Human umbilical cord-derived mesenchymal stem cells ameliorate muscle dysfunction and metabolic dysregulation in the CuZnSOD null mouse model of sarcopenia.
Age-related sarcopenia is a progressive skeletal muscle disorder driven by oxidative stress and metabolic dysregulation. Cu/Zn superoxide dismutase-deficient (Sod1-/-) mice recapitulate key features of oxidative stress-induced muscle degeneration and provide a robust preclinical model for mechanistic and therapeutic studies. Here, we investigated whether systemic administration of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) could modulate muscle function and metabolic homeostasis under both pathological and physiological conditions. In Sod1-/- mice, UC-MSC treatment significantly improved motor coordination and grip endurance, restored gastrocnemius myofiber number, markedly reduced mitochondrial reactive oxygen species production and catalase expression levels in skeletal muscle, and restored muscle ATP content. UC-MSCs also restored circulating insulin-like growth factor-1 (IGF-1) levels. Untargeted lipidomic profiling revealed profound depletion of lipid species in Sod1-/- muscle, particularly omega-3 fatty acids, which was selectively rescued by UC-MSC therapy, including restoration of α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, without substantial recovery of disrupted polar metabolic pathways such as aminoacyl-tRNA biosynthesis. In contrast, UC-MSC administration in wild-type mice induced a distinct metabolic remodeling characterized by reduced n-3 and n-6 fatty acid-associated lipid species and concomitant enrichment of fructose-related glycolytic intermediates, indicating a shift toward carbohydrate-based energy utilization in metabolically intact muscle. Together, these findings demonstrate that UC-MSCs function as context-dependent metabolic modulators, alleviating oxidative stress-induced sarcopenia through attenuation of oxidative stress, restoration of systemic IGF-1, and selective reprogramming of lipid metabolism, while dynamically adjusting energy metabolism in physiological skeletal muscle.