Abstract 1327: Beneficial Effects of Physical Exercise on Myocardial Telomere Regulating Proteins, Survival Pathways and Apoptosis
Background: Physical exercise is associated with positive cardiovascular effects, but the underlying molecular mechanisms are incompletely understood. Telomere-regulating proteins have been shown to affect cellular senescence, survival and regeneration.
Methods and Results: C57/Bl6 mice were randomized to voluntary training on running wheels (n=12 per group, mean running distance 5100 ± 800 m/24h) or no running wheel condition. Voluntary running for 21 days did not change cardiac mass or function (echocardiography) but upregulated cardiac telomerase activity (Telomerase Repeat Amplification Protocols) to 230±22% of sedentary controls. Western analyses showed increased expression of telomer-ase reverse transcriptase (TERT) to 165±4.1% and telomere-repeat binding factor (TRF) 2 to 149±8.4%. This was associated with reduced myocardial expression of DNA damage checkpoint-kinase 2 (Chk2) to 21±3 %, p53 to 44±2.7% and p16 to 47±3.4%. Long term voluntary exercise (6 month, n=12 per group) induced mild myocardial hypertrophy as expected. Telomerase activity, TRF2- and TERT expression remained persistently increased. The expression of cell-cycle inhibitors Chk2, p53 and p16 remained down-regulated (34.8±5%, 43±4.3%, 29±3% of control, respectively). Voluntary running increased cardiac expression of eNOS and IGF-1. In eNOS −/− mice, exercise (n=8, 12 days) had no effect on IGF-1, telomerase, TERT, TRF2 or cell cycle regulators. To test the physiologic relevance of exercise-induced pro-survival pathways, apoptotic cardiomyopathy was induced by treatment with doxorubicin. Upregulation of telomere-stabilizing proteins in running mice was associated with marked reduction of doxorubicin-induced p53 expression and complete prevention of apoptosis (hairpin oligonucleotid assay). All effects are significant with p<0.05.
Conclusion: Upregulation of telomere-stabilizing proteins may represent an important cardio-protective anti-apoptotic effect of physical exercise.