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Hypertrophic cardiomyopathy R403Q mutation in rabbit ?-myosin reduces contractile function at the molecular and myofibrillar levels.

ABSTRACT: In 1990, the Seidmans showed that a single point mutation, R403Q, in the human ?-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 ?-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 ?- or ?-MHC backbone. This led to the generation of a transgenic rabbit model with the R403Q mutation in a ?-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 ?-cardiac myosin.

SUBMITTER: Lowey S

PROVIDER: S-EPMC6217429 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Hypertrophic cardiomyopathy R403Q mutation in rabbit β-myosin reduces contractile function at the molecular and myofibrillar levels.

Lowey Susan S Bretton Vera V Joel Peteranne B PB Trybus Kathleen M KM Gulick James J Robbins Jeffrey J Kalganov Albert A Cornachione Anabelle S AS Rassier Dilson E DE

Proceedings of the National Academy of Sciences of the United States of America 20181015 44

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 ...[more]

PMID: 30322937

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Project description:BackgroundDespite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM.Methods and resultsWe generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions.ConclusionsInteractions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes.

Dataset Information

Hypertrophic cardiomyopathy R403Q mutation in rabbit ?-myosin reduces contractile function at the molecular and myofibrillar levels.

Publications

Hypertrophic cardiomyopathy R403Q mutation in rabbit β-myosin reduces contractile function at the molecular and myofibrillar levels.

Similar Datasets

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