling and macrophage immunomodulation via fibro-adipogenic progenitors

Skeletal muscle regeneration depends on the function of fibro/adipogenic progenitors (FAPs). Here we show that aging impairs myogenic stem cells and immunomodulatory processes by disrupting extracellular matrix function, thereby inhibiting regeneration in aged muscle. We identify the FAP-secreted matricellular protein Periostin as a niche factor that is decreased in aged murine muscle and in circulation of aged humans with low-exercise lifestyle. Periostin controls FAP-expansion after injury and its loss fate-regulates FAPs to contribute to fibro/fatty infiltration. This causes stem cell defects and attenuates 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 anti-inflammatory niche formation and regeneration. Mechanistically, Periostin activates Focal adhesion kinase- and AKT-signaling in macrophages via integrin binding to promote an anti-inflammatory profile, which synchronizes matrix-derived mechanosensory signaling and immunomodulation. These results uncover a key role of FAP-based matrix regulation via niche factors that orchestrate successful muscle regeneration. ### Competing Interest Statement The authors have declared no competing interest.