Sun Xiongshan, Wang Jia, Xiao Yi, Li De, Wang Qiang, Guo Wei, Yang Yongjian
Department of Cardiovascular Medicine, the General Hospital of Western Theater Command, Chengdu 610083, China.
Department of Laboratory Medicine, the General Hospital of Western Theater Command, Chengdu 610083, China.
Acta Biochim Biophys Sin (Shanghai). 2024 Dec 5. doi: 10.3724/abbs.2024214.
Exercise ameliorates pulmonary hypertension (PH) progression. However, the underlying mechanisms are largely unclear. Musclin is an exercise-responsive myokine that exerts protective effects on cardiovascular diseases. The current study aims to explore the role of musclin in the development of PH. A monocrotaline (MCT)-induced mouse PH model is established. Adeno-associated virus serotype 6 (AAV6)-mediated gene transfer is used to induce musclin overexpression in skeletal muscle. Ultrasound and morphological analyses are utilized to assess the severity of PH. Cell viability assay, Ki-67 immunofluorescence staining, wound healing assay, and transwell assay are used to evaluate the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). We find that the musclin levels in both plasma and skeletal muscle are decreased in MCT-treated mice. The external expression of musclin in skeletal muscle ameliorates pulmonary arterial remodeling and right ventricular dysfunction. , musclin treatment suppresses hypoxia-induced glycolysis, oxidative stress, proliferation, and migration. Further experiments reveal that musclin inhibits mechanistic target of rapamycin complex 1 (mTORC1) activity in hypoxia-stimulated PASMCs and pulmonary arteries of MCT-treated mice. Reactivating mTORC1 abolishes the protective role of musclin against PH. Additionally, musclin enhances its interaction with natriuretic peptide receptor 3 (NPR3) in PASMCs. Silencing of reverses the inhibitory effects of musclin on AKT phosphorylation, mTORC1 activity, glycolysis, oxidative stress, proliferation, and migration in hypoxia-challenged PASMCs. In conclusion, our study highlights the inhibitory role of musclin in the proliferation and migration of PASMCs and PH progression, thereby providing a novel potent therapeutic strategy for treating PH and partly clarifying the mechanism of exercise-mediated protection against PH.
运动可改善肺动脉高压（PH）的进展。然而，其潜在机制在很大程度上尚不清楚。肌肉素是一种运动反应性肌动蛋白，对心血管疾病具有保护作用。本研究旨在探讨肌肉素在PH发生发展中的作用。建立了野百合碱（MCT）诱导的小鼠PH模型。利用腺相关病毒6型（AAV6）介导的基因转移在骨骼肌中诱导肌肉素过表达。采用超声和形态学分析评估PH的严重程度。通过细胞活力测定、Ki-67免疫荧光染色、伤口愈合测定和Transwell测定来评估肺动脉平滑肌细胞（PASMCs）的增殖和迁移。我们发现，MCT处理的小鼠血浆和骨骼肌中的肌肉素水平均降低。骨骼肌中肌肉素的外源性表达可改善肺动脉重塑和右心室功能障碍。此外，肌肉素治疗可抑制缺氧诱导的糖酵解、氧化应激、增殖和迁移。进一步的实验表明，肌肉素可抑制MCT处理的小鼠缺氧刺激的PASMCs和肺动脉中雷帕霉素复合物1（mTORC1）的活性。重新激活mTORC1可消除肌肉素对PH的保护作用。此外，肌肉素增强了其在PASMCs中与利钠肽受体3（NPR3） 的相互作用。沉默NPR3可逆转肌肉素对缺氧刺激的PASMCs中AKT磷酸化、mTORC1活性、糖酵解、氧化应激、增殖和迁移的抑制作用。总之，我们的研究突出了肌肉素在PASMCs增殖和迁移以及PH进展中的抑制作用，从而为治疗PH提供了一种新的有效治疗策略，并部分阐明了运动介导的抗PH保护机制。
