Year: 2026
Type: preprint
Abstract: Aging reduces skeletal muscle regenerative capacity, but how the aged environment impairs muscle stem cells (MuSCs) remains unclear. Skeletal muscle acts as a secretory organ, yet age-related changes in its secretome and impact on stem cells are poorly understood. We performed proteomic and lipidomic analyses of conditioned media from primary muscle cells of young (15–25 years) and aged (60–86 years) donors. We identified 127 age-dependent secreted proteins, revealing major remodeling. The lysosomal enzyme acid sphingomyelinase (ASM), which converts sphingomyelin into ceramide, was the most upregulated factor. Recombinant ASM reduced PAX7+ MuSCs in young cultures, showing extracellular ASM impairs stem cell maintenance. Lipidomics revealed disruption of the sphingomyelin–ceramide–S1P axis, with decreased sphingomyelin and S1P, a lipid promoting MuSC proliferation. Exogenous S1P restored the stem cell pool in aged cultures. These findings link secretome remodeling and sphingolipid metabolism to MuSC decline and identify ASM and S1P as targets.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G231039123, Epigenetic Regulation of Secretome in Duchenne Muscular Dystrophy: role of the Histone Methyltransferase SETDB1 in TGFbeta-induced Fibrosis, Dietary induced methylome and transcriptome dynamics assessing nutrition impacts on cardiovascular and metabolic health, G7080048889, Performing a Rare disease-Oriented Master Observational Trial to decipher complexity and optimize trial readiness
OpenAlex ID: W7215747050