Skeletal muscle stem cells mitigate obesity and insulin resistance through producing myokine IGF2 that promotes thermogenic adipogenesis

Skeletal muscle mass is inversely correlated with the development of obesity and related insulin resistance. Accordingly, in addition to its critical role in metabolically balancing energy, skeletal muscle tissue also secretes various factors known as myokines. In this study, we isolated human muscle stem cells (hMuSCs), expanded them in vitro and tested their therapeutic efficacy on obesity and related insulin resistance. Upon adoptive transfer into high-fat diet (HFD)-induced obese mice, hMuSCs effectively reduced obesity and insulin resistance. Mass spectrometry analysis and functional investigations revealed that insulin-like growth factor 2 (IGF2) redirects the preadipocytes to undergo beige adipocyte differentiation. Mechanistically, IGF2 upregulates peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and uncoupling protein 1 (UCP1), leading to enhanced mitochondrial biogenesis, oxidative phosphorylation (OXPHOS) and thermogenic adipogenesis. Mice lacking PGC1α in PDGFR+ pre-adipocytes were less responsive to hMuSCs infusion, indicating that the therapeutic effect of hMuSCs on obesity required PGC1α-mediated mitochondrial biogenesis. Moreover, the beiging process induced by IGF2 is mediated by the PI3K-AKT-mTOR signaling pathway following IGF2R activation. Additionally, pre-clinical research on macaque monkeys suffering from type II diabetes further supported the significant therapeutic potential of MuSCs. Our findings demonstrate the potential therapeutic effect of muscle stem cells in treating obesity and metabolic disorders.