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Cardiac Myosin - DOAJ

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Last Updated: 16 January 2023

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The Novel Cardiac Myosin Activator Danicamtiv Improves Cardiac Systolic Function at the Expense of Diastolic Dysfunction In Vitro and In Vivo: Implications for Clinical Applications

Danicamtiv, the second direct myosin activator, has found promising results in preclinical and clinical studies, indicating its potential use in heart failure treatment with reduced ejection fractions. With decreasing danicamtiv kinetics without changes in intracellular Ca 2+ transients in vitro, the systolic and diastolic sarcomere lengths gradually diminished; contraction and relaxation kinetics slowed, but with increasing danicamtiv concentrations, no changes in intracellular Ca 2+ transients were slowed down. However, the systolic ejection time was significantly increased, the ratio of diastolic to systolic length was reduced, and signs of diastolic dysfunction were also present during danicamtiv therapy in vivo.

Source link: https://doi.org/10.3390/ijms24010446


Hypertrophic cardiomyopathy mutations in the pliant and light chain-binding regions of the lever arm of human β-cardiac myosin have divergent effects on myosin function

Both motor function and myosin subfragment 2 tail-based autoinhibition were investigated by our investigators. D778V increased power production, L781P reduced power output, and S782N had no effect on power output, although all three reduced the actin detachment rate's external force sensitivity. Mutation in the presence of filamentous actin and the proximal S2 tail with a myosin and the proximal S2 tail attenuated autoinhibition in the presence of filamentous actin, but had no effect in the absence of actin. Those mutations in the lever arm of a b3b-cardiac myosin may have divergent allosteric effects on myosin function, depending on whether they are in the pliant or light chain-binding regions.

Source link: https://doi.org/10.7554/eLife.76805


Dilated cardiomyopathy mutation E525K in human beta-cardiac myosin stabilizes the interacting-heads motif and super-relaxed state of myosin

To demonstrate that a dilated cardiomyopathy mutation in human beta-cardiac myosin raises the number of myosin heads in the SRX region, particularly in physiological ionic strength conditions, we conducted single ATP turnover experiments. Our studies also show a correlation between the SRX biochemical state and the IHM structural state in cardiac muscle myosin.

Source link: https://doi.org/10.7554/eLife.77415


Molecular mimicry between cardiac myosin and Trypanosoma cruzi antigen B13: identification of a B13-driven human T cell clone that recognizes cardiac myosin

We investigated whether T cells sensitized by T. cruzi B13 protein sensitivity to cardiac myosin in the present study. B13-stimulated T cell clones isolated from a peripheral blood of a B13-responsive normal donor were tested for proliferation against B13 protein and human cardiac myosin. These results reveal that B13 and cardiac myosin share epitopes at the T cell level, as well as the sensitization of a T cell with B13 protein findings in response to cardiac myosin.

Source link: https://doaj.org/article/3173172f7e764473bccd1cbcd4721258


Length-dependent changes in contractile dynamics are blunted due to cardiac myosin binding protein-C ablation

In part, a decrease in the radial distance between myosin heads and actin facilitated enhanced cardiac contractile function with increased sarcomere length. Myosin heads relative to actin's cellular function is modulated by cardiac myosin binding protein-C, indicating that cMyBP-C contributes to the myocardium's length-dependent transcription. In the KO preparations, maximum force was not significantly different between KO and WT preparations, according to our results, but a length-dependent rise in pCa50 was delayed. pCa50 was not significantly different between WT and KO preparations at long SL, although pCa50 was not significantly different between WT and KO preparations at short SL, whereas pCa50 was not significantly different between WT and KO preparations at long SL, whereas pCa50 was not significantly different between WT and KO preparations at short SL, whereas pCa50 was significantly different between WT and pCa50 was not significantly different between WT and KO preparations at long SL KI KO pCa50 between WT and KO plans at long SL, SL KO, KO KO, KO preparations, KO preparations at long SL o SL KO KO, pCa50, SK, KO SL, vs SL a50, KO preparationst KO SK, KO t versus t KO & KO t & &t In the same way, KO preparations did not show length-dependent changes in krel and kdf. Our results reveal that cMyBP-C is a key regulator of LDA due to changes in SL's dynamic XB behavior.

