Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis.
OBJECTIVE
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.
Werner
Christian
C
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
Hanhoun
Milad
M
Widmann
Thomas
T
Kazakov
Andrey
A
Semenov
Alexander
A
Pöss
Janine
J
Bauersachs
Johann
J
Thum
Thomas
T
Pfreundschuh
Michael
M
Müller
Patrick
P
Haendeler
Judith
J
Böhm
Michael
M
Laufs
Ulrich
U
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002470:Cell Survival; D016922:Cellular Senescence / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency; D012420:Running / Q000502:physiology*; D016615:Telomere / Q000235:genetics*; D013997:Time Factors
D051017:Apoptosis Regulatory Proteins; D052250:Nitric Oxide Synthase Type III