Hypertrophic cardiomyopathy R403Q mutation in rabbit β-myosin reduces contractile function at the molecular and myofibrillar levels
In 1990, the Seidmans showed that a single point mutation, R403Q, in the human β-myosin heavy chain (MHC) of heart muscle caused a particularly malignant form of familial hypertrophic cardiomyopathy (HCM) [Geisterfer-Lowrance AA, et al. (1990) Cell 62:999-1006.]. Since then, more than 300 mutations in the β-MHC have been reported, and yet there remains a poor understanding of how a single missense mutation in the MYH7 gene can lead to heart disease. Previous studies with a transgenic mouse model showed that the myosin phenotype depended on whether the mutation was in an α- or β-MHC backbone. This led to the generation of a transgenic rabbit model with the R403Q mutation in a β-MHC backbone. We find that the in vitro motility of heterodimeric R403Q myosin is markedly reduced, whereas the actin-activated ATPase activity of R403Q subfragment-1 is about the same as myosin from a nontransgenic littermate. Single myofibrils isolated from the ventricles of R403Q transgenic rabbits and analyzed by atomic force microscopy showed reduced rates of force development and relaxation, and achieved a significantly lower steady-state level of isometric force compared with nontransgenic myofibrils. Myofibrils isolated from the soleus gave similar results. The force-velocity relationship determined for R403Q ventricular myofibrils showed a decrease in the velocity of shortening under load, resulting in a diminished power output. We conclude that independent of whether experiments are performed with isolated molecules or with ordered molecules in the native thick filament of a myofibril, there is a loss-of-function induced by the R403Q mutation in β-cardiac myosin.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:115 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 115(2018), 44 vom: 30. Okt., Seite 11238-11243 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lowey, Susan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.12.2018 Date Revised 30.04.2019 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.1802967115 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM289577608 |
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| 100 | 1 | |a Lowey, Susan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Hypertrophic cardiomyopathy R403Q mutation in rabbit β-myosin reduces contractile function at the molecular and myofibrillar levels |
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| 500 | |a Date Revised 30.04.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a In 1990, the Seidmans showed that a single point mutation, R403Q, in the human β-myosin heavy chain (MHC) of heart muscle caused a particularly malignant form of familial hypertrophic cardiomyopathy (HCM) [Geisterfer-Lowrance AA, et al. (1990) Cell 62:999-1006.]. Since then, more than 300 mutations in the β-MHC have been reported, and yet there remains a poor understanding of how a single missense mutation in the MYH7 gene can lead to heart disease. Previous studies with a transgenic mouse model showed that the myosin phenotype depended on whether the mutation was in an α- or β-MHC backbone. This led to the generation of a transgenic rabbit model with the R403Q mutation in a β-MHC backbone. We find that the in vitro motility of heterodimeric R403Q myosin is markedly reduced, whereas the actin-activated ATPase activity of R403Q subfragment-1 is about the same as myosin from a nontransgenic littermate. Single myofibrils isolated from the ventricles of R403Q transgenic rabbits and analyzed by atomic force microscopy showed reduced rates of force development and relaxation, and achieved a significantly lower steady-state level of isometric force compared with nontransgenic myofibrils. Myofibrils isolated from the soleus gave similar results. The force-velocity relationship determined for R403Q ventricular myofibrils showed a decrease in the velocity of shortening under load, resulting in a diminished power output. We conclude that independent of whether experiments are performed with isolated molecules or with ordered molecules in the native thick filament of a myofibril, there is a loss-of-function induced by the R403Q mutation in β-cardiac myosin | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cardiac myosin | |
| 650 | 4 | |a hypertrophic cardiomyopathy | |
| 650 | 4 | |a myofibril kinetics | |
| 650 | 4 | |a myofibril power output | |
| 650 | 7 | |a Actins |2 NLM | |
| 650 | 7 | |a Myosin Heavy Chains |2 NLM | |
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| 650 | 7 | |a Myosins |2 NLM | |
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| 700 | 1 | |a Bretton, Vera |e verfasserin |4 aut | |
| 700 | 1 | |a Joel, Peteranne B |e verfasserin |4 aut | |
| 700 | 1 | |a Trybus, Kathleen M |e verfasserin |4 aut | |
| 700 | 1 | |a Gulick, James |e verfasserin |4 aut | |
| 700 | 1 | |a Robbins, Jeffrey |e verfasserin |4 aut | |
| 700 | 1 | |a Kalganov, Albert |e verfasserin |4 aut | |
| 700 | 1 | |a Cornachione, Anabelle S |e verfasserin |4 aut | |
| 700 | 1 | |a Rassier, Dilson E |e verfasserin |4 aut | |
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