scholarly journals 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

FEBS Journal ◽  
2020 ◽  
Vol 287 (18) ◽  
pp. 3989-4004 ◽  
Author(s):  
Yoel H. Sitbon ◽  
Katarzyna Kazmierczak ◽  
Jingsheng Liang ◽  
Sunil Yadav ◽  
Melanie Veerasammy ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Mutant Mice ◽  
Essential Light Chain ◽  
N Terminus

scholarly journals Deletion of the N-Terminus of Myosin Essential Light Chain (N-ELC) in the Background of HCM-A57G Mutation in Double Mutant Mice Rescues Hypercontractile Myosin Phenotype

2020 ◽  
Vol 118 (3) ◽  
pp. 328a
Author(s):  
Yoel H. Sitbon ◽  
Katarzyna Kazmierczak ◽  
Melanie Veerasammy ◽  
Jingsheng Liang ◽  
Danuta Szczesna-Cordary
Keyword(s):  
Light Chain ◽  
Double Mutant ◽  
Mutant Mice ◽  
Essential Light Chain ◽  
N Terminus

scholarly journals Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

2013 ◽  
Vol 305 (4) ◽  
pp. H575-H589 ◽  
Author(s):  
Katarzyna Kazmierczak ◽  
Ellena C. Paulino ◽  
Wenrui Huang ◽  
Priya Muthu ◽  
Jingsheng Liang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Left Ventricular ◽  
Compensatory Hypertrophy ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Heart Weight ◽  
Myocardial Stiffness ◽  
Essential Light Chain

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.

scholarly journals Deletion of 1- 43 Amino Acids from the N-terminus of Myosin Essential Light Chain in Transgenic Mice Decreases Force Production by Reducing the Number of Myosin Cross-Bridges

2011 ◽  
Vol 100 (3) ◽  
pp. 126a
Author(s):  
John J. Michael ◽  
Steven J. Ford ◽  
Katarzyna Kazmierczak ◽  
Danuta Szczesna-Cordary ◽  
Chandra Murali
Keyword(s):  
Amino Acids ◽  
Transgenic Mice ◽  
Light Chain ◽  
Force Production ◽  
Essential Light Chain ◽  
N Terminus ◽  
Cross Bridges

Transgenic Rabbits Expressing Mutant Essential Light Chain do not Develop Hypertrophic Cardiomyopathy

2002 ◽  
Vol 34 (7) ◽  
pp. 873-882 ◽  
Author(s):  
Jeanne James ◽  
Yan Zhang ◽  
Kathy Wright ◽  
Sra Witt ◽  
Elizabeth Glascock ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Essential Light Chain ◽  
Transgenic Rabbits

scholarly journals A Novel Myosin Essential Light Chain Mutation Causes Hypertrophic Cardiomyopathy with Late Onset and Low Expressivity

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Paal Skytt Andersen ◽  
Paula Louise Hedley ◽  
Stephen P. Page ◽  
Petros Syrris ◽  
Johanna Catharina Moolman-Smook ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Late Onset ◽  
Large Family ◽  
Left Ventricular ◽  
Cascade Screening ◽  
Essential Light Chain ◽  
Mutation Carriers ◽  
Genes Encoding ◽  
The Mean

Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding sarcomere proteins. Mutations inMYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT 21 mm), a resting left ventricular outflow gradient of 36 mm Hg, and left atrial dilation (54 mm). Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, inMYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion,MYL3mutations can present with low expressivity and late onset.

scholarly journals N-Terminus of Cardiac Myosin Essential Light Chain Modulates Myosin Step-Size

Biochemistry ◽  
2015 ◽  
Vol 55 (1) ◽  
pp. 186-198 ◽  
Author(s):  
Yihua Wang ◽  
Katalin Ajtai ◽  
Katarzyna Kazmierczak ◽  
Danuta Szczesna-Cordary ◽  
Thomas P. Burghardt
Keyword(s):  
Light Chain ◽  
Cardiac Myosin ◽  
Step Size ◽  
Essential Light Chain ◽  
N Terminus

scholarly journals Cardiomyopathic mutations in essential light chain reveal mechanisms regulating the super relaxed state of myosin

