Myosin inhibition enhances cardiomyocyte cell cycle activity through SIRT1-NFAT-mediated H3K9me3 modification
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...
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Elsevier
2025-09-01
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| Series: | European Journal of Cell Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171933525000299 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Rui Jiang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b1048acb532e4c2199f35f07c0136b29 |
| institution | DOAJ |
| issn | 0171-9335 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Cell Biology |
| spelling | doaj-art-b1048acb532e4c2199f35f07c0136b292025-08-20T03:13:30ZengElsevierEuropean Journal of Cell Biology0171-93352025-09-01104315150410.1016/j.ejcb.2025.151504Myosin inhibition enhances cardiomyocyte cell cycle activity through SIRT1-NFAT-mediated H3K9me3 modificationRui Jiang0Jiayu Chen1Lijuan Pei2Shiqi Huang3Mengying Feng4Zhaohui Ouyang5Min Yuan6Yalin Zhu7Su Yao8Fenglian He9Hongjie Zhang10Xin Dong11Peng Xie12Ke Wei13Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaSchool of Biological Science and Medical Engineering, Southeast University, Nanjing 211189, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaInstitute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaSchool of Biological Science and Medical Engineering, Southeast University, Nanjing 211189, China; Corresponding author.Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Correspondence to: School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, ChinaThe 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.http://www.sciencedirect.com/science/article/pii/S0171933525000299SIRT1NFATCytoskeletonH3K9me3Cardiomyocyte cell cycleCardiomyocyte binucleation |
| spellingShingle | 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 Myosin inhibition enhances cardiomyocyte cell cycle activity through SIRT1-NFAT-mediated H3K9me3 modification European Journal of Cell Biology SIRT1 NFAT Cytoskeleton H3K9me3 Cardiomyocyte cell cycle Cardiomyocyte binucleation |
| title | Myosin inhibition enhances cardiomyocyte cell cycle activity through SIRT1-NFAT-mediated H3K9me3 modification |
| title_full | Myosin inhibition enhances cardiomyocyte cell cycle activity through SIRT1-NFAT-mediated H3K9me3 modification |
| title_fullStr | Myosin inhibition enhances cardiomyocyte cell cycle activity through SIRT1-NFAT-mediated H3K9me3 modification |
| title_full_unstemmed | Myosin inhibition enhances cardiomyocyte cell cycle activity through SIRT1-NFAT-mediated H3K9me3 modification |
| title_short | Myosin inhibition enhances cardiomyocyte cell cycle activity through SIRT1-NFAT-mediated H3K9me3 modification |
| title_sort | myosin inhibition enhances cardiomyocyte cell cycle activity through sirt1 nfat mediated h3k9me3 modification |
| topic | SIRT1 NFAT Cytoskeleton H3K9me3 Cardiomyocyte cell cycle Cardiomyocyte binucleation |
| url | http://www.sciencedirect.com/science/article/pii/S0171933525000299 |
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