Source link: https://doi.org/10.3389/fphys.2014.00461


Cardiac Myosin Binding Protein-C Phosphorylation Mitigates Age-Related Cardiac Dysfunction

Correction-related cardiac dysfunction is prevented by cardiac myosin binding protein-C phosphorylation. CMyBP-C phosphorylation decreased with increasing cardiac function and hypertrophy in hypophosphorylated cMyBP-C mice in wild-type equivalent mice, as well as increasing cardiac function and hypertrophy similar to those found in hypophosphorylated cMyBP-C mice. The underlying mechanism, according to Intact papillary muscle studies, cMyBP-C phosphorylation raised cross-bridge detachment rates as the primary cause.

Source link: https://doi.org/10.1016/j.jacbts.2019.06.003


Heart failure induced by perinatal ablation of cardiac myosin light chain kinase

Acute heart failure with cardiomyocyte hypertrophy is limited by heart contraction with chronic heart disease, caused by ablation in adult hearts, but cardiomyocyte hypertrophy is not affected by cardiac myosin light chain kinase. Human implantation and perinatal-onset cMLCK ablation began on the 19th day of pregnancy, but less so when compared to adult-onset ablation. Methods and Results: The floxed-Mylk3 gene was activated at the start of the perinatal period as a result of more prominent heart failure than germline ablation, but less effective when compared to adult-onset ablation. Compared to the two control groups, the ratio of the heart weight relative to body mass had significantly increased at 6. 68 u00b1 0. 28 mg/g, followed by reduced body mass.

Source link: https://doi.org/10.3389/fphys.2016.00480


Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model

Variants in cardiac myosin-binding protein C are the leading cause of inherited hypertrophic cardiomyopathy, according to a novel role that cMyBP-C plays in the gastrointestinal machinery. At systolic and diastolic states at the larval stages, these knockout zebrafish displayed significant morphological heart changes due to a significant decrease in ventricular and atrial diameters at systolic and diastolic states. In both the mypbc3 heterozygous and homozygous groups, the examination of zebrafish adults revealed a thickened ventricular wall with reduced heart rate, swimming speed, and endurance endurance. Also, heart transcriptome profiling showed a significant decrease in the actin-filament-based process, showing an ineffective actin cytoskeleton organization as the key dysregulating factor associated with early ventricular cardiac hypertrophy in the zebrafish mypbc3 HCM model's early ventricular cardiac hypertrophy.

Source link: https://doi.org/10.3390/ijms23168840


Single molecule mechanics resolves the earliest events in force generation by cardiac myosin

Before releasing ATP hydrolysis products, the initial actomyosin state can tolerate loads of at least 4. 5 pN and then goes directly to the stroke or detaches. The time between binding and stroke is unaffected by ten mM Pi, which, alongside other findings, shows that the stroke precedes phosphate release. Pi can rebind following Pi's launch of Pi, enabling the reversal of the stroke. Detecting these rapid events under physiological stress gives a clear indication of how actomyosin converts biochemical energy into mechanical labor.

Source link: https://doi.org/10.7554/eLife.49266


Cardiac myosin binding protein-C phosphorylation modulates myofilament length-dependent activation

Following an increase in SL in 3SA skinned myocardium relative to WT skinned myocardium, a decrease in the length-dependent rise in myofilament Ca2+-sensitivity of force generation was revealed, according to Steady's skinned myocardium's response to force generation. In 3SA skinned myocardium with short and long SL, and before and after PKA therapy, the incidence and rate of XB detachment following stretch was greatly reduced in 3SA skinned myocardium was markedly reduced in 3SA skinned myocardium under pressure. At any condition measured, the amplitude of the increase in force generation above initial pre-stretch steady-state averages was not different between WT and 3SA skinned myocardium. However, the severity of the entire delayed force phase, which could plunge below initial pre-stretch steady-state levels, was notable lower in 3SA skinned myocardium under all conditions, in part due to a decreased XB detachment in 3SA skinned myocardium in comparison to WT skinned myocardium.

Source link: https://doi.org/10.3389/fphys.2016.00038

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions