Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation.
Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation.
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DOI：
10.1016/j.redox.2021.102094
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Hill BG
中科院分区：
文献类型：
--
作者：
Abouleisa RRE;McNally L;Salama ABM;Hammad SK;Ou Q;Wells C;Lorkiewicz PK;Bolli R;Mohamed TMA;Hill BG
人们对促进心肌细胞进入细胞周期和进展的协调基因和代谢程序知之甚少。本研究的目的是确定影响肌细胞增殖的代谢变化。在成年小鼠心肌细胞和人诱导多能干细胞心肌细胞 (hiPS-CM) 中，Cyclin B1、Cyclin D1、CDK1 和 CDK4（称为 4F）的异位表达启动细胞周期，下调氧化磷酸化基因并上调调节葡萄糖代谢辅助生物合成途径的基因。代谢分析和稳定同位素示踪实验的结果表明，hiPS-CM 中 4F 介导的细胞周期诱导减少了葡萄糖氧化和氧化磷酸化，并增强了 NAD+、糖原、己糖胺、磷脂和丝氨酸生物合成途径活性。减少 NAD+ 合成、丝氨酸合成或蛋白质 O-GlcNAc 化的干预措施会减少 4F 介导的细胞周期进入。在功能获得方法中，我们过表达磷酸烯醇丙酮酸羧激酶 2 (PCK2)，它可以将碳从克雷布斯循环驱动到糖酵解中间池，并发现 PCK2 增强了 4F 介导的细胞周期进入。这些发现表明，从分解代谢活动向合成代谢活动的代谢转变是心肌细胞进入细胞周期的关键步骤，并且是促进增殖所必需的。
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. 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. 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.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
DOI：
10.1126/science.1199010
发表时间：
2011-04-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Heallen T;Zhang M;Wang J;Bonilla-Claudio M;Klysik E;Johnson RL;Martin JF
通讯作者：
Martin JF
影响因子：
37.8
作者：
Bae J;Salamon RJ;Brandt EB;Paltzer WG;Zhang Z;Britt EC;Hacker TA;Fan J;Mahmoud AI
通讯作者：
Mahmoud AI
影响因子：
3
作者：
Bilan, Dmitry S.;Matlashov, Mikhail E.;Gorokhovatsky, Andrey Yu.;Schultz, Carsten;Enikolopov, Grigori;Belousov, Vsevolod V.
通讯作者：
Belousov, Vsevolod V.
GLUT1过表达增强了葡萄糖代谢并促进新生儿心脏再生。
影响因子：
4.6
作者：
Fajardo VM;Feng I;Chen BY;Perez-Ramirez CA;Shi B;Clark P;Tian R;Lien CL;Pellegrini M;Christofk H;Nakano H;Nakano A
通讯作者：
Nakano A