Dynamic resistance exercise increases skeletal muscle-derived FSTL1 inducing cardiac angiogenesis via DIP2A-Smad2/3 in rats following myocardial infarction.
Dynamic resistance exercise increases skeletal muscle-derived FSTL1 inducing cardiac angiogenesis via DIP2A-Smad2/3 in rats following myocardial infarction.
复制标题
动态阻力运动可增加心肌梗塞后大鼠中骨骼肌衍生的 FSTL1，通过 DIP2A-Smad2/3 诱导心脏血管生成。
DOI：
10.1016/j.jshs.2020.11.010
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发表时间：
2021-09
影响因子：
11.7
通讯作者：
Tian Z
中科院分区：
文献类型：
--
作者：
Xi Y;Hao M;Liang Q;Li Y;Gong DW;Tian Z
动态抗阻运动可刺激骨骼肌分泌卵泡抑素样蛋白1（FSTL1）。
骨骼肌分泌的FSTL1可补充心肌FSTL1的不足，促进心肌血管生成，保护心脏免受心肌梗死的损伤。
外源性FSTL1可提高人脐静脉内皮细胞（HUVECs）的增殖能力及小管形成能力。
FSTL1 - DIP2A主要通过Smad2/3信号通路调节血管生成，且不受转化生长因子β受体1（TGFβR1）的影响。
FSTL1、DIP2A、Smad2/3以及fstl1基因转录形成了一种反馈回路的调控模式。
本研究旨在探讨动态抗阻运动促使骨骼肌生成卵泡抑素样蛋白1（FSTL1）的潜力，该蛋白可能通过诱导血管生成，对心肌梗死（MI）后的大鼠起到心脏保护作用。
成年雄性Sprague - Dawley大鼠随机分为5组（每组n = 12）：假手术组（S）、久坐不动心肌梗死组（MI）、心肌梗死 + 抗阻运动组（MR）、心肌梗死 + 腺相关病毒（AAV） - FSTL1注射组（MA）以及心肌梗死 + AAV - FSTL1注射 + 抗阻运动组（MAR）。采用分子生物学方法制备AAV - FSTL1载体，并将其注射至胫骨前肌。通过结扎左冠状动脉前降支建立心肌梗死模型。MR组和MAR组大鼠使用负重爬梯进行为期4周的动态抗阻运动训练。通过血流动力学指标评估心脏功能。采用Masson染色观察并分析心肌胶原容积分数。利用人脐静脉血管内皮细胞培养以及重组人FSTL1蛋白或TGFβR1抑制剂处理，以阐明FSTL1的分子信号机制。通过免疫荧光染色观察血管生成、细胞增殖以及盘状结构相互作用蛋白2同源物A（DIP2A）的定位。采用蛋白质免疫印迹法检测FSTL1、DIP2A的表达以及信号通路的激活情况。通过小管实验观察内皮细胞的血管生成情况。采用单因素方差分析和Student's t检验进行统计学分析。
抗阻运动可刺激骨骼肌分泌FSTL1，促进心肌梗死大鼠的心肌血管生成，抑制病理性重构，并保护心脏功能。运动有助于骨骼肌FSTL1发挥心脏保护作用。外源性FSTL1可促进人脐静脉血管内皮细胞增殖并上调DIP2A的表达，而TGFβR1抑制剂干预则下调Smad2/3的磷酸化水平以及血管内皮生长因子 - A的表达，不利于血管生成。FSTL1与受体DIP2A结合，主要通过Smad2/3信号通路调节血管生成。FSTL1 - DIP2A可直接激活Smad2/3，且不受TGFβR1的影响。
动态抗阻运动可刺激骨骼肌源性FSTL1的表达，在心肌梗死大鼠中，该蛋白可补充心肌FSTL1的不足，并通过DIP2A - Smad2/3信号通路促进心脏康复。
The secretion of skeletal muscle FSTL1 was stimulated by dynamic resistance exercise. FSTL1 from skeletal muscle supplemented the insufficiency of cardiac FSTL1, which promoted myocardial angiogenesis and protected the heart from myocardial infarction. Exogenous FSTL1 improved the proliferation and the small tubes formation ability of HUVECs. FSTL1-DIP2A regulated angiogenesis mainly through the Smad2/3 but was not affected by TGFβR1. FSTL1, DIP2A, Smad2/3, and fstl1 gene transcription formed a regulation mode of feedback loop. The aim of this study was to investigate the potential of dynamic resistance exercise to generate skeletal muscle-derived follistatin like-1 (FSTL1), which may induce cardioprotection in rats following myocardial infarction (MI) by inducing angiogenesis. Male, adult Sprague-Dawley rats were randomly divided into 5 groups (n = 12 in each group): sham group (S), sedentary MI group (MI), MI + resistance exercise group (MR), MI + adeno-associated virus (AAV)–FSTL1 injection group (MA), and MI + AAV–FSTL1 injection + resistance exercise group (MAR). The