Archives of Gerontology and Geriatrics · Nov 2026
Integrated Single-cell and Bulk Transcriptomic Analysis Suggest a Possible Association Between M1-like Macrophage Cuproptosis and Angiogenic Impairment in Exercise-Deficiency-Associated Sarcopenia
By Li S, Wu X, Jia R et al.
Sarcopenia is a geriatric syndrome characterized by the progressive loss of skeletal muscle mass and function. While physical inactivity is a primary risk factor of sarcopenia, the underlying molecular mediators remain poorly studied. By combined analysis of human bulk transcriptomic data and single-cell RNA sequencing data, we identified a cuproptosis-associated transcriptional signature significantly enriched in both human sarcopenia and exercise-deprivation models. Our analyses suggest that M1-like macrophage may be particularly vulnerable to cuproptosis due to elevated SLC31A2 expression, potentially contributing to their depletion in the sedentary muscle microenvironment. Intercellular communication modeling further implied that the reduction in M1-like macrophage may impair CXCL8-mediated (or its murine functional analogs) signaling to endothelial tip cells, a process essential for microvascular maintenance. To provide physiological context, we validated these findings in an aged sarcopenia murine model (24-month-old C57BL/6J). In the gastrocnemius muscle of sarcopenic mice, we observed a significant decrease in muscle fiber cross-sectional area (CSA) alongside a concurrent reduction in F4/80⁺CD86⁺ M1-like macrophage and VEGFR2⁺/CD31⁺ endothelial tip cells. Collectively, our study provides associative link for a candidate mechanistic axis—SLC31A2-mediated cuproptosis in M1-like macrophage—that potentially links physical inactivity to vascular rarefaction in sarcopenia. These findings offer a new framework for investigating the immune-vascular crosstalk in muscle aging and highlight potential therapeutic targets for intervention.