Stimulation of glycolysis via the pyruvate dehydrogenase axis promotes cardiomyocyte proliferation after injury in adult zebrafish.

Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac contractions. However, the role of metabolism in cardiomyocyte proliferation 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), specifically in tissues bordering the damaged area. We proceed to show that impaired glycolysis decreases the number of proliferating cardiomyocytes following cardiac injury. These observations are further supported by analyses using loss-of-function models for the metabolic regulators Pkm2a and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Ppargc1a). Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 and a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation. 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.心脏代谢在生成充足能量以维持心肌收缩方面发挥着至关重要的作用。然而，代谢在心肌细胞增殖中的作用仍尚不明确。本研究以成年斑马鱼心脏再生模型为研究对象，首次发现：在受损区域边缘的组织中，编码调控葡萄糖与丙酮酸代谢的酶（包括丙酮酸激酶M1/2（Pkm）及丙酮酸脱氢酶激酶（Pdks））的mRNA水平显著升高。后续实验证实，糖酵解功能受损会降低心脏损伤后增殖心肌细胞的数量。针对代谢调节因子Pkm2a与过氧化物酶体增殖物激活受体γ辅激活因子1α（Ppargc1a）的功能丧失模型分析，进一步验证了上述观察结果。通过利用Pdk3及丙酮酸脱氢酶复合物（PDC）的催化亚基，对心肌细胞进行丙酮酸代谢的特异性功能丧失与功能获得性操作，揭示了丙酮酸代谢在心肌细胞去分化与增殖中的重要作用。此外，本研究发现，PDK的活性可调控培养环境中哺乳动物心肌细胞的细胞周期进程与突起活动。本研究结果揭示了心脏代谢及PDK-PDC轴在心脏损伤后心肌细胞行为调控中的全新作用。