Secreted protein acidic and rich in cysteine internalization and its age-related alterations in skeletal muscle progenitor cells.

Aging causes phenotypic changes in skeletal muscle progenitor cells (Skm-PCs), such as reduced myogenesis and increased adipogenesis due to alterations in their environment or niche. Secreted protein acidic and rich in cysteine (SPARC), which is secreted into the niche of Skm-PCs, inhibits adipogenesis and promotes myogenesis. We have previously reported that Skm-PC responsiveness to SPARC declines with age, although the mechanism underlying this decline is unknown. In this study, we found that SPARC is internalized by Skm-PCs and that this uptake increases with age. Internalization is dependent on integrin-α5, a cell surface SPARC-binding molecule, and clathrin-mediated endocytosis. We also demonstrated that internalized SPARC is transported to Rab7-positive endosomes. Skm-PCs from old rats exhibited increased clathrin expression and decreased Rab7 expression exclusively in MyoD-negative cells. In loss-of-function analyses, clathrin knockdown increased the anti-adipogenic effect of SPARC, whereas Rab7 knockdown reduced it, indicating that alterations in SPARC internalization may mediate the age-related decline in its anti-adipogenic effect. These results provide insights into age-related SPARC resistance in Skm-PCs, which may lead to sarcopenia.