Abstract 1478: Myocardial “Anti-aging” Effects of Physical Exercise in Voluntary Running Mice
Background: Telomere-regulating proteins affect cellular senescence, survival and regeneration. The purpose of this study was the investigation of myocardial “anti-aging” effects of physical exercise and the underlying molecular mechanisms.
Methods: C57/Bl6 wildtype and telomerase reverse transcriptase (TERT) deficient mice were randomized to voluntary running or no running wheel conditions (n=8–12 per group).
Results: Short-term running for 3 weeks upregulated cardiac telomerase activity to 231 ± 21% (p<0.01) of sedentary controls, increased protein expression of TERT (165 ± 4%, p<0.05) and telomere-repeat binding factor (TRF) 2 (169 ± 8%, p<0.05) and reduced protein expression of the senescence / apoptosis regulators Chk2 (79 ± 3%), p53 (56 ± 3%) and p16 (53 ± 3%). These effects were paralleled by the changes in mRNA expression of these factors and upregulation of the repair protein Ku80. These exercise-induced changes were absent in TERT−/− mice. Myocardial (QFISH assay) and leukocyte (FlowFISH assay) telomere length did not differ between 3 week and 6 months old sedentary or running mice (21.6 kbp vs. 21.4 kbp), 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 number of proliferating cardiomyocytes as determined by Ki67 / alpha-sarcomeric actin staining was significantly increased in the hearts of running mice (0% in control mice vs. 0.023 ± 0.01 %, p<0.02). To test the physiologic relevance of these exercise-mediated “anti-aging” pathways, apoptotic cardiomyopathy was induced by treatment with doxorubicin. Telomerase activity was not impaired by doxorubicin in this model. Upregulation of telomere-stabilizing proteins by physical exercise in mice reduced doxorubicin-induced p53 expression and potently prevented cardiomyocyte apoptosis in wildtype, but not in TERT−/− mice.
Conclusions: These results identify physical activity as a powerful and long-acting intervention with beneficial effects on myocardial to telomere biology, thereby inducing anti-senescent and cardioprotective effects, e.g. to prevent doxorubicin induced cardiomyopathy. Impaired TERT function abrogates the positive effects of physical exercise.