AAV–FSTL1 vector was prepared by molecular biology methods and injected into the anterior tibialis muscle. The MI model was established by ligation of the left anterior descending coronary artery. Rats in the MR and MAR groups underwent 4 weeks of dynamic resistance exercise training using a weighted climbing-up ladder. Heart function was evaluated by hemodynamic measures. Collagen volume fraction of myocardium was observed and analyzed by Masson's staining. Human umbilical vein vessel endothelial cells culture and recombinant human FSTL1 protein or transforming growth factor-β receptor 1 (TGFβR1) inhibitor treatment were used to elucidate the molecular signaling mechanism of FSTL1. Angiogenesis, cell proliferation, and disco interacting protein 2 homolog A (DIP2A) location were observed by immunofluorescence staining. The expression of FSTL1, DIP2A, and the activation of signaling pathways were detected by Western blotting. Angiogenesis of endothelial cells was observed by tubule experiment. One-way analysis of variance and Student's t test were used for statistical analysis. Resistance exercise stimulated the secretion of skeletal muscle FSTL1, which promoted myocardial angiogenesis, inhibited pathological remodeling, and protected cardiac function in MI rats. Exercise facilitated skeletal muscle FSTL1 to play a role in protecting the heart. Exogenous FSTL1 promoted the human umbilical vein vessel endothelial cells proliferation and up-regulated the expression of DIP2A, while TGFβR1 inhibitor intervention down-regulated the phosphorylation level of Smad2/3 and the expression of vascular endothelial growth factor-A, which was not conducive to angiogenesis. FSTL1 bound to the receptor, DIP2A, to regulate angiogenesis mainly through the Smad2/3 signaling pathway. FSTL1–DIP2A directly activated Smad2/3 and was not affected by TGFβR1. Dynamic resistance exercise stimulates the expression of skeletal muscle-derived FSTL1, which could supplement the insufficiency of cardiac FSTL1 and promote cardiac rehabilitation through the DIP2A–Smad2/3 signaling pathway in MI rats.
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影响因子：
3.7
作者：
Kolasa-Trela R;Konieczynska M;Bazanek M;Undas A
通讯作者：
Undas A
影响因子：
4.6
作者：
Hagg A;Colgan TD;Thomson RE;Qian H;Lynch GS;Gregorevic P
通讯作者：
Gregorevic P
影响因子：
2.6
作者：
Tania NP;Maarsingh H;T Bos IS;Mattiotti A;Prakash S;Timens W;Gunst QD;Jimenez-Borreguero LJ;Schmidt M;van den Hoff MJB;Gosens R
通讯作者：
Gosens R
影响因子：
37.8
作者：
Ogura Y;Ouchi N;Ohashi K;Shibata R;Kataoka Y;Kambara T;Kito T;Maruyama S;Yuasa D;Matsuo K;Enomoto T;Uemura Y;Miyabe M;Ishii M;Yamamoto T;Shimizu Y;Walsh K;Murohara T
通讯作者：
Murohara T
影响因子：
168.9
作者：
Shah, Ajay M.;Mann, Douglas L.
通讯作者：
Mann, Douglas L.