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

被引：81

作者：

Zhang, Naijin ^{[1
,2
]}

Zhang, Ying ^{[1
,3
]}

Xu, Jiaqi ^{[1
]}

Wang, Pengbo ^{[1
]}

Wu, Boquan ^{[1
]}

Lu, Saien ^{[1
]}

Lu, Xinxin ^{[1
]}

You, Shilong ^{[1
]}

Huang, Xinyue ^{[1
]}

Li, Mohan ^{[1
]}

Zou, Yuanming ^{[1
]}

Liu, Mengke ^{[1
]}

Zhao, Yuanhui ^{[1
]}

Sun, Guozhe ^{[1
]}

Wang, Wenbin ^{[1
]}

Geng, Danxi ^{[1
]}

Liu, Jingwei ^{[4
,5
]}

Cao, Liu ^{[4
,5
]}

Sun, Yingxian ^{[1
,3
,6
]}

机构：

[1] China Med Univ, Hosp 1, Dept Cardiol, Shenyang, Liaoning, Peoples R China

[2] China Med Univ, NHC Key Lab Adv Reprod Med & Fertil, Natl Hlth Commiss, Shenyang, Liaoning, Peoples R China

[3] China Med Univ, Inst Hlth Sci, Shenyang, Liaoning, Peoples R China

[4] Minist Educ, Key Lab Med Cell Biol, Shenyang, Liaoning, Peoples R China

[5] China Med Univ, Inst Sch Basic Med, Shenyang, Liaoning, Peoples R China

[6] China Med Univ, Key Lab Environm Stress & Chron Dis Control & Prev, Minist Educ, Shenyang, Liaoning, Peoples R China

来源：

CELL RESEARCH | 2023年 / 33卷 / 09期

基金：

中国国家自然科学基金;

关键词：

CARDIAC ENERGY-METABOLISM; GENE-EXPRESSION; TITIN;

D O I：

10.1038/s41422-023-00844-w

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The sarcomeric interaction of & alpha;-myosin heavy chain (& alpha;-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 & alpha;-MHC undergoes lactylation on lysine 1897 to regulate the interaction of & alpha;-MHC with Titin. We observed a reduction of & alpha;-MHC K1897 lactylation in mice and patients with heart failure. Loss of K1897 lactylation in & alpha;-MHC K1897R knock-in mice reduces & alpha;-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 & alpha;-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation reduces & alpha;-MHC lactylation, impairs & alpha;-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 & alpha;-MHC K1897 lactylation and & alpha;-MHC-Titin interaction, thereby alleviating heart failure. In conclusion, & alpha;-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 & alpha;-MHC K1897 lactylation during myocardial injury. Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification of & alpha;-MHC.

引用

页码：679 / 698

页数：20