Rui Jiang , Jiayu Chen , Lijuan Pei , Shiqi Huang , Mengying Feng , Zhaohui Ouyang , Min Yuan , Yalin Zhu , Su Yao , Fenglian He , Hongjie Zhang , Xin Dong , Peng Xie , Ke Wei
{"title":"肌球蛋白抑制通过sirt1 - nfat介导的H3K9me3修饰增强心肌细胞周期活性","authors":"Rui Jiang , Jiayu Chen , Lijuan Pei , Shiqi Huang , Mengying Feng , Zhaohui Ouyang , Min Yuan , Yalin Zhu , Su Yao , Fenglian He , Hongjie Zhang , Xin Dong , Peng Xie , Ke Wei","doi":"10.1016/j.ejcb.2025.151504","DOIUrl":null,"url":null,"abstract":"<div><div>The limited regenerative capacity in adult mammalian heart is mainly attributed to the low cell cycle activity of cardiomyocytes. Achieving cardiomyocyte division is a challenging undertaking, as the contractile function, a major characteristic of cardiomyocytes, is not overall compatible with cell cycle progression. To dissect the relationship between sarcomeric contraction and proliferation in cardiomyocytes, we utilized Blebbistatin (Blebb), a Myosin II inhibitor commonly used for cardiomyocyte culture <em>ex vivo</em>, and revealed that Myosin inhibition by Blebb in cardiomyocytes resulted in enhanced cell cycle entry with cytokinesis failure, thus increasing polyploidy. Elevated H3K9me3 modification was found to be required for the increased cell cycle entry induced by Blebb, and the increased H3K9me3 modifications were enriched on genes that encode negative regulators of cell cycle and controlled by NFAT transcription factors. Furthermore, SIRT1 was identified to be a nucleocytoplasmic shuttling protein that dissociates from Z lines of sarcomeres and translocates into the nucleus upon Myosin inhibition, directly interacts with NFATc3, and is required for the Blebb-induced elevation of H3K9me3 modification and cell cycle activity. Our results identified a signaling pathway transducing sarcomeric signals to epigenetic modifications modulating the cardiomyocyte cell cycle, which may facilitate the understanding of the complex regulatory network controlling cardiomyocyte proliferation and provide therapeutic targets for regenerative medicine.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 3","pages":"Article 151504"},"PeriodicalIF":4.3000,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Myosin inhibition enhances cardiomyocyte cell cycle activity through SIRT1-NFAT-mediated H3K9me3 modification\",\"authors\":\"Rui Jiang , Jiayu Chen , Lijuan Pei , Shiqi Huang , Mengying Feng , Zhaohui Ouyang , Min Yuan , Yalin Zhu , Su Yao , Fenglian He , Hongjie Zhang , Xin Dong , Peng Xie , Ke Wei\",\"doi\":\"10.1016/j.ejcb.2025.151504\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The limited regenerative capacity in adult mammalian heart is mainly attributed to the low cell cycle activity of cardiomyocytes. Achieving cardiomyocyte division is a challenging undertaking, as the contractile function, a major characteristic of cardiomyocytes, is not overall compatible with cell cycle progression. To dissect the relationship between sarcomeric contraction and proliferation in cardiomyocytes, we utilized Blebbistatin (Blebb), a Myosin II inhibitor commonly used for cardiomyocyte culture <em>ex vivo</em>, and revealed that Myosin inhibition by Blebb in cardiomyocytes resulted in enhanced cell cycle entry with cytokinesis failure, thus increasing polyploidy. Elevated H3K9me3 modification was found to be required for the increased cell cycle entry induced by Blebb, and the increased H3K9me3 modifications were enriched on genes that encode negative regulators of cell cycle and controlled by NFAT transcription factors. Furthermore, SIRT1 was identified to be a nucleocytoplasmic shuttling protein that dissociates from Z lines of sarcomeres and translocates into the nucleus upon Myosin inhibition, directly interacts with NFATc3, and is required for the Blebb-induced elevation of H3K9me3 modification and cell cycle activity. Our results identified a signaling pathway transducing sarcomeric signals to epigenetic modifications modulating the cardiomyocyte cell cycle, which may facilitate the understanding of the complex regulatory network controlling cardiomyocyte proliferation and provide therapeutic targets for regenerative medicine.</div></div>\",\"PeriodicalId\":12010,\"journal\":{\"name\":\"European journal of cell biology\",\"volume\":\"104 3\",\"pages\":\"Article 151504\"},\"PeriodicalIF\":4.3000,\"publicationDate\":\"2025-07-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European journal of cell biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0171933525000299\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of cell biology","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0171933525000299","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
The limited regenerative capacity in adult mammalian heart is mainly attributed to the low cell cycle activity of cardiomyocytes. Achieving cardiomyocyte division is a challenging undertaking, as the contractile function, a major characteristic of cardiomyocytes, is not overall compatible with cell cycle progression. To dissect the relationship between sarcomeric contraction and proliferation in cardiomyocytes, we utilized Blebbistatin (Blebb), a Myosin II inhibitor commonly used for cardiomyocyte culture ex vivo, and revealed that Myosin inhibition by Blebb in cardiomyocytes resulted in enhanced cell cycle entry with cytokinesis failure, thus increasing polyploidy. Elevated H3K9me3 modification was found to be required for the increased cell cycle entry induced by Blebb, and the increased H3K9me3 modifications were enriched on genes that encode negative regulators of cell cycle and controlled by NFAT transcription factors. Furthermore, SIRT1 was identified to be a nucleocytoplasmic shuttling protein that dissociates from Z lines of sarcomeres and translocates into the nucleus upon Myosin inhibition, directly interacts with NFATc3, and is required for the Blebb-induced elevation of H3K9me3 modification and cell cycle activity. Our results identified a signaling pathway transducing sarcomeric signals to epigenetic modifications modulating the cardiomyocyte cell cycle, which may facilitate the understanding of the complex regulatory network controlling cardiomyocyte proliferation and provide therapeutic targets for regenerative medicine.
期刊介绍:
The European Journal of Cell Biology, a journal of experimental cell investigation, publishes reviews, original articles and short communications on the structure, function and macromolecular organization of cells and cell components. Contributions focusing on cellular dynamics, motility and differentiation, particularly if related to cellular biochemistry, molecular biology, immunology, neurobiology, and developmental biology are encouraged. Manuscripts describing significant technical advances are also welcome. In addition, papers dealing with biomedical issues of general interest to cell biologists will be published. Contributions addressing cell biological problems in prokaryotes and plants are also welcome.