ArticleProceedings of the National Academy of Sciences of the United States of America2018
Hypertrophic cardiomyopathy R403Q mutation in rabbit β-myosin reduces contractile function at the molecular and myofibrillar levels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 40 citations in OpenAlex.
- Molecular mechanisms of altered contraction with the β-myosin R403Q mutation in porcine ventricular muscle and a human stem cell-derived cardiomyocyte model.Journal of molecular and cellular cardiology · 2025Article
- Knockout of the Staphylococcus aureus virulence gene sdrC promotes Myh7 expression to inhibit the progression of osteomyelitis.Journal of molecular histology · 2025Article
- Experimental Models of Hypertrophic Cardiomyopathy: A Systematic Review.JACC. Basic to translational science · 2025Review
- Hypertrophic Cardiomyopathy Through the Lens of Mitochondria.Biomedicines · 2025Review
- Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy.European journal of cell biology · 2024Article
- Transcriptomic and epigenomic landscapes of muscle growth during the postnatal period of broilers.Journal of animal science and biotechnology · 2024Article
- Allele-specific dysregulation of lipid and energy metabolism in early-stage hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology plus · 2024Article
- Incomplete-penetrant hypertrophic cardiomyopathyProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Single-nucleus RNA/ATAC-seq in early-stage HCM models predicts SWI/SNF-activation in mutant-myocytes, and allele-specific differences in fibroblasts.bioRxiv : the preprint server for biology · 2024Article
- Cooperativity of myosin II motors in the non-regulated and regulated thin filaments investigated with high-speed AFM.The Journal of general physiology · 2023Article
- Human engineered cardiac tissue model of hypertrophic cardiomyopathy recapitulates key hallmarks of the disease and the effect of chronic mavacamten treatment.Frontiers in bioengineering and biotechnology · 2023Article
- Regulation of the evolutionarily conserved muscle myofibrillar matrix by cell type dependent and independent mechanisms.Nature communications · 2022Article
- Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy.International journal of molecular sciences · 2022Review
- Article
- Complexity in genetic cardiomyopathies and new approaches for mechanism-based precision medicine.The Journal of general physiology · 2021Article
- Force Measurements From Myofibril to Filament.Frontiers in physiology · 2021Review
- Fropofol prevents disease progression in mice with hypertrophic cardiomyopathy.Cardiovascular research · 2020Article
- Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.Circulation · 2020Article
- Metoprolol alleviates arginine vasopressin-induced cardiomyocyte hypertrophy by upregulating the AKT1-SERCA2 cascade in H9C2 cells.Cell & bioscience · 2020Article
- Cycling Cross-Bridges Contribute to Thin Filament Activation in Human Slow-Twitch Fibers.Frontiers in physiology · 2020Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
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