Postnatal cardiomyocyte cell cycle withdrawal is a critical step wherein the mammalian heart loses regenerative potential after birth. Here, we conducted interspecies multi-omic comparisons between the mouse heart and that of the opossum, which have different postnatal time-windows for cardiomyocyte cell cycle withdrawal. Xanthine metabolism was activated in both postnatal hearts in parallel with cardiomyocyte cell cycle arrest. The pentose phosphate pathway (PPP) which produces NADPH was found to decrease simultaneously. Postnatal myocardial tissues became oxidized accordingly, and administration of antioxidants to neonatal mice altered the PPP and suppressed the postnatal activation of cardiac xanthine metabolism. These results suggest a redox-driven postnatal switch from purine synthesis to degradation in the heart. Importantly, inhibition of xanthine metabolism in the postnatal heart extended postnatal duration of cardiomyocyte proliferation and maintained postnatal heart regeneration potential in mice. These findings highlight a novel role of xanthine metabolism as a redox-dependent metabolic regulator of cardiac regeneration potential.

中文翻译：

---

氧化还原依赖性嘌呤降解触发出生后心脏再生电位丧失


出生后心肌细胞周期撤退是哺乳动物心脏在出生后失去再生潜力的关键步骤。在这里，我们对小鼠心脏和负鼠的心脏进行了种间多组学比较，它们具有不同的心肌细胞周期退出的出生后时间窗口。黄嘌呤代谢在两个出生后心脏中被激活，与心肌细胞周期停滞同时被激活。发现产生 NADPH 的磷酸戊糖途径 （PPP） 同时降低。出生后心肌组织相应被氧化，给新生小鼠服用抗氧化剂改变了 PPP 并抑制了出生后心脏黄嘌呤代谢的激活。这些结果表明，氧化还原驱动的出生后从嘌呤合成转变为心脏降解。重要的是，抑制出生后心脏中的黄嘌呤代谢延长了小鼠心肌细胞增殖的出生后持续时间，并维持了小鼠出生后心脏再生的潜力。这些发现强调了黄嘌呤代谢作为心脏再生电位的氧化还原依赖性代谢调节剂的新作用。