Single-cell profiling of skeletal muscle reveals a novel senolytic target: CRYAB

Abstract Skeletal muscle mass and function can decline with aging, resulting in a syndrome known as sarcopenia. This decline is linked to functional alterations in critical cell types within mature muscle, including fibro-adipogenic progenitors (FAPs) and satellite cells (SCs), driven in part by cellular senescence. We utilized single-cell RNA sequencing and isolated FAPs and SCs to identify novel targets responsible for senescent cell killing - senolysis. We identified the small alpha-crystalline heat shock protein CRYAB as a novel senolytic target. Using chemical inhibitor screening of CRYAB, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic capable of killing senescent cells. We validated 25HC as a senolytic in mouse and human cells in culture and in vivo in mouse skeletal muscle. Thus, 25HC represents a potential new class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.