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Effects of Physical Exercise on Myocardial Telomere-Regulating Proteins, Survival Pathways, and Apoptosis
Open accessAbstract
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.
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“Short-term (3 wk) voluntary wheel running started at 8 wk of age significantly increased myocardial telomerase activity and the protein expression of two telomere-stabilizing proteins, telomerase reverse transcriptase (TERT) and TRF2 in male mice compared with sedentary controls.”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [50]
In the citing paper
“When endothelial nitric oxide synthase (eNOS) knockout mice or TERT knockout mice (8-wk-old) were subjected to the same training stimulus, the positive effects of exercise were not present, suggesting that these enzymes are crucial mediators of myocardial and aortic adaptation.”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [50]
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“Increased telomerase activity was associated with reduced myocardial levels of P16, P53, and cell-cycle-checkpoint kinase 2 (Chk2) (50).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [50]
In the citing paper
“Physical activity also bolsters mediating immune proteins and gene expression (74,75) and more distal biological aging endpoints, such as mitochondrial health and telomerase levels (76–79), which are intimately related to telomere maintenance (20,80,81).”
From Determinants of telomere attrition over 1 year in healthy older women: stress and health behaviors matter (2015) · cites this paper as [77]
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Metadata
- Authors
- Werner, C., Hanhoun, M., Widmann, T., Kazakov, A., Semenov, A., Pöss, J., Bauersachs, J., Thum, T., Pfreundschuh, M., Müller, P., Haendeler, J., Böhm, M., & Laufs, U.
- Affiliations
- Universitätsklinikum des Saarlandes (DE)
- Universitätsklinikum Würzburg (DE)
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Laufs, Ulrich
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 52
- Issue
- 6
- Pages
- 470-482
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2055146811
- Cited by
- 239
- References
- 55
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 13 · 2023: 16 · 2022: 14 · 2021: 15 · 2020: 15 · 2019: 12 · 2018: 20 · 2017: 11 · 2016: 16 · 2015: 16 · 2014: 11 · 2013: 10 · 2012: 13
- FWCI
- 9.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (KFO-196)
- Universität des Saarlandes
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
- Keywords
- physical activity, telomerase, telomerase reverse transcriptase, endothelial nitric oxide synthase, insulin-like growth factor I, Akt signaling, cardiomyocyte apoptosis, doxorubicin-induced cardiomyopathy, p53, p16, Chk2, cellular senescence, voluntary running, cardioprotection
- MeSH terms
- Animals, Cell Survival, Male, Mice, Inbred C57BL, Motor Activity, Myocardium, Running, Time Factors, Telomere, Cellular Senescence, Apoptosis, Apoptosis Regulatory Proteins, Mice, Nitric Oxide Synthase Type III
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