Abstract: Objective To investigate the effects of age-related changes in fibro-adipogenic progenitors (FAPs) on the senescence of muscle stem cells (MuSCs). Methods MuSCs and FAPs were isolated from skeletal muscle of young and aged mice. The proliferative capacity, fibrogenic differentiation potential, and expression of related genes were compared between FAPs from young and aged mice. A D-galactose-induced senescence model in C2C12 cells and a replicative senescence model in MuSCs were established. The conditioned medium of young mice-derived FAPs was used for intervention of the model cells, and the proliferation and senescence of MuSCs were evaluated by EdU incorporation, senescence-associated β-galactosidase (SA-β-gal) staining, and qPCR. In addition, conditioned media of FAPs from mice of different ages were used to treat primary MuSCs to evaluate the effect of the age of FAPs on the function of MuSCs. Results Compared with the FAPs from young mice, the FAPs from aged mice exhibited significantly reduced proliferative capacity and enhanced fibrogenic differentiation, accompanied by increased expression of p21 and decreased expression of IGF1. The conditioned medium of FAPs from young mice markedly alleviated D-galactose-induced senescence in C2C12 cells. In the MuSC model of replicative senescence, treatment with the conditioned medium of FAPs from young mice decreased the proportion of SA-β-gal-positive cells and reduced p21 expression while restoring proliferative capacity. Furthermore, the conditioned medium of FAPs from young mice significantly ameliorated the senescent phenotype of MuSCs isolated from aged mice, whereas the conditioned medium of FAPs from aged mice showed no obvious effect. Conclusions Aging significantly alters the functional state of FAPs. Factors secreted by FAPs from young mice can partially restore the proliferative capacity of aged MuSCs and reduce their senescence level, which suggests that age-related alterations in FAPs represent a key microenvironmental factor regulating the senescence of muscle stem cells.

Key words: sarcopenia, muscle stem cells, fibro-adipogenic progenitors