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J Am Coll Cardiol, 2008; 52:470-482, doi:10.1016/j.jacc.2008.04.034
© 2008 by the American College of Cardiology Foundation
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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{dagger}, Andrey Kazakov, MD*, Alexander Semenov, MD*, Janine Pöss, MD*, Johann Bauersachs, MD{ddagger}, Thomas Thum, MD{ddagger}, Michael Pfreundschuh, MD{dagger}, 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
{dagger} Klinik für Innere Medizin I, Hämatologie, Onkologie und Rheumatologie Universitätsklinikum des Saarlandes, Homburg, Germany
{ddagger} 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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