Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy
Abstract Familial hypertrophic cardiomyopathy (FHC) patients are advised to avoid strenuous exercise due to increased risk of arrhythmias. Mice expressing the human FHC-causing mutation R403Q in the myosin heavy chain gene (MYH6) recapitulate the human phenotype, including cytoskeletal disarray and...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-38296-2 |
| _version_ | 1797778933803909120 |
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| author | Henrietta Cserne Szappanos Helena M. Viola Danica W. Ito Seakcheng Lim Melissa Mangala Mira Holliday Samantha Barratt Ross Christopher Semsarian Adam Hill Rose E. Dixon Livia C. Hool |
| author_facet | Henrietta Cserne Szappanos Helena M. Viola Danica W. Ito Seakcheng Lim Melissa Mangala Mira Holliday Samantha Barratt Ross Christopher Semsarian Adam Hill Rose E. Dixon Livia C. Hool |
| author_sort | Henrietta Cserne Szappanos |
| collection | DOAJ |
| description | Abstract Familial hypertrophic cardiomyopathy (FHC) patients are advised to avoid strenuous exercise due to increased risk of arrhythmias. Mice expressing the human FHC-causing mutation R403Q in the myosin heavy chain gene (MYH6) recapitulate the human phenotype, including cytoskeletal disarray and increased arrhythmia susceptibility. Following in vivo administration of isoproterenol, mutant mice exhibited tachyarrhythmias, poor recovery and fatigue. Arrhythmias were attenuated with the β-blocker atenolol and protein kinase A inhibitor PKI. Mutant cardiac myocytes had significantly prolonged action potentials and triggered automaticity due to reduced repolarization reserve and connexin 43 expression. Isoproterenol shortened cycle length, and escalated electrical instability. Surprisingly isoproterenol did not increase CaV1.2 current. We found alterations in CaV1.2-β1 adrenergic receptor colocalization assessed using super-resolution nanoscopy, and increased CaV1.2 phosphorylation in mutant hearts. Our results reveal for the first time that altered ion channel expression, co-localization and β-adrenergic receptor signaling associated with myocyte disarray contribute to electrical instability in the R403Q mutant heart. |
| first_indexed | 2024-03-12T23:24:41Z |
| format | Article |
| id | doaj.art-e1010dcf8ddf4f0397cc92001ff5aa96 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-12T23:24:41Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e1010dcf8ddf4f0397cc92001ff5aa962023-07-16T11:16:25ZengNature PortfolioScientific Reports2045-23222023-07-0113111610.1038/s41598-023-38296-2Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathyHenrietta Cserne Szappanos0Helena M. Viola1Danica W. Ito2Seakcheng Lim3Melissa Mangala4Mira Holliday5Samantha Barratt Ross6Christopher Semsarian7Adam Hill8Rose E. Dixon9Livia C. Hool10School of Human Sciences, University of Western AustraliaSchool of Human Sciences, University of Western AustraliaDepartment of Physiology and Membrane Biology, University of CaliforniaAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteVictor Chang Cardiac Research InstituteAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteVictor Chang Cardiac Research InstituteDepartment of Physiology and Membrane Biology, University of CaliforniaSchool of Human Sciences, University of Western AustraliaAbstract Familial hypertrophic cardiomyopathy (FHC) patients are advised to avoid strenuous exercise due to increased risk of arrhythmias. Mice expressing the human FHC-causing mutation R403Q in the myosin heavy chain gene (MYH6) recapitulate the human phenotype, including cytoskeletal disarray and increased arrhythmia susceptibility. Following in vivo administration of isoproterenol, mutant mice exhibited tachyarrhythmias, poor recovery and fatigue. Arrhythmias were attenuated with the β-blocker atenolol and protein kinase A inhibitor PKI. Mutant cardiac myocytes had significantly prolonged action potentials and triggered automaticity due to reduced repolarization reserve and connexin 43 expression. Isoproterenol shortened cycle length, and escalated electrical instability. Surprisingly isoproterenol did not increase CaV1.2 current. We found alterations in CaV1.2-β1 adrenergic receptor colocalization assessed using super-resolution nanoscopy, and increased CaV1.2 phosphorylation in mutant hearts. Our results reveal for the first time that altered ion channel expression, co-localization and β-adrenergic receptor signaling associated with myocyte disarray contribute to electrical instability in the R403Q mutant heart.https://doi.org/10.1038/s41598-023-38296-2 |
| spellingShingle | Henrietta Cserne Szappanos Helena M. Viola Danica W. Ito Seakcheng Lim Melissa Mangala Mira Holliday Samantha Barratt Ross Christopher Semsarian Adam Hill Rose E. Dixon Livia C. Hool Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy Scientific Reports |
| title | Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy |
| title_full | Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy |
| title_fullStr | Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy |
| title_full_unstemmed | Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy |
| title_short | Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy |
| title_sort | cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy |
| url | https://doi.org/10.1038/s41598-023-38296-2 |
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