中国医科大学孙英贤研究团队揭示α-肌球蛋白重链(α-MHC)乳酸化维持肌体结构和功能，缓解心力衰竭的进展。相关论文于2023年7月13日发表在《细胞研究》杂志上。

乳酸是心脏重要的能量基质。他们发现α-MHC在赖氨酸1897上发生乳酸化，以调节α-MHC与Titin的相互作用。他们观察到小鼠和心力衰竭患者α-MHC K1897乳酸化降低。在α-MHC K1897R敲入小鼠中，K1897乙酰化缺失会降低α-MHC - Titin相互作用，导致心脏结构和功能受损。此外，他们发现p300和Sirtuin 1分别作为α-MHC的酰基转移酶和去乙酰化酶。通过化学或基因操作减少乳酸生成，减少α-MHC的乳酸化，削弱α-MHC -Titin的相互作用，加重心力衰竭。相反，通过给药乳酸钠或抑制心肌细胞中关键乳酸转运蛋白上调乳酸浓度可促进α-MHC K1897的乳酸化和α-MHC -Ttin的相互作用，从而减轻心力衰竭。

综上所述，α-MHC的乳酸化是动态调节的，是心脏整体结构和功能的重要决定因素。心肌细胞过多的乳酸外排和消耗可降低细胞内乳酸水平，这是心肌损伤时α-MHC K1897乳酸化降低的主要原因。他们的研究表明，心脏代谢通过α-MHC的乳酸依赖性修饰直接调节肌体结构和功能。

研究人员表示，α-MHC与Titin的相互作用对心脏结构和收缩至关重要。然而，在正常心脏和衰竭心脏中调节这种相互作用的机制尚不清楚。

附：英文原文

Title: α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure

Author: Zhang, Naijin, Zhang, Ying, Xu, Jiaqi, Wang, Pengbo, Wu, Boquan, Lu, Saien, Lu, Xinxin, You, Shilong, Huang, Xinyue, Li, Mohan, Zou, Yuanming, Liu, Mengke, Zhao, Yuanhui, Sun, Guozhe, Wang, Wenbin, Geng, Danxi, Liu, Jingwei, Cao, Liu, Sun, Yingxian

Issue&Volume: 2023-07-13

Abstract: The sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this interaction in normal and failing hearts remains unknown. Lactate is a crucial energy substrate of the heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate the interaction of α-MHC with Titin. We observed a reduction of α-MHC K1897 lactylation in mice and patients with heart failure. Loss of K1897 lactylation in α-MHC K1897R knock-in mice reduces α-MHC–Titin interaction and leads to impaired cardiac structure and function. Furthermore, we identified that p300 and Sirtuin 1 act as the acyltransferase and delactylase of α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation reduces α-MHC lactylation, impairs α-MHC–Titin interaction and worsens heart failure. By contrast, upregulation of the lactate concentration by administering sodium lactate or inhibiting the pivotal lactate transporter in cardiomyocytes can promote α-MHC K1897 lactylation and α-MHC–Titin interaction, thereby alleviating heart failure. In conclusion, α-MHC lactylation is dynamically regulated and an important determinant of overall cardiac structure and function. Excessive lactate efflux and consumption by cardiomyocytes may decrease the intracellular lactate level, which is the main cause of reduced α-MHC K1897 lactylation during myocardial injury. Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification of α-MHC.

DOI: 10.1038/s41422-023-00844-w

Source: https://www.nature.com/articles/s41422-023-00844-w