Skeletal muscle-derived Metrnl induced by exercise displays the roles of endothelioprotective and anti-atherosclerosis in male mice through KIT/NFκB signaling.

The mechanisms by which skeletal muscle activity during exercise state modulates vascular function and atherosclerosis remain poorly understood. The aim of this study was to investigate the function of skeletal muscle/endothelium axis and determine whether and how skeletal muscle-derived Meteorin-like (Metrnl), a myokine implicated in metabolism and inflammation, exerts endothelioprotective and anti-atherosclerotic effects. In in vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of skeletal muscle-derived Metrnl on vascular endothelial function and atherosclerosis. For loss-of-function, we generated skeletal muscle-targeted Metrnl-null mice on an apolipoprotein E gene knockout background. For gain-of-function, we restored skeletal muscle-derived Metrnl by systemic plasma administration and skeletal muscle-specific Metrnl overexpression mouse. In in vitro and ex-vivo experiments were conducted. The expression of Metrnl from skeletal muscle markedly increased in human and mice, thereby increased circulating Metrnl levels, mitigated inflammation responses and improved vascular endothelial function, consequently ameliorated atherosclerosis under chronic aerobic exercise condition. Importantly, the Metrnl loss-of-function experiments by skeletal muscle-specific Metrnl deficiency and neutralizing antibody against Metrnl exacerbated vascular inflammation, promoted leukocyte homing, and increased endothelial injury and atherosclerosis in mice. Conversely, the gain of skeletal muscle Metrnl function experiment by adeno-associated virus assay reversed these issues. In vitro and ex-vivo experiments exhibited that Metrnl decreased inflammation and endothelial damage. Mechanistically, the KIT/protein kinase B (Akt)/nuclear factor-κB signaling is essential for the benefits of Metrnl on endothelial cells. The findings concluded that skeletal muscle/artery axis exists and skeletal muscle modulates cardiovascular function via skeletal muscle-derived Metrnl under chronic aerobic exercise, and skeletal muscle-derived Metrnl may serve as a novel therapeutic target for metabolic disorders.