Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation
Aims: The coordinated gene and metabolic programs that facilitate cardiomyocyte entry and progression in the cell cycle are poorly understood. The purpose of this study was to identify the metabolic changes that influence myocyte proliferation. Methods and results: In adult mouse cardiomyocytes and...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-10-01
|
| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721002536 |
| _version_ | 1818643494489554944 |
|---|---|
| author | Riham R.E. Abouleisa Lindsey McNally Abou bakr M. Salama Sally K. Hammad Qinghui Ou Collin Wells Pawel K. Lorkiewicz Roberto Bolli Tamer M.A. Mohamed Bradford G. Hill |
| author_facet | Riham R.E. Abouleisa Lindsey McNally Abou bakr M. Salama Sally K. Hammad Qinghui Ou Collin Wells Pawel K. Lorkiewicz Roberto Bolli Tamer M.A. Mohamed Bradford G. Hill |
| author_sort | Riham R.E. Abouleisa |
| collection | DOAJ |
| description | Aims: The coordinated gene and metabolic programs that facilitate cardiomyocyte entry and progression in the cell cycle are poorly understood. The purpose of this study was to identify the metabolic changes that influence myocyte proliferation. Methods and results: In adult mouse cardiomyocytes and human induced pluripotent stem cell cardiomyocytes (hiPS-CMs), cell cycle initiation by ectopic expression of Cyclin B1, Cyclin D1, CDK1, and CDK4 (termed 4F) downregulated oxidative phosphorylation genes and upregulated genes that regulate ancillary biosynthetic pathways of glucose metabolism. Results from metabolic analyses and stable isotope tracing experiments indicate that 4F-mediated cell cycle induction in hiPS-CMs decreases glucose oxidation and oxidative phosphorylation and augments NAD+, glycogen, hexosamine, phospholipid, and serine biosynthetic pathway activity. Interventions that diminish NAD+ synthesis, serine synthesis, or protein O-GlcNAcylation decreased 4F-mediated cell cycle entry. In a gain of function approach, we overexpressed phosphoenolpyruvate carboxykinase 2 (PCK2), which can drive carbon from the Krebs cycle to the glycolytic intermediate pool, and found that PCK2 augments 4F-mediated cell cycle entry. Conclusions: These findings suggest that a metabolic shift from catabolic to anabolic activity is a critical step for cardiomyocyte cell cycle entry and is required to facilitate proliferation. |
| first_indexed | 2024-12-16T23:59:51Z |
| format | Article |
| id | doaj.art-8a813a80fa3b441081af554c8527baeb |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-16T23:59:51Z |
| publishDate | 2021-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-8a813a80fa3b441081af554c8527baeb2022-12-21T22:11:06ZengElsevierRedox Biology2213-23172021-10-0146102094Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activationRiham R.E. Abouleisa0Lindsey McNally1Abou bakr M. Salama2Sally K. Hammad3Qinghui Ou4Collin Wells5Pawel K. Lorkiewicz6Roberto Bolli7Tamer M.A. Mohamed8Bradford G. Hill9Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, USAInstitute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Cardiovascular Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt; Department of Cardiac Surgery, Verona University, Verona, ItalyInstitute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Biochemistry, Faculty of Pharmacy, Zagazig University, EgyptInstitute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Chemistry, University of Louisville, KY, USAInstitute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USAInstitute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA; Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, KY, USA; Institute of Cardiovascular Sciences, University of Manchester, UK; Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Egypt; Corresponding author. Department of Medicine, Division of Cardiovascular Medicine, Institute of Molecular Cardiology, 580 S. Preston St., Rm 121F, Louisville, KY, 40202; USA.Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA; Corresponding author. Department of Medicine, Christina Lee Brown Envirome Institute, Diabetes and Obesity Center, University of Louisville, 580 S. Preston St., Rm 321E, Louisville, KY, 40202, USA.Aims: The coordinated gene and metabolic programs that facilitate cardiomyocyte entry and progression in the cell cycle are poorly understood. The purpose of this study was to identify the metabolic changes that influence myocyte proliferation. Methods and results: In adult mouse cardiomyocytes and human induced pluripotent stem cell cardiomyocytes (hiPS-CMs), cell cycle initiation by ectopic expression of Cyclin B1, Cyclin D1, CDK1, and CDK4 (termed 4F) downregulated oxidative phosphorylation genes and upregulated genes that regulate ancillary biosynthetic pathways of glucose metabolism. Results from metabolic analyses and stable isotope tracing experiments indicate that 4F-mediated cell cycle induction in hiPS-CMs decreases glucose oxidation and oxidative phosphorylation and augments NAD+, glycogen, hexosamine, phospholipid, and serine biosynthetic pathway activity. Interventions that diminish NAD+ synthesis, serine synthesis, or protein O-GlcNAcylation decreased 4F-mediated cell cycle entry. In a gain of function approach, we overexpressed phosphoenolpyruvate carboxykinase 2 (PCK2), which can drive carbon from the Krebs cycle to the glycolytic intermediate pool, and found that PCK2 augments 4F-mediated cell cycle entry. Conclusions: These findings suggest that a metabolic shift from catabolic to anabolic activity is a critical step for cardiomyocyte cell cycle entry and is required to facilitate proliferation.http://www.sciencedirect.com/science/article/pii/S2213231721002536 |
| spellingShingle | Riham R.E. Abouleisa Lindsey McNally Abou bakr M. Salama Sally K. Hammad Qinghui Ou Collin Wells Pawel K. Lorkiewicz Roberto Bolli Tamer M.A. Mohamed Bradford G. Hill Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation Redox Biology |
| title | Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation |
| title_full | Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation |
| title_fullStr | Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation |
| title_full_unstemmed | Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation |
| title_short | Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation |
| title_sort | cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231721002536 |
| work_keys_str_mv | AT rihamreabouleisa cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation AT lindseymcnally cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation AT aboubakrmsalama cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation AT sallykhammad cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation AT qinghuiou cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation AT collinwells cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation AT pawelklorkiewicz cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation AT robertobolli cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation AT tamermamohamed cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation AT bradfordghill cellcycleinductioninhumancardiomyocytesisdependentonbiosyntheticpathwayactivation |