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

Christian Werner, MD^_*, Milad Hanhoun, MD^_*, Thomas Widmann, MD, Andrey Kazakov, MD^_*, Alexander Semenov, MD^_*, Janine Pöss, MD^_*, Johann Bauersachs, MD, Thomas Thum, MD, Michael Pfreundschuh, MD, Patrick Müller, MD^_*, Judith Haendeler, MD, Michael Böhm, MD^_* and Ulrich Laufs, MD^_*,_*

^_* Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
Klinik für Innere Medizin I, Hämatologie, Onkologie und Rheumatologie Universitätsklinikum des Saarlandes, Homburg, Germany
Medizinische Klinik I, Kardiologie, Universitätsklinikum Würzburg, Germany
Institut für Umweltmedizinische Forschung at the Universität Düsseldorf gGmbH, Düsseldorf, Germany.

Manuscript received February 7, 2008; revised manuscript received March 21, 2008, accepted April 14, 2008.

^_* Reprint requests and correspondence: Dr. Ulrich Laufs, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66424 Homburg/Saar, Germany. (Email: ulrich{at}laufs.com).

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.

Key Words: exercise • myocardium • aging • prevention • telomere

Abbreviations and Acronyms   BSA = bovine serum albumin   Chk2 = cell-cycle–checkpoint kinase 2   eNOS = endothelial nitric oxide synthase   FISH = fluorescence in-situ hybridization   GAPDH = glyceraldehyde-3-phosphate dehydrogenase   GH = growth hormone   HEK = human embryonic kidney   Ig = immunoglobulin   IGF = insulin-like growth factor   i.p. = intraperitoneally   mRNA = messenger ribonucleic acid   PBS = phosphate buffered saline   TERT = telomerase reverse transcriptase   TFU = telomeric fluorescence units   TRF = telomere repeat binding factor   Tris = tris(hydroxymethyl) aminomethane   WT = wild-type

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