ArticleAmerican journal of physiology. Heart and circulatory physiology2013
Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy.
Article in American journal of physiology. Heart and circulatory physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 37 citations in OpenAlex.
- Modulating the myosin super-relaxed state as a therapeutic strategy for myosin light chain-linked cardiomyopathies.Biophysical reviews · 2026Review
- Experimental Models of Hypertrophic Cardiomyopathy: A Systematic Review.JACC. Basic to translational science · 2025Review
- Dual effect of N-terminal deletion of cardiac myosin essential light chain in mitigating cardiomyopathy.iScience · 2024Article
- Assessing Cardiac Contractility From Single Molecules to Whole Hearts.JACC. Basic to translational science · 2024Review
- Efficacy of a growth hormone-releasing hormone agonist in a murine model of cardiometabolic heart failure with preserved ejection fraction.American journal of physiology. Heart and circulatory physiology · 2023Article
- Hydroxychloroquine Mitigates Dilated Cardiomyopathy Phenotype in Transgenic D94A Mice.International journal of molecular sciences · 2022Article
- Hypertrophic cardiomyopathy associated E22K mutation in myosin regulatory light chain decreases calcium-activated tension and stiffness and reduces myofilament CaThe FEBS journal · 2021Article
- Cardiomyopathic mutations in essential light chain reveal mechanisms regulating the super relaxed state of myosin.The Journal of general physiology · 2021Article
- Insights into myosin regulatory and essential light chains: a focus on their roles in cardiac and skeletal muscle function, development and disease.Journal of muscle research and cell motility · 2020Article
- Ablation of the N terminus of cardiac essential light chain promotes the super-relaxed state of myosin and counteracts hypercontractility in hypertrophic cardiomyopathy mutant mice.The FEBS journal · 2020Article
- Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations.Journal of cardiovascular translational research · 2019Article
- The R249Q hypertrophic cardiomyopathy myosin mutation decreases contractility in Drosophila by impeding force production.The Journal of physiology · 2019Article
- Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains.Pflugers Archiv : European journal of physiology · 2019Review
- Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells.Circulation · 2018Article
- Phenotyping cardiomyopathy in adult zebrafish.Progress in biophysics and molecular biology · 2018Review
- Single cardiac ventricular myosins are autonomous motors.Open biology · 2018Article
- Targeted next generation sequencing in a young population with suspected inherited malignant cardiac arrhythmias.European journal of human genetics : EJHG · 2018Article
- Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice.Cardiovascular research · 2017Article
- A Cardiomyopathy Mutation in the Myosin Essential Light Chain Alters Actomyosin Structure.Biophysical journal · 2017Article
- Aggregate penetrance of genomic variants for actionable disorders in European and African Americans.Science translational medicine · 2016Article
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Authors and funding
9 authors at 1 institution in 1 country.
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Abstract
The functional consequences of the familial hypertrophic cardiomyopathy A57G (alanine-to-glycine) mutation in the myosin ventricular essential light chain (ELC) were assessed in vitro and in vivo using previously generated transgenic (Tg) mice expressing A57G-ELC mutant vs. wild-type (WT) of human cardiac ELC and in recombinant A57G- or WT-protein-exchanged porcine cardiac muscle strips. Compared with the Tg-WT, there was a significant increase in the Ca²⁺ sensitivity of force (ΔpCa₅₀ ≅ 0.1) and an ~1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations. In addition, a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness. Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios and a decreased number of nuclei indicating an increase in the two-dimensional size of Tg-A57G vs. Tg-WT myocytes. Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness. Invasive hemodynamics data revealed significantly increased end-systolic elastance, defined by the slope of the pressure-volume relationship, indicating a mutation-induced increase in cardiac contractility. Our results suggest that the A57G allele causes disease by means of a discrete modulation of myofilament function, increased Ca²⁺ sensitivity, and decreased maximal tension followed by compensatory hypertrophy and enhanced contractility. These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling.
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