Key points are not available for this paper at this time.
Skeletal muscle-derived Musclin exerts multiple effects on the cardiovascular system. However, the role of Musclin in vascular intimal hyperplasia (IH) remains unclear. This study aims to investigate the role and underlying mechanism of Musclin in IH. We overexpress Musclin in skeletal muscle via adeno-associated virus serotype 6 (AAV6)-mediated gene transfer (AAV-Musclin) in an injury-induced mouse vascular IH model. Morphological analyses, including hematoxylin and eosin (H&E) staining and Ki-67 immunohistochemistry, are used to evaluate IH severity. Ki-67 immunofluorescence, transwell assay, wound healing assay, and analysis of vascular smooth muscle cell (VSMC) differentiation markers are conducted to assess VSMC phenotypic switching. The extracellular acidification rate (ECAR) assay is utilized to measure glycolysis in VSMCs. Following AAV-Musclin transfection, Musclin levels are increased in both skeletal muscle and peripheral blood. Muscle-specific Musclin overexpression ameliorates injury-induced vascular IH. In vitro, Musclin represses glycolysis, proliferation, and migration while increasing VSMC differentiation markers in PDGF-BB-stimulated VSMCs. Mechanistically, Musclin inhibits mammalian target of rapamycin complex 1 (mTORC1) activity and induces NPR3-raptor interaction. Restoring mTORC1 activity abolishes the inhibitory effects of Musclin on PDGF-BB-induced VSMC phenotypic switching and its protective role against injury-induced vascular IH. Additionally, NPR3 silencing abrogates Musclin-mediated suppression of mTORC1 activity, glycolysis, and phenotypic switching in PDGF-BB-treated VSMCs. Collectively, external Musclin supplementation may represent a promising therapeutic strategy for preventing vascular IH-related pathologies.
Wei et al. (Wed,) studied this question.