ArticleProceedings of the National Academy of Sciences of the United States of America2006
Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 99 citations in OpenAlex.
- S2Tag, a novel affinity tag for the capture and immobilization of coiled-coil proteins: Application to the study of human β-cardiac myosin.The Journal of biological chemistry · 2025Article
- Dilated Cardiomyopathy - Exploring the Underlying Causes.Medical research archives · 2024Article
- Unlocking the dark matter: noncoding RNAs and RNA modifications in cardiac aging.American journal of physiology. Heart and circulatory physiology · 2024Review
- MYH7 in cardiomyopathy and skeletal muscle myopathy.Molecular and cellular biochemistry · 2024Review
- STIGMA: Single-cell tissue-specific gene prioritization using machine learning.American journal of human genetics · 2024Article
- Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM.Life (Basel, Switzerland) · 2023Article
- Mechanisms of Sarcomere Protein Mutation-Induced Cardiomyopathies.Current cardiology reports · 2023Review
- Cardiac Sarcomere Signaling in Health and Disease.International journal of molecular sciences · 2022Review
- Article
- Genetic predisposition study of heart failure and its association with cardiomyopathy.The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology · 2022Review
- Cardiac sarcomere mechanics in health and disease.Biophysical reviews · 2021Review
- Myosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation inMolecular biology of the cell · 2021Article
- A troponin T variant linked with pediatric dilated cardiomyopathy reduces the coupling of thin filament activation to myosin and calcium binding.Molecular biology of the cell · 2021Article
- From Genetic Mutations to Molecular Basis of Heart Failure Treatment: An Overview of the Mechanism and Implication of the Novel Modulators for Cardiac Myosin.International journal of molecular sciences · 2021Review
- Cardiomyopathy mutations impact the actin-activated power stroke of human cardiac myosin.Biophysical journal · 2021Article
- The mesa trail and the interacting heads motif of myosin II.Archives of biochemistry and biophysics · 2020Article
- Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies.International journal of molecular sciences · 2019Review
- Dilated cardiomyopathy mutation in the converter domain of human cardiac myosin alters motor activity and response to omecamtiv mecarbil.The Journal of biological chemistry · 2019Article
- Activin type II receptor signaling in cardiac aging and heart failure.Science translational medicine · 2019Article
- Converter domain mutations in myosin alter structural kinetics and motor function.The Journal of biological chemistry · 2019Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the alpha-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V(actin)) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V(actin) in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.
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