AIMS There is a large subpopulation of multinucleated polyploid cardiomyocytes (M*Pc CMs) in the adult mammalian heart. However, the pathophysiological significance of increased M*Pc CMs in heart disease is poorly understood. We sought to determine the pathophysiological significance of increased M*Pc CMs during hypoxia adaptation. METHODS AND RESULTS A model of hypoxia-induced cardiomyocyte (CM) multinucleation and polyploidization was established and found to be associated with less apoptosis and less reactive oxygen species (ROS) production. Compared to mononucleated diploid CMs (1*2c CMs), tetraploid CMs (4c CMs) exhibited better mitochondria quality control via increased mitochondrial autophagy (mitophagy). RNA-seq revealed Prkaa2, the gene for AMPKα2, was the most obviously up-regulated autophagy-related gene. Knockdown of AMPKα2 increased apoptosis and ROS production and suppressed mitophagy in 4c CMs compared to 1*2c CMs. Rapamycin, an autophagy activator, alleviated the adverse effect of AMPKα2 knockdown. Furthermore, silencing PINK1 also increased apoptosis and ROS in 4c CMs and weakened the adaptive superiority of 4c CMs. Finally, AMPKα2-/- mutant mice exhibited exacerbation of apoptosis and ROS production via decreases in AMPKα2-mediated mitophagy in 4c CMs compared to 1*2c CMs during hypoxia. CONCLUSIONS Compared to 1*2c CMs, hypoxia-induced 4c CMs exhibited enhanced mitochondria quality control and less apoptosis via AMPKα2-mediated mitophagy. These results suggest that multinucleation and polyploidization allow CM to better adapt to stress via enhanced mitophagy. In addition, activation of AMPKα2 may be a promising target for myocardial hypoxia-related diseases.

中文翻译：

---

多核多倍体心肌细胞通过线粒体细胞对缺氧的适应性增强。

目的成年哺乳动物心脏中有大量的多核多倍体心肌细胞（M * Pc CM）亚群。但是，人们对M * Pc CMs在心脏病中的病理生理意义了解甚少。我们试图确定缺氧适应过程中增加的M * Pc CM的病理生理意义。方法和结果建立了低氧诱导的心肌细胞多核化和多倍体化的模型，发现该模型与较少的细胞凋亡和较少的活性氧（ROS）产生有关。与单核二倍体CM（1 * 2c CM）相比，四倍体CM（4c CM）通过增加线粒体自噬（线粒体）表现出更好的线粒体质量控制。RNA-seq揭示了AMPKα2的基因Prkaa2是最明显上调的自噬相关基因。与1 * 2c CM相比，敲低AMPKα2可以增加4c CM中的细胞凋亡和ROS的产生，并抑制线粒体的吞噬。自噬激活剂雷帕霉素减轻了AMPKα2敲低的不利影响。此外，沉默PINK1还增加了4c CMs的凋亡和ROS，并削弱了4c CMs的适应性优势。最后，与缺氧期间的1 * 2c CM相比，在4c CM中AMPKα2介导的线粒体吞噬能力降低，而AMPKα2-/-突变小鼠表现出凋亡和ROS产生加重。结论与1 * 2c CMs相比，低氧诱导的4c CMs通过AMPKα2介导的线粒体细胞显示出增强的线粒体质量控制和更少的细胞凋亡。这些结果表明，多核化和多倍体化使CM能够通过增强的线粒体更好地适应压力。此外，