• 心肌细胞限制性缺失MPC亚基1(cMPC1-/-)的小鼠出现了年龄依赖性病理性心肌肥大,扩张型心肌病和过早死亡;
  • 肥大的心脏积累乳酸、丙酮酸和糖原,且蛋白O连接的N-乙酰氨基葡萄糖增加,而生酮饮食(KD)或高脂饮食增加体内非葡萄糖底物,可逆转非应激状态下cMPC1−/−心脏的结构、代谢和功能重构;
  • 短期的生酮饮食不能使cMPC1−/−心脏免于压力超负荷后快速代偿失调和早期死亡,但在主动脉弓缩窄前进行3周的生酮饮食可避免这一结果。
在生理和应激条件下,脂肪酸、葡萄糖和乳酸都是重要的心肌基质。它们可被代谢为丙酮酸,丙酮酸通过线粒体丙酮酸载体(MPC)进入线粒体,用于柠檬酸循环代谢。Nature Metabolism近期发表的文章,发现MPC介导的线粒体丙酮酸利用一旦缺失,葡萄糖衍生的胞浆代谢中间产物就累积增多,这些代谢中间产物导致心肌的应激适应失调。而生酮饮食或高脂饮食可改善非应激状态的心脏结构、代谢和功能。

Mitochondrial pyruvate carriers are required for myocardial stress adaptation



2020-10-26, Article

Abstract & Authors:展开

In addition to fatty acids, glucose and lactate are important myocardial substrates under physiologic and stress conditions. They are metabolized to pyruvate, which enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle metabolism. In the present study, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1−/−) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate and glycogen, and displayed increased protein O-linked N-acetylglucosamine, which was prevented by increasing availability of non-glucose substrates in vivo by a ketogenic diet (KD) or a high-fat diet, which reversed the structural, metabolic and functional remodelling of non-stressed cMPC1−/− hearts. Although concurrent short-term KDs did not rescue cMPC1−/− hearts from rapid decompensation and early mortality after pressure overload, 3 weeks of a KD before transverse aortic constriction was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function.

First Authors:
Yuan Zhang

Correspondence Authors:
E Dale Abel

All Authors:
Yuan Zhang,Paul V Taufalele,Jesse D Cochran,Isabelle Robillard-Frayne,Jonas Maximilian Marx,Jamie Soto,Adam J Rauckhorst,Fariba Tayyari,Alvin D Pewa,Lawrence R Gray,Lynn M Teesch,Patrycja Puchalska,Trevor R Funari,Rose McGlauflin,Kathy Zimmerman,William J Kutschke,Thomas Cassier,Shannon Hitchcock,Kevin Lin,Kevin M Kato,Jennifer L Stueve,Lauren Haff,Robert M Weiss,James E Cox,Jared Rutter,Eric B Taylor,Peter A Crawford,E Douglas Lewandowski,Christine Des Rosiers,E Dale Abel

Nature Metabolism期刊

Ketone bodies for the starving heart