Muscle stem cell treatment mitigates stress-associated multiorgan dysfunction in D-galactose-induced accelerated aging mice and improves behavior in naturally aged mice

Muscle stem cells (MuSCs) support skeletal muscle repair, but whether systemic MuSC administration mitigates stress-associated multiorgan dysfunction remains unclear. We evaluated MuSCs in a D-galactose-induced accelerated aging model and performed additional behavioral validation in naturally aged mice. Female KM mice received D-galactose for eight weeks with or without weekly intravenous MuSCs. Behavioral performance, serum injury, oxidative and inflammatory biomarkers, multiorgan histopathology, and heart/skeletal muscle transcriptomes were assessed. Naturally aged mice were tested for motor and cognitive behaviors after MuSC treatment. MuSC administration improved motor endurance, foraging, and spatial learning/memory in D-gal-treated mice, reduced ALT/AST and BUN, increased SOD/GSH-Px, and decreased TNF-alpha/IL-6. Histology showed attenuation of hepatic lipid accumulation, renal/glomerular injury, dermal and gastrointestinal atrophy, pulmonary inflammation, sarcopenia, lipid deposition, and fibrosis, with lower p16/p21 in heart and gastrocnemius. Transcriptomics indicated partial restoration of metabolic, genomic-stability, and immune pathways. In naturally aged mice, MuSCs improved rotarod, food-maze, navigation, and spatial-probe performance. These data support MuSCs as a candidate transient cell-based modulator of oxidative stress-associated dysfunction and behavioral decline, while further work is required to define cell fate, sex-specific responses, cell specificity, and chronological aging mechanisms.