2021 ◽  
Vol 153 (7) ◽  
Author(s):  
Yoel H. Sitbon ◽  
Francisca Diaz ◽  
Katarzyna Kazmierczak ◽  
Jingsheng Liang ◽  
Medhi Wangpaichitr ◽  
...  
Keyword(s):  
Light Chain ◽  
Physiological Model ◽  
Papillary Muscles ◽  
Myosin Regulatory Light Chain ◽  
Essential Light Chain ◽  
Sarcomeric Protein ◽  
N Terminus ◽  
Ventricular Myosin ◽  
Energy Conserving ◽  
Cross Bridges

In this study, we assessed the super relaxed (SRX) state of myosin and sarcomeric protein phosphorylation in two pathological models of cardiomyopathy and in a near-physiological model of cardiac hypertrophy. The cardiomyopathy models differ in disease progression and severity and express the hypertrophic (HCM-A57G) or restrictive (RCM-E143K) mutations in the human ventricular myosin essential light chain (ELC), which is encoded by the MYL3 gene. Their effects were compared with near-physiological heart remodeling, represented by the N-terminally truncated ELC (Δ43 ELC mice), and with nonmutated human ventricular WT-ELC mice. The HCM-A57G and RCM-E143K mutations had antagonistic effects on the ATP-dependent myosin energetic states, with HCM-A57G cross-bridges fostering the disordered relaxed (DRX) state and the RCM-E143K model favoring the energy-conserving SRX state. The HCM-A57G model promoted the switch from the SRX to DRX state and showed an ∼40% increase in myosin regulatory light chain (RLC) phosphorylation compared with the RLC of normal WT-ELC myocardium. On the contrary, the RCM-E143K–associated stabilization of the SRX state was accompanied by an approximately twofold lower level of myosin RLC phosphorylation compared with the RLC of WT-ELC. Upregulation of RLC phosphorylation was also observed in Δ43 versus WT-ELC hearts, and the Δ43 myosin favored the energy-saving SRX conformation. The two disease variants also differently affected the duration of force transients, with shorter (HCM-A57G) or longer (RCM-E143K) transients measured in electrically stimulated papillary muscles from these pathological models, while no changes were displayed by Δ43 fibers. We propose that the N terminus of ELC (N-ELC), which is missing in the hearts of Δ43 mice, works as an energetic switch promoting the SRX-to-DRX transition and contributing to the regulation of myosin RLC phosphorylation in full-length ELC mice by facilitating or sterically blocking RLC phosphorylation in HCM-A57G and RCM-E143K hearts, respectively.

scholarly journals Cardiac Myosin Essential Light Chain N-Terminus Regulates Motor Step-Size

2015 ◽  
Vol 108 (2) ◽  
pp. 598a
Author(s):  
Yihua Wang ◽  
Katalin Ajtai ◽  
Katarzyna Kazmierczak ◽  
Danuta Szczesna-Cordary ◽  
Thomas P. Burghardt
Keyword(s):  
Light Chain ◽  
Cardiac Myosin ◽  
Step Size ◽  
Essential Light Chain ◽  
N Terminus

scholarly journals The Role of the N-Terminus of the Myosin Essential Light Chain in Cardiac Muscle Contraction

2009 ◽  
Vol 387 (3) ◽  
pp. 706-725 ◽  
Author(s):  
Katarzyna Kazmierczak ◽  
Yuanyuan Xu ◽  
Michelle Jones ◽  
Georgianna Guzman ◽  
Olga M. Hernandez ◽  
...  
Keyword(s):  
Muscle Contraction ◽  
Cardiac Muscle ◽  
Light Chain ◽  
Cardiac Muscle Contraction ◽  
Essential Light Chain ◽  
N Terminus
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