Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis
Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis
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DOI：
10.1016/j.jacc.2008.04.034
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发表时间：
2008-08-05
影响因子：
24
通讯作者：
Laufs, Ulrich
中科院分区：
文献类型：
--
作者：
Werner, Christian;Hanhoun, Milad;Laufs, Ulrich
目的研究运动对心脏保护作用的分子机制。背景端粒调节蛋白影响细胞的衰老、存活和再生。方法C57/B16野生型，将内皮一氧化氮合酶（eNOS）缺陷和端粒酶逆转录酶（TERT）缺陷的小鼠随机分为自愿跑步或无跑步轮条件结果短期跑步（21天）可上调心脏端粒酶活性至久坐对照组的2倍以上，增加端粒酶和端粒重复序列结合因子（TRF）2的蛋白表达，降低促凋亡介质细胞周期检查点激酶2（Chk 2）、p53和p16的表达。心肌和白细胞端粒长度没有不同3周龄和6个月大的久坐或跑步的小鼠，但端粒酶活性，TRF 2和TERT表达持续增加6个月后，Chk 2，p53和p16的表达仍然下调。运动诱导的变化在TERT-/-和eNOS（-/-）小鼠中均不存在。跑步增加心脏胰岛素样生长因子（IGF）-1的表达。用IGF-1处理使心肌端粒酶活性上调>14倍，并增加磷酸化Akt蛋白激酶和磷酸化eNOS的表达。为了测试这些运动介导的促生存途径的生理相关性，通过阿霉素治疗诱导凋亡性心肌病。上调端粒稳定蛋白的体育锻炼在小鼠中减少阿霉素诱导的p53表达和有效地防止心肌细胞凋亡的野生型，但不是在TERT-/- mice.Conclusions长期和短期自愿体育锻炼上调心脏端粒稳定蛋白，从而诱导抗衰老和保护作用，例如，以防止阿霉素诱导的心肌病。这些有益的心脏效应由TERT、eNOS和IGF-1介导。
Objectives The purpose of this study was to study the underlying molecular mechanisms of the protective cardiac effects of physical exercise.Background Telomere-regulating proteins affect cellular senescence, survival, and regeneration.Methods C57/Bl6 wild-type, endothelial nitric oxide synthase (eNOS)-deficient and telomerase reverse transcriptase (TERT)-deficient mice were randomized to voluntary running or no running wheel conditions (n = 8 to 12 per group).Results Short-term running (21 days) up-regulated cardiac telomerase activity to >2-fold of sedentary controls, increased protein expression of TERT and telomere repeat binding factor (TRF) 2, and reduced expression of the proapoptotic mediators cell-cycle-checkpoint kinase 2 (Chk2), p53, and p16. Myocardial and leukocyte telomere length did not differ between 3-week- and 6-month-old sedentary or running mice, but telomerase activity, TRF2 and TERT expression were persistently increased after 6 months and the expression of Chk2, p53, and p16 remained down-regulated. The exercise-induced changes were absent in both TERT-/- and eNOS(-/-) mice. Running increased cardiac expression of insulin-like growth factor (IGF)-1. Treatment with IGF-1 up-regulated myocardial telomerase activity >14- fold and increased the expression of phosphorylated Akt protein kinase and phosphorylated eNOS. To test the physiologic relevance of these exercise-mediated prosurvival pathways, apoptotic cardiomyopathy was induced by treatment with doxorubicin. Up-regulation of telomere-stabilizing proteins by physical exercise in mice reduced doxorubicin-induced p53 expression and potently prevented cardiomyocyte apoptosis in wild-type, but not in TERT-/- mice.Conclusions Long- and short-term voluntary physical exercise up-regulates cardiac telomere-stabilizing proteins and thereby induces antisenescent and protective effects, for example, to prevent doxorubicin-induced cardiomyopathy. These beneficial cardiac effects are mediated by TERT, eNOS, and IGF-1.