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Published on: October 10, 2020
Restoration of Cardiomyogenesis in Aged Mouse Hearts by Voluntary Exercise
Carolin Lerchenmüller1,2,3, Ana Vujic4, Sonja Mittag1,2,3
1Department of Cardiology, University Hospital Heidelberg, Germany (C.L., S.M., C.P.R., C.H., F.B., A.Y.R., N.F., C.D.).
Insights
Exercise can stimulate new heart cell (cardiomyocyte) generation in aged mice, partially restoring cardiac regeneration. This suggests that circadian rhythm pathways may be key to exercise-induced cardiomyogenesis in older hearts.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Aging Research
Background:
- The adult human heart has a limited capacity for cardiomyocyte generation, which declines with age.
- Loss of cardiomyocytes contributes to heart failure, necessitating exploration of endogenous cardiac regeneration stimuli.
- Previous studies showed exercise activates cardiomyogenesis in young adult mouse hearts; its effect on aged hearts remains unknown.
Purpose of the Study:
- To investigate the impact of exercise on the generation of new cardiomyocytes in aged mouse hearts.
- To determine if voluntary running can stimulate cardiac regeneration in elderly mice.
Main Methods:
- Aged mice (20 months old) underwent an 8-week voluntary running program; age-matched sedentary mice served as controls.
- Cardiomyogenesis was assessed using 15N-thymidine incorporation and multi-isotope imaging mass spectrometry.
- RNA sequencing analyzed transcriptional changes in aged exercised hearts compared to young and sedentary controls.
Main Results:
- Significantly higher frequency of cardiomyogenesis (mononucleated/diploid 15N-thymidine-labeled cardiomyocytes) was observed in exercised aged hearts.
- No new cardiomyocyte formation was detected in sedentary aged mice; exercised aged mice showed an annual rate of 2.3%.
- Exercise upregulated circadian rhythm pathways, with isoform 1.4 of regulator of calcineurin exclusively upregulated in aged exercised hearts.
Conclusions:
- Voluntary running partially restores cardiomyocyte generation in aged mice, indicating a potential for exercise-mediated cardiac repair.
- Circadian rhythm pathways are implicated in physiologically stimulated cardiomyogenesis, offering potential therapeutic targets for age-related cardiac decline.
Background:
The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in the aged heart. We have previously shown that cardiomyogenesis can be activated by exercise in the young adult mouse heart. Whether exercise also induces cardiomyogenesis in aged hearts, however, is still unknown. Here, we aim to investigate the effect of exercise on the generation of new cardiomyocytes in the aged heart.
Methods:
Aged (20-month-old) mice were subjected to an 8-week voluntary running protocol, and age-matched sedentary animals served as controls. Cardiomyogenesis in aged hearts was assessed on the basis of 15N-thymidine incorporation and multi-isotope imaging mass spectrometry. We analyzed 1793 cardiomyocytes from 5 aged sedentary mice and compared these with 2002 cardiomyocytes from 5 aged exercised mice, followed by advanced histology and imaging to account for ploidy and nucleation status of the cell. RNA sequencing and subsequent bioinformatic analyses were performed to investigate transcriptional changes induced by exercise specifically in aged hearts in comparison with young hearts.
Results:
Cardiomyogenesis was observed at a significantly higher frequency in exercised compared with sedentary aged hearts on the basis of the detection of mononucleated/diploid 15N-thymidine-labeled cardiomyocytes. No mononucleated/diploid 15N-thymidine-labeled cardiomyocyte was detected in sedentary aged mice. The annual rate of mononucleated/diploid 15N-thymidine-labeled cardiomyocytes in aged exercised mice was 2.3% per year. This compares with our previously reported annual rate of 7.5% in young exercised mice and 1.63% in young sedentary mice. Transcriptional profiling of young and aged exercised murine hearts and their sedentary controls revealed that exercise induces pathways related to circadian rhythm, irrespective of age. One known oscillating transcript, however, that was exclusively upregulated in aged exercised hearts, was isoform 1.4 of regulator of calcineurin, whose regulation and functional role were explored further.
Conclusions:
Our data demonstrate that voluntary running in part restores cardiomyogenesis in aged mice and suggest that pathways associated with circadian rhythm may play a role in physiologically stimulated cardiomyogenesis.
