PMID- 32648304 OWN - NLM STAT- MEDLINE DCOM- 20210427 LR - 20240329 IS - 1469-3178 (Electronic) IS - 1469-221X (Print) IS - 1469-221X (Linking) VI - 21 IP - 8 DP - 2020 Aug 5 TI - Stimulation of glycolysis promotes cardiomyocyte proliferation after injury in adult zebrafish. PG - e49752 LID - 10.15252/embr.201949752 [doi] LID - e49752 AB - Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac function. However, the role of metabolism in different aspects of cardiomyocyte regeneration remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), especially in tissues bordering the damaged area. We further find that impaired glycolysis decreases the number of proliferating cardiomyocytes following injury. These observations are supported by analyses using loss-of-function models for the metabolic regulators Pkma2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 as well as a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation after injury. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury. CI - (c) 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license. FAU - Fukuda, Ryuichi AU - Fukuda R AUID- ORCID: 0000-0002-0281-5161 AD - Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. AD - The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - Marin-Juez, Ruben AU - Marin-Juez R AD - Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. AD - The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - El-Sammak, Hadil AU - El-Sammak H AD - Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. AD - The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - Beisaw, Arica AU - Beisaw A AD - Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. AD - The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - Ramadass, Radhan AU - Ramadass R AD - Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. AD - The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - Kuenne, Carsten AU - Kuenne C AD - The Cardio-Pulmonary Institute (CPI) and Deep Sequencing Platform, Bad Nauheim, Germany. FAU - Guenther, Stefan AU - Guenther S AD - The Cardio-Pulmonary Institute (CPI) and Deep Sequencing Platform, Bad Nauheim, Germany. AD - Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - Konzer, Anne AU - Konzer A AD - The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. AD - Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - Bhagwat, Aditya M AU - Bhagwat AM AD - The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. AD - Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - Graumann, Johannes AU - Graumann J AUID- ORCID: 0000-0002-3015-5850 AD - The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. AD - Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - Stainier, Didier Yr AU - Stainier DY AUID- ORCID: 0000-0002-0382-0026 AD - Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. AD - The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. LA - eng SI - GEO/GSE147073 GR - F32 HL143839/HL/NHLBI NIH HHS/United States GR - 394046768/Deutsche Forschungsgemeinschaft DFG/International PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200709 PL - England TA - EMBO Rep JT - EMBO reports JID - 100963049 RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Animals MH - Cell Proliferation MH - Glycolysis MH - *Myocytes, Cardiac/metabolism MH - Protein Serine-Threonine Kinases/genetics/metabolism MH - *Zebrafish/metabolism PMC - PMC7403660 OTO - NOTNLM OT - cardiac regeneration OT - cardiomyocyte proliferation OT - glycolysis OT - metabolism OT - zebrafish COIS- The authors declare no competing financial interests. EDAT- 2020/07/11 06:00 MHDA- 2021/04/28 06:00 PMCR- 2020/07/09 CRDT- 2020/07/11 06:00 PHST- 2019/11/26 00:00 [received] PHST- 2020/05/11 00:00 [revised] PHST- 2020/05/20 00:00 [accepted] PHST- 2020/07/11 06:00 [pubmed] PHST- 2021/04/28 06:00 [medline] PHST- 2020/07/11 06:00 [entrez] PHST- 2020/07/09 00:00 [pmc-release] AID - EMBR201949752 [pii] AID - 10.15252/embr.201949752 [doi] PST - ppublish SO - EMBO Rep. 2020 Aug 5;21(8):e49752. doi: 10.15252/embr.201949752. Epub 2020 Jul 9.