Aerobic exercise induced skeletal muscle MOTS-c secretion: A novel therapy for MASLD via hepatic ACE2 regulation

Aerobic exercise is pivotal for managing metabolic dysfunction-associated steatotic liver disease (MASLD), but its mechanisms remain unclear. This study investigates the anti-MASLD effects of MOTS-c, a mitochondrial peptide secreted during aerobic exercise, in diabetic MASLD mice and HepG2 cells. Our study found MOTS-c expression in skeletal muscle was reduced in the MASLD mice but restored by aerobic exercise. Both MOTS-c and aerobic exercise significantly improved hepatic steatosis in MASLD mice by suppressing lipid synthesis and inflammation. MOTS-c’s protective effects were diminished in ACE2-knockout mice. The results revealed a synergistic reduction in pAMPK and ACE2 expression in the MASLD mice, partially reversible by MOTS-c intervention. In HepG2 cells, MOTS-c-induced hepatic ACE2 upregulation was counteracted by the AMPK inhibitor Compound C. These findings suggest that aerobic exercise-induced secretion of skeletal muscle MOTS-c ameliorates MASLD via hepatic ACE2 upregulation, providing a novel non-pharmacological target for metabolic liver diseases.