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A metabolic switch from OXPHOS to glycolysis is essential for cardiomyocyte proliferation in the regenerating heart

Hessel Honkoop, Dennis E.M. de Bakker, Alla Aharonov, Fabian Kruse, Avraham Shakked, Phong Nguyen, Cecilia de Heus, Laurence Garric, Mauro J Muraro, Adam Shoffner, Federico Tessadori, Joshua C. Peterson, Wendy Noort, George Posthuma, Dominic Grün, Willem J. van der Laarse, Judith Klumperman, Richard T. Jaspers, Kenneth D. Poss, Alexander van Oudenaarden, Eldad Tzahor, Jeroen Bakkers
doi: https://doi.org/10.1101/498899
Hessel Honkoop
1Hubrecht Institute and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
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Dennis E.M. de Bakker
1Hubrecht Institute and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
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Alla Aharonov
2Weizmann Institute of Science, Department of Molecular Cell Biology, Rehovot 7610001, Israel
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Fabian Kruse
1Hubrecht Institute and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
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Avraham Shakked
2Weizmann Institute of Science, Department of Molecular Cell Biology, Rehovot 7610001, Israel
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Phong Nguyen
1Hubrecht Institute and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
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Cecilia de Heus
3Department of Cell Biology and Institute of Biomembranes, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
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Laurence Garric
1Hubrecht Institute and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
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Mauro J Muraro
1Hubrecht Institute and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
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Adam Shoffner
4Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA
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Federico Tessadori
1Hubrecht Institute and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
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Joshua C. Peterson
5Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.
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Wendy Noort
5Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.
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George Posthuma
3Department of Cell Biology and Institute of Biomembranes, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
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Dominic Grün
7Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
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Willem J. van der Laarse
8Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
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Judith Klumperman
3Department of Cell Biology and Institute of Biomembranes, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
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Richard T. Jaspers
5Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.
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Kenneth D. Poss
4Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA
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Alexander van Oudenaarden
1Hubrecht Institute and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
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Eldad Tzahor
2Weizmann Institute of Science, Department of Molecular Cell Biology, Rehovot 7610001, Israel
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Jeroen Bakkers
1Hubrecht Institute and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
9Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands.
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  • For correspondence: j.bakkers@hubrecht.eu
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Summary

The capacity to regenerate damaged tissues, such as the heart, various enormously amongst species. While heart regeneration is generally very low in mammals 1–3, it can regenerate efficiently in certain amphibian and fish species 4,5. Zebrafish has been used extensively to study heart regeneration, resulting in the identification of proliferating cardiomyocytes that drive this process 5–7. However, mechanisms that drive cardiomyocyte proliferation are largely unknown. Here, using a single-cell mRNA-sequencing approach, we find a transcriptionally distinct population of dedifferentiated and proliferating cardiomyocytes in regenerating zebrafish hearts. While adult cardiomyocytes are known to rely on mitochondrial oxidative phosphorylation (OXPHOS) for energy production, these proliferating cardiomyocytes show reduced mitochondrial gene expression and decreased OXPHOS activity. Strikingly, we find that genes encoding rate-limiting enzymes of the glycolysis pathway are induced in the proliferating cardiomyocytes, and inhibiting glycolysis impairs cardiomyocyte cell cycle reentry. Mechanistically, glycolytic gene expression is induced by Nrg1/Erbb2 signaling, and this is conserved in a mouse model of enhanced regeneration. Moreover, inhibiting glycolysis in murine cardiomyocytes abrogates the mitogenic effects of Nrg1/ErbB2 signaling. Together these results reveal a conserved mechanism in which cardiomyocytes undergo metabolic reprogramming by activating glycolysis, which is essential for cell cycle reentry and heart regeneration. This could ultimately help develop therapeutic interventions that promote the regenerative capacity of the mammalian heart.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 18, 2018.
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A metabolic switch from OXPHOS to glycolysis is essential for cardiomyocyte proliferation in the regenerating heart
Hessel Honkoop, Dennis E.M. de Bakker, Alla Aharonov, Fabian Kruse, Avraham Shakked, Phong Nguyen, Cecilia de Heus, Laurence Garric, Mauro J Muraro, Adam Shoffner, Federico Tessadori, Joshua C. Peterson, Wendy Noort, George Posthuma, Dominic Grün, Willem J. van der Laarse, Judith Klumperman, Richard T. Jaspers, Kenneth D. Poss, Alexander van Oudenaarden, Eldad Tzahor, Jeroen Bakkers
bioRxiv 498899; doi: https://doi.org/10.1101/498899
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A metabolic switch from OXPHOS to glycolysis is essential for cardiomyocyte proliferation in the regenerating heart
Hessel Honkoop, Dennis E.M. de Bakker, Alla Aharonov, Fabian Kruse, Avraham Shakked, Phong Nguyen, Cecilia de Heus, Laurence Garric, Mauro J Muraro, Adam Shoffner, Federico Tessadori, Joshua C. Peterson, Wendy Noort, George Posthuma, Dominic Grün, Willem J. van der Laarse, Judith Klumperman, Richard T. Jaspers, Kenneth D. Poss, Alexander van Oudenaarden, Eldad Tzahor, Jeroen Bakkers
bioRxiv 498899; doi: https://doi.org/10.1101/498899

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