Insulin signaling is critical for sinoatrial node maintenance and function
Abstract Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cellular growth and glucose metabolism in the myocardium. However, their physiological role in the cells of the cardiac conduction system has never been explored. Therefore, we sought to determine the spatiotemporal functio...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-05-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-023-00988-0 |
| _version_ | 1797811902070390784 |
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| author | Sangmi Ock Seong Woo Choi Seung Hee Choi Hyun Kang Sung Joon Kim Wang-Soo Lee Jaetaek Kim |
| author_facet | Sangmi Ock Seong Woo Choi Seung Hee Choi Hyun Kang Sung Joon Kim Wang-Soo Lee Jaetaek Kim |
| author_sort | Sangmi Ock |
| collection | DOAJ |
| description | Abstract Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cellular growth and glucose metabolism in the myocardium. However, their physiological role in the cells of the cardiac conduction system has never been explored. Therefore, we sought to determine the spatiotemporal function of insulin/IGF-1 receptors in the sinoatrial node (SAN). We generated cardiac conduction cell-specific inducible IGF-1 receptor (IGF-1R) knockout (KO) (CSIGF1RKO), insulin receptor (IR) KO (CSIRKO), and IR/IGF-1R double-KO (CSDIRKO) mice and evaluated their phenotypes. Telemetric electrocardiography revealed regular sinus rhythm in CSIGF1RKO mice, indicating that IGF-1R is dispensable for normal pacemaking. In contrast, CSIRKO and CSDIRKO mice exhibited profound sinus bradycardia. CSDIRKO mice showed typical sinus node dysfunction characterized by junctional rhythm and sinus pauses on electrocardiography. Interestingly, the lack of an insulin receptor in the SAN cells of CSIRKO and CSDIRKO mice caused sinus nodal fibrosis. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) protein expression significantly decreased in the CSIRKO and CSDIRKO mice relative to the controls. A patch-clamp study of the SAN cells of CSIRKO mice revealed a significant decrease in the funny current, which is responsible for spontaneous diastolic depolarization in the SAN. This result suggested that insulin receptor loss reduces the heart rate via downregulation of the HCN4 channel. Additionally, HCN1 expression was decreased in CSDIRKO mice, explaining their sinus node dysfunction. Our results reveal a previously unrecognized role of insulin/IGF-1 signaling in sinus node structural maintenance and pacemaker function. |
| first_indexed | 2024-03-13T07:30:40Z |
| format | Article |
| id | doaj.art-865718cf7dc6405cb64261d3030c95ac |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-03-13T07:30:40Z |
| publishDate | 2023-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-865718cf7dc6405cb64261d3030c95ac2023-06-04T11:07:32ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132023-05-0155596597310.1038/s12276-023-00988-0Insulin signaling is critical for sinoatrial node maintenance and functionSangmi Ock0Seong Woo Choi1Seung Hee Choi2Hyun Kang3Sung Joon Kim4Wang-Soo Lee5Jaetaek Kim6Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang UniversityDepartments of Physiology and Biomedical Sciences, College of Medicine, Seoul National UniversityDivision of Endocrinology and Metabolism, Departments of Internal Medicine and Biochemistry and Cell Biology, Kyungpook National University School of MedicineDepartment of Anesthesiology, College of Medicine, Chung-Ang UniversityDepartments of Physiology and Biomedical Sciences, College of Medicine, Seoul National UniversityDivision of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang UniversityDivision of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang UniversityAbstract Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cellular growth and glucose metabolism in the myocardium. However, their physiological role in the cells of the cardiac conduction system has never been explored. Therefore, we sought to determine the spatiotemporal function of insulin/IGF-1 receptors in the sinoatrial node (SAN). We generated cardiac conduction cell-specific inducible IGF-1 receptor (IGF-1R) knockout (KO) (CSIGF1RKO), insulin receptor (IR) KO (CSIRKO), and IR/IGF-1R double-KO (CSDIRKO) mice and evaluated their phenotypes. Telemetric electrocardiography revealed regular sinus rhythm in CSIGF1RKO mice, indicating that IGF-1R is dispensable for normal pacemaking. In contrast, CSIRKO and CSDIRKO mice exhibited profound sinus bradycardia. CSDIRKO mice showed typical sinus node dysfunction characterized by junctional rhythm and sinus pauses on electrocardiography. Interestingly, the lack of an insulin receptor in the SAN cells of CSIRKO and CSDIRKO mice caused sinus nodal fibrosis. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) protein expression significantly decreased in the CSIRKO and CSDIRKO mice relative to the controls. A patch-clamp study of the SAN cells of CSIRKO mice revealed a significant decrease in the funny current, which is responsible for spontaneous diastolic depolarization in the SAN. This result suggested that insulin receptor loss reduces the heart rate via downregulation of the HCN4 channel. Additionally, HCN1 expression was decreased in CSDIRKO mice, explaining their sinus node dysfunction. Our results reveal a previously unrecognized role of insulin/IGF-1 signaling in sinus node structural maintenance and pacemaker function.https://doi.org/10.1038/s12276-023-00988-0 |
| spellingShingle | Sangmi Ock Seong Woo Choi Seung Hee Choi Hyun Kang Sung Joon Kim Wang-Soo Lee Jaetaek Kim Insulin signaling is critical for sinoatrial node maintenance and function Experimental and Molecular Medicine |
| title | Insulin signaling is critical for sinoatrial node maintenance and function |
| title_full | Insulin signaling is critical for sinoatrial node maintenance and function |
| title_fullStr | Insulin signaling is critical for sinoatrial node maintenance and function |
| title_full_unstemmed | Insulin signaling is critical for sinoatrial node maintenance and function |
| title_short | Insulin signaling is critical for sinoatrial node maintenance and function |
| title_sort | insulin signaling is critical for sinoatrial node maintenance and function |
| url | https://doi.org/10.1038/s12276-023-00988-0 |
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