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Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation.


ABSTRACT:

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.

SUBMITTER: Abouleisa RRE 

PROVIDER: S-EPMC8379496 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation.

Abouleisa Riham R E RRE   McNally Lindsey L   Salama Abou Bakr M ABM   Hammad Sally K SK   Ou Qinghui Q   Wells Collin C   Lorkiewicz Pawel K PK   Bolli Roberto R   Mohamed Tamer M A TMA   Hill Bradford G BG  

Redox biology 20210805


<h4>Aims</h4>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.<h4>Methods and results</h4>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 phos  ...[more]

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