抗阻运动激活FSTL1-Akt-mTOR信号通路促进心梗大鼠心肌细胞增殖

Resistance Training Activates the Signaling Pathway of FSTL1-Akt-mTOR and Induces Cardiomyocyte Proliferation in Rats with Myocardial Infarction

目的:探讨抗阻运动对心肌梗死(Myocardial Infarction,MI)大鼠卵泡抑素样蛋白1(Follistatin-like Protein 1,FSTL1)及其受体DIP2A(Disco-interacting Protein 2 homolog A)表达和下游Akt-mTOR信号通路与心肌细胞增殖的影响。方法:雄性SPrague-Dawley大鼠30只,体重180~220 g,左冠状动脉前降支结扎制备心梗模型,术后随机分为假手术组(S)、心梗安静对照组(MI)、心梗+抗阻运动组(MR),每组10只,其中S组只穿线不结扎。术后1周,MR组先进行1周适应性无负重爬梯运动,再进行4周递增负荷抗阻运动。训练结束后24 h,腹腔麻醉,测定LVSP、LVEDP和±d P/dt max评价心功能。Western blot实验测定心肌FSTL1/DIP2A、PAkt/Akt、P-mTOR/mTOR、Cyclin D1、CDK4蛋白表达;免疫荧光实验观察心肌细胞增殖;Masson染色观察并计算心肌胶原容积百分比(CVF%)。结果:与S组比较,MI组心肌FSTL1/DIP2A、Cyclin D1和CDK4蛋白表达增加,PAkt/Akt、P-mTOR/mTOR比值显著上升,心肌细胞增殖百分率显著升高,CVF%和LVEDP显著增加,LVSP和±d P/dt max显著降低;与MI组比较,MR组心肌FSTL1/DIP2A、Cyclin D1和CDK4蛋白表达显著升高,PAkt/Akt、PmTOR/mTOR比值显著上升,心肌细胞增殖百分率显著升高,CVF%和LVEDP显著降低,LVSP和±d P/dt max显著升高。结论:抗阻运动上调FSTL1及其受体DIP2A的表达,激活其下游AktmTOR信号通路。表明,FSTL1-DIP2A-Akt-mTOR信号通路在抗阻运动促进心梗大鼠心肌细胞增殖、降低心肌纤维化面积和改善心功能中发挥重要作用。

Objectives： This study aimed at discussing the effect of resistance training on expression of Follistatin-like protein 1（FSTL1） and its receptor Disco-interacting protein 2 homolog A（ DIP2 A）, downstream signaling pathway of Akt-mTOR and cardiomyocyte proliferation in rats with Myocardial Infarction（MI）. Methods： 30 male Sprague-Dawley rats, weight about 180-220 g were randomly divided into three groups： Sham-operated group（S）, sedentary MI group（MI） and MI with resistance training group（MR） after the MI model was established by ligation of left anterior descending coronary artery. After surgery 1 week, rats in MR took adaptability climbing up ladder unload training for 1 week. Then subjected progressive loading training for 4 weeks. The 24 hours after training, rats were anesthetized, the LVSP, LVEDP, ± dp/dt max were tested in order to evaluate cardiac function. The protein expression of FSTL1, DIP2A, p Akt, Akt, p-mTOR, mTOR, Cyclin D1 and CDK4 in Myocardium were measured by Western blot, cardiomyocyte proliferation was observed and analyzed by immunofluorescence. Collagen volume fraction（%） of Myocardium were calculated by Masson Staining. Results： Compared with S, the protein expression of FSTL1, DIP2A, p Akt/Akt, p-mTOR/mTOR, Cyclin D1 and CDK4, cardiomyocyte proliferation, the CVF% and LVEDP of MI increased, the LVSP and ± dp/dt max significantly decreased; Compared with MI, the protein expression of FSTL1, DIP2A, p Akt/Akt, pmTOR/mTOR, Cyclin D1 and CDK4, cardiomyocyte proliferation, the CVF% and LVEDP of MR significantly upregulated, the LVSP, ± dp/dt max significantly downregulated. Conclusions： Resistance training may via upregulate the expression of FSTL1 and its receptor DIP2A in Myocardium, activates the signaling pathway of Akt-mTOR, induces cardiomyocyte proliferation, and improves cardiac function.