Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis

J Am Coll Cardiol. 2008 Aug 5;52(6):470-82. doi: 10.1016/j.jacc.2008.04.034.


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.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / genetics*
  • Cell Survival
  • Cellular Senescence / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / physiology
  • Myocardium / metabolism*
  • Nitric Oxide Synthase Type III / deficiency
  • Running / physiology*
  • Telomere / genetics*
  • Time Factors


  • Apoptosis Regulatory Proteins
  • Nitric Oxide Synthase Type III