Volume 33, No 9, Sep 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 9, September 2023: 679-698   |  Open Access

ORIGINAL ARTICLES

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

Naijin Zhang^1,2,† , Ying Zhang^1,3,† , Jiaqi Xu¹ , Pengbo Wang¹ , Boquan Wu¹ , Saien Lu¹ , Xinxin Lu¹ , Shilong You¹ , Xinyue Huang¹ , Mohan Li¹ , Yuanming Zou¹ , Mengke Liu¹ , Yuanhui Zhao¹ , Guozhe Sun¹ , Wenbin Wang¹ , Danxi Geng¹ , Jingwei Liu^4,5 , Liu Cao^4,5 , Yingxian Sun^1,3,6,*

¹Department of Cardiology, First Hospital of China Medical University, Shenyang, Liaoning, China
²NHC Key Laboratory of Advanced Reproductive Medicine and Fertility, National Health Commission, China Medical University, Shenyang, Liaoning, China
³Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China
⁴Key Laboratory of Medical Cell Biology, Ministry of Education, Shenyang, Liaoning, China
⁵Institute of School of Basic Medicine, China Medical University, Shenyang, Liaoning, China
⁶Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, China
^†These authors contributed equally: Naijin Zhang, Ying Zhang
Correspondence: Yingxian Sun(yxsun@cmu.edu.cn)

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.

https://doi.org/10.1038/s41422-023-00844-w

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