Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation
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
Affiliations
Riham R.E. Abouleisa
Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA
Lindsey McNally
Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA
Abou bakr M. Salama
Institute 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, Italy
Sally K. Hammad
Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Egypt
Qinghui Ou
Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA
Collin Wells
Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA
Pawel K. Lorkiewicz
Diabetes 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, USA
Roberto Bolli
Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA
Tamer M.A. Mohamed
Institute 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.
Bradford G. Hill
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.
