| 2 | α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure显示文摘The sarcomeric interaction ofα-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 thatα-MHC undergoes lactylation on lysine 1897 to regulate the interaction ofα-MHC with Titin.We observed a reduction ofα-MHC K1897 lactylation in mice and patients with heart failure.Loss of K1897 lactylation inα-MHC K1897R knock-in mice reducesα-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 ofα-MHC,respectively.Decreasing lactate production by chemical or genetic manipulation reducesα-MHC lactylation,impairsα-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 promoteα-MHC K1897 lactylation andα-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 reducedα-MHC K1897 lactylation during myocardial injury.Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification ofα-MHC. | Naijin Zhang Ying Zhang Jiaqi Xu Pengbo Wang Boquan Wu Saien Lu Xinxin Lu Shilong You Xinyue Huang Mohan Li Yuanming Zou Mengke Liu Yuanhui Zhao Guozhe Sun Wenbin Wang Danxi Geng Jingwei Liu Liu Cao Yingxian Sun | 2023 | Cell Research2023，33，9： | 0 |
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