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α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure
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 unde...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Nature Singapore
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474270/ https://www.ncbi.nlm.nih.gov/pubmed/37443257 http://dx.doi.org/10.1038/s41422-023-00844-w |
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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 |
author_facet | 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 |
author_sort | Zhang, Naijin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10474270 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Nature Singapore |
record_format | MEDLINE/PubMed |
spelling | pubmed-104742702023-09-03 α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure 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 Cell Res Article 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. Springer Nature Singapore 2023-07-13 2023-09 /pmc/articles/PMC10474270/ /pubmed/37443257 http://dx.doi.org/10.1038/s41422-023-00844-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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 α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure |
title | α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure |
title_full | α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure |
title_fullStr | α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure |
title_full_unstemmed | α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure |
title_short | α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure |
title_sort | α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474270/ https://www.ncbi.nlm.nih.gov/pubmed/37443257 http://dx.doi.org/10.1038/s41422-023-00844-w |
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