scholarly journals Ablation of cardiac myosin–binding protein-C accelerates contractile kinetics in engineered cardiac tissue

2012 ◽  
Vol 141 (1) ◽  
pp. 73-84 ◽  
Author(s):  
Willem J. de Lange ◽  
Adrian C. Grimes ◽  
Laura F. Hegge ◽  
J. Carter Ralphe
Keyword(s):  
Protein C ◽  
Cardiac Tissue ◽  
Binding Protein ◽  
Cardiac Cells ◽  
Cardiac Myosin ◽  
Adrenergic Stimulation ◽  
Transient Kinetics ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Hypertrophic cardiomyopathy (HCM) caused by mutations in cardiac myosin–binding protein-C (cMyBP-C) is a heterogenous disease in which the phenotypic presentation is influenced by genetic, environmental, and developmental factors. Though mouse models have been used extensively to study the contractile effects of cMyBP-C ablation, early postnatal hypertrophic and dilatory remodeling may overshadow primary contractile defects. The use of a murine engineered cardiac tissue (mECT) model of cMyBP-C ablation in the present study permits delineation of the primary contractile kinetic abnormalities in an intact tissue model under mechanical loading conditions in the absence of confounding remodeling events. We generated mechanically integrated mECT using isolated postnatal day 1 mouse cardiac cells from both wild-type (WT) and cMyBP-C–null hearts. After culturing for 1 wk to establish coordinated spontaneous contraction, we measured twitch force and Ca2+ transients at 37°C during pacing at 6 and 9 Hz, with and without dobutamine. Compared with WT, the cMyBP-C–null mECT demonstrated faster late contraction kinetics and significantly faster early relaxation kinetics with no difference in Ca2+ transient kinetics. Strikingly, the ability of cMyBP-C–null mECT to increase contractile kinetics in response to adrenergic stimulation and increased pacing frequency were severely impaired. We conclude that cMyBP-C ablation results in constitutively accelerated contractile kinetics with preserved peak force with minimal contractile kinetic reserve. These functional abnormalities precede the development of the hypertrophic phenotype and do not result from alterations in Ca2+ transient kinetics, suggesting that alterations in contractile velocity may serve as the primary functional trigger for the development of hypertrophy in this model of HCM. Our findings strongly support a mechanism in which cMyBP-C functions as a physiological brake on contraction by positioning myosin heads away from the thin filament, a constraint which is removed upon adrenergic stimulation or cMyBP-C ablation.

Biological variation of cardiac myosin-binding protein C in healthy individuals

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Bashir Alaour ◽  
Torbjørn Omland ◽  
Janniche Torsvik ◽  
Thomas E. Kaier ◽  
Marit S. Sylte ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Protein C ◽  
Myocardial Injury ◽  
Binding Protein ◽  
Biological Variation ◽  
Cardiac Myosin ◽  
Analytical Quality ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Abstract Objectives Cardiac myosin-binding protein C (cMyC) is a novel biomarker of myocardial injury, with a promising role in the triage and risk stratification of patients presenting with acute cardiac disease. In this study, we assess the weekly biological variation of cMyC, to examine its potential in monitoring chronic myocardial injury, and to suggest analytical quality specification for routine use of the test in clinical practice. Methods Thirty healthy volunteers were included. Non-fasting samples were obtained once a week for ten consecutive weeks. Samples were tested in duplicate on the Erenna® platform by EMD Millipore Corporation. Outlying measurements and subjects were identified and excluded systematically, and homogeneity of analytical and within-subject variances was achieved before calculating the biological variability (CVI and CVG), reference change values (RCV) and index of individuality (II). Results Mean age was 38 (range, 21–64) years, and 16 participants were women (53%). The biological variation, RCV and II with 95% confidence interval (CI) were: CVA (%) 19.5 (17.8–21.6), CVI (%) 17.8 (14.8–21.0), CVG (%) 66.9 (50.4–109.9), RCV (%) 106.7 (96.6–120.1)/−51.6 (−54.6 to −49.1) and II 0.42 (0.29–0.56). There was a trend for women to have lower CVG. The calculated RCVs were comparable between genders. Conclusions cMyC exhibits acceptable RCV and low II suggesting that it could be suitable for disease monitoring, risk stratification and prognostication if measured serially. Analytical quality specifications based on biological variation are similar to those for cardiac troponin and should be achievable at clinically relevant concentrations.

scholarly journals Cardiac Myosin-Binding Protein C Modulates the Tuning of the Molecular Motor in the Heart

2008 ◽  
Vol 95 (2) ◽  
pp. 720-728 ◽  
Author(s):  
Yves Lecarpentier ◽  
Nicolas Vignier ◽  
Patricia Oliviero ◽  
Aziz Guellich ◽  
Lucie Carrier ◽  
...  
Keyword(s):  
Protein C ◽  
Molecular Motor ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals Phosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments

2017 ◽  
Vol 114 (8) ◽  
pp. E1355-E1364 ◽  
Author(s):  
Robert W. Kensler ◽  
Roger Craig ◽  
Richard L. Moss
Keyword(s):  
Protein C ◽  
Structural Changes ◽  
Binding Protein ◽  
Cardiac Contraction ◽  
Cardiac Myosin ◽  
Cross Bridge ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Thick Filaments ◽  
Myosin Binding

