Garcia-Carrizo, F.; Gohlke, S.; Lenihan-Geels, G.; Jank, A.-M.; Leer, M.; Soultoukis, G. A.; Oveisi, M.; Herpich, C.; Garrido, C. A.; Kotsaris, G.; Poehle-Kronawitter, S.; Tsamo-Tetou, A.; Graja, A.; Ost, M.; Villacorta, L.; Knecht, R. S.; Klaus, S.; Schuermann, A.; Stricker, S.; Schmidt-Bleek, K.; Cipitria, A.; Duda, G. N.; Benes, V.; Mueller-Werdan, U.; Norman, K.; Schulz, T. J.

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.