Sarcopenia promotes tumorigenesis by disrupting NOTCH-SDC2-regulated biogenesis of muscle-derived extracellular vesicles.

Abstract

Sarcopenia is an age-related condition characterized by loss of skeletal muscle mass and strength and is associated with increased cancer incidence and mortality, yet how muscle decline promotes tumorigenesis remains unclear. Here, we show that skeletal muscle functions as an anti-tumor organ by secreting extracellular vesicles (EVs) that suppress tumor growth. Using Drosophila melanogaster and mouse cancer models, we demonstrate that muscle-derived EVs inhibit tumorigenesis. In contrast, sarcopenic muscle exhibits reduced EV secretion and altered EV cargo, resulting in loss of tumor-suppressive activity. We identify miR-7a-5p as a tumor-suppressive microRNA enriched in EVs from healthy muscle but diminished with aging, where it restrains tumor growth by inhibiting TEAD1 signaling. Mechanistically, muscle EV biogenesis is regulated by a NOTCH-SDC2 pathway that declines with age but is reactivated by exercise. Together, these findings define a muscle-to-tumor communication axis with therapeutic potential.