Carolin Lerchenmüller1,2,3, Ana Vujic4, Anthony Rosenzweig5, Richard T Lee4,6, Sonja Mittag1,2,3, Annie Wang4, Charles P Rabolli1,3, Chiara Heß1, Fynn Betge1,2, Ashraf Y Rangrez1,3, Malay Chaklader7, Christelle Guillermier5,8, Frank Gyngard5,8, Jason D Roh3,5, Haobo Li3,5, Matthew L Steinhauser5,8,9, Norbert Frey1,2, Beverly Rothermel7,10, Christoph Dieterich1,2. 1. Department of Cardiology, University Hospital Heidelberg, Germany (C.L., S.M., C.P.R., C.H., F.B., A.Y.R., N.F., C.D.). 2. German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany (C.L., S.M., F.B., N.F., C.D.). 3. Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Boston (C.L., S.M., C.P.R., J.D.R., H.L., A.R.). 4. Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, MA (A.V., A.W., R.T.L.). 5. Harvard Medical School, Boston, MA (C.G., F.G., J.D.R., H.L., M.L.S., A.R.). 6. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA (R.T.L.). 7. Department of Internal Medicine, Division of Cardiology (M.C., B.R.), The University of Texas Southwestern Medical Center, TX. 8. Center for NanoImaging and Division of Genetics, Brigham and Women's Hospital, Cambridge, MA (C.G., F.G., M.L.S.). 9. Aging Institute, University of Pittsburgh School of Medicine, PA (M.L.S.). 10. Department of Molecular Biology (B.R.), The University of Texas Southwestern Medical Center, TX.
Abstract
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.
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.
Entities:
Keywords:
age factors; circadian rhythm; exercise; heart failure; muscle development
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