Human umbilical cord-derived mesenchymal stromal cells ameliorate chronic stress-associated skeletal muscle wasting with involvement of MAPK signaling

Depression has been increasingly associated with sarcopenia, yet the causal relationship and effective therapeutic strategies remain unclear. Here, we combined Mendelian randomization analysis with in vivo and in vitro experiments to investigate the relationship between depression liability and sarcopenia-related phenotypes and to evaluate the therapeutic potential of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in CUMS-associated skeletal muscle wasting. Flow cytometry confirmed the canonical MSC phenotype of hUC-MSCs before transplantation. Mendelian randomization analysis suggested that depression was associated with adverse sarcopenia-related phenotypes. In a chronic unpredictable mild stress (CUMS) mouse model, depression-like behaviors were accompanied by CUMS-associated skeletal muscle wasting, as shown by reduced gastrocnemius muscle mass, impaired grip strength, myofiber atrophy, and a decreased proportion of slow-twitch fibers. hUC-MSC treatment significantly improved muscle performance, preserved myofiber morphology, and increased the proportion of slow-twitch fibers in CUMS mice. In vitro, hUC-MSCs promoted C2C12 myoblast proliferation and myogenic differentiation. Transcriptomic profiling identified enrichment of MAPK-related signaling after hUC-MSC treatment. In vivo, hUC-MSC treatment increased phosphorylation of RAF, MEK, and ERK1/2 in gastrocnemius muscle. In vitro, hUC-MSC co-culture partially rescued C2C12 proliferation and myogenic differentiation under ERK inhibition. These findings provide supportive evidence linking depression liability to sarcopenia-related phenotypes and suggest that hUC-MSC-mediated alleviation of CUMS-associated skeletal muscle wasting is closely associated with the activation of MAPK-related signaling.