Effects of Physical Exercise on Myocardial Telomere-Regulating Proteins, Survival Pathways, and Apoptosis

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• 作者：Christian Werner ; Milad Hanhoun ; Thomas Widmann ; Andrey Kazakov ; Alex ; er Semenov ; Janine P&#xf6 ; ss ; Johann Bauersachs ; Thomas Thum ; Michael Pfreundschuh ; Patrick Mü ; ller ; Judith Haendeler ; Michael B&#xf6 ; hm ; Ulrich Laufs
• 关键词：exercise ; myocardium ; aging ; prevention ; telomere
• 刊名：Journal of the American College of Cardiology
• 出版年：2008
• 出版时间：5 August 2008
• 年：2008
• 卷：52
• 期：6
• 页码：470-482
• 全文大小：475 K

文摘

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.