Skeletal muscle-derived musclin attenuates glycolysis, oxidative stress, and pulmonary hypertension through the NPR3/AKT/mTORC1 pathway

• Musclin levels are reduced in plasma and skeletal muscle of MCT-induced PH mice, and overexpression of musclin in skeletal muscle ameliorates pulmonary arterial remodeling and right ventricular dysfunction. • Musclin suppresses hypoxia-induced glycolysis, oxidative stress, proliferation, and migration of pulmonary arterial smooth muscle cells (PASMCs) via inhibition of mTORC1 activity. • The protective effects of musclin are mediated through its interaction with NPR3, which inhibits AKT phosphorylation and mTORC1 signaling. • This study identifies musclin as a potential therapeutic target for pulmonary hypertension and provides mechanistic insight into exercise-mediated cardiovascular protection.