Cardiac myosin binding protein C (cMyBP-C) has a key regulatory role in cardiac contraction, but the mechanism by which changes in phosphorylation of cMyBP-C accelerate cross-bridge kinetics remains unknown. In this study, we isolated thick filaments from the hearts of mice in which the three serine residues (Ser273, Ser282, and Ser302) that are phosphorylated by protein kinase A in the m-domain of cMyBP-C were replaced by either alanine or aspartic acid, mimicking the fully nonphosphorylated and the fully phosphorylated state of cMyBP-C, respectively. We found that thick filaments from the cMyBP-C phospho-deficient hearts had highly ordered cross-bridge arrays, whereas the filaments from the cMyBP-C phospho-mimetic hearts showed a strong tendency toward disorder. Our results support the hypothesis that dephosphorylation of cMyBP-C promotes or stabilizes the relaxed/superrelaxed quasi-helical ordering of the myosin heads on the filament surface, whereas phosphorylation weakens this stabilization and binding of the heads to the backbone. Such structural changes would modulate the probability of myosin binding to actin and could help explain the acceleration of cross-bridge interactions with actin when cMyBP-C is phosphorylated because of, for example, activation of β1-adrenergic receptors in myocardium.

scholarly journals S ‐glutathiolation impairs phosphoregulation and function of cardiac myosin‐binding protein C in human heart failure

2016 ◽  
Vol 30 (5) ◽  
pp. 1849-1864 ◽  
Author(s):  
Konstantina Stathopoulou ◽  
Ilka Wittig ◽  
Juliana Heidler ◽  
Angelika Piasecki ◽  
Florian Richter ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein C ◽  
Human Heart ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Human Heart Failure ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
And Function

scholarly journals Calcium Handling Derangement is Associated with Conditional Cardiac Myosin Binding Protein C Knock Out

2012 ◽  
Vol 102 (3) ◽  
pp. 226a-227a
Author(s):  
Erin M. Capes ◽  
Randall Loaiza ◽  
Peter P. Chen ◽  
Daniel P. Fitzsimons ◽  
Hector H. Valdivia ◽  
...  
Keyword(s):  
Protein C ◽  
Binding Protein ◽  
Calcium Handling ◽  
Cardiac Myosin ◽  
Knock Out ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Cardiac myosin binding protein-C phosphorylation accelerates β-cardiac myosin detachment rate in mouse myocardium

2021 ◽  
Author(s):  
Bertrand C.W. Tanner ◽  
Michael J. Previs ◽  
Yuan Wang ◽  
Jeffrey Robbins ◽  
Bradley M. Palmer
Keyword(s):  
Protein C ◽  
Binding Protein ◽  
Cardiac Contraction ◽  
Power Stroke ◽  
Cardiac Myosin ◽  
Force Development ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Detachment Rate ◽  
Myosin Binding

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament protein that modulates cardiac contraction-relaxation through its phosphorylation. Phosphorylation of cMyBP-C and ablation of cMyBP-C have been shown to increase the rate of MgADP release in the acto-myosin crossbridge cycle in the intact sarcomere. The influence of cMyBP-C on Pi-dependent myosin kinetics has not yet been examined. We investigated the effect of cMyBP-C and its phosphorylation on myosin kinetics in demembranated papillary muscle strips bearing the b-cardiac myosin isoform from non-transgenic (NTGβ) and transgenic mice lacking cMyBP-C (t/tβ). We used quick stretch and stochastic length-perturbation analysis to characterize rates of myosin detachment and force development over 0-12 mM Pi. Protein kinase-A (PKA) treatment was applied to half the strips to probe the effect of cMyBP-C phosphorylation on Pi-sensitivity of myosin kinetics. Increasing Pi increased myosin crossbridge detachment rate similarly for muscles with and without cMyBP-C, although these rates were higher in muscle without cMyBP-C. Treating myocardial strips with PKA accelerated detachment rate when cMyBP-C was present over all Pi, but not when cMyBP-C was absent. The rate of force development increased with Pi in all muscles. However, Pi sensitivity of the rate force development was reduced when cMyBP-C was present vs. absent, suggesting that cMyBP-C inhibits Pi-dependent reversal of the power stroke or stabilizes crossbridge attachment to enhance the probability of completing the power stroke. PKA treatment reduces the role for cMyBP-C to slow myosin detachment and thus effectively accelerates b-myosin detachment in the intact myofilament lattice.

Diagnostic and Prognostic Value of Plasma Levels of Cardiac Myosin Binding Protein-C as a Novel Biomarker in Heart Failure

2016 ◽  
Vol 38 (2) ◽  
pp. 418-424 ◽  
Author(s):  
Doaa El Amrousy ◽  
Hossam Hodeib ◽  
Ghada Suliman ◽  
Nahed Hablas ◽  
Eman Ramadan Salama ◽  
...  
Keyword(s):  
Heart Failure ◽  
Plasma Levels ◽  
Protein C ◽  
Prognostic Value ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Diagnostic And Prognostic Value
Sign in / Sign up

Export Citation Format

Share Document