Direct visualization of myosin-binding protein C bridging myosin and actin filaments in intact muscle

Myosin-Binding protein-C (MyBP-C) is a family of accessory proteins of striated muscles that contributes to the assembly and stabilization of thick filaments, and regulates the formation of actomyosin cross-bridges, via direct interactions with both thick myosin and thin actin filaments. Three distinct MyBP-C isoforms have been characterized; cardiac, slow skeletal, and fast skeletal. Numerous mutations in the gene for cardiac MyBP-C (cMyBP-C) have been associated with familial hypertrophic cardiomyopathy (FHC) and have led to increased interest in the regulation and roles of the cardiac isoform. This review will summarize our current knowledge on MyBP-C and its role in modulating contractility, focusing on its interactions with both myosin and actin filaments in cardiac and skeletal muscles.

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Effects of Myosin Binding Protein-C Isoform, Phosphorylation, and Domains on the Rotational Dynamics of Actin Filaments

Biophysical Journal ◽

10.1016/j.bpj.2011.11.2383 ◽

2012 ◽

Vol 102 (3) ◽

pp. 435a

Author(s):

Brett A. Colson ◽

Inna N. Rybakova ◽

Richard L. Moss ◽

Ewa Prochniewicz ◽

David D. Thomas

Keyword(s):

Actin Filaments ◽

Protein C ◽

Binding Protein ◽

Rotational Dynamics ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

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Effects of Cardiac Myosin Binding Protein-C and its Domains on the Rotational Dynamics of Actin Filaments

Biophysical Journal ◽

10.1016/j.bpj.2010.12.3379 ◽

2011 ◽

Vol 100 (3) ◽

pp. 585a

Author(s):

Brett A. Colson ◽

Inna N. Rybakova ◽

Ewa Prochniewicz ◽

Richard L. Moss ◽

David D. Thomas

Keyword(s):

Actin Filaments ◽

Protein C ◽

Binding Protein ◽

Rotational Dynamics ◽

Cardiac Myosin ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

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The N terminus of myosin-binding protein C extends toward actin filaments in intact cardiac muscle

The Journal of General Physiology ◽

10.1085/jgp.202012726 ◽

2021 ◽

Vol 153 (3) ◽

Cited By ~ 3

Author(s):

Sheema Rahmanseresht ◽

Kyoung H. Lee ◽

Thomas S. O’Leary ◽

James W. McNamara ◽

Sakthivel Sadayappan ◽

...

Keyword(s):

Actin Filaments ◽

Protein C ◽

Myosin Head ◽

Binding Protein ◽

Myosin Filament ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

N Terminus ◽

Myosin Binding ◽

Terminal Domains

Myosin and actin filaments are highly organized within muscle sarcomeres. Myosin-binding protein C (MyBP-C) is a flexible, rod-like protein located within the C-zone of the sarcomere. The C-terminal domain of MyBP-C is tethered to the myosin filament backbone, and the N-terminal domains are postulated to interact with actin and/or the myosin head to modulate filament sliding. To define where the N-terminal domains of MyBP-C are localized in the sarcomere of active and relaxed mouse myocardium, the relative positions of the N terminus of MyBP-C and actin were imaged in fixed muscle samples using super-resolution fluorescence microscopy. The resolution of the imaging was enhanced by particle averaging. The images demonstrate that the position of the N terminus of MyBP-C is biased toward the actin filaments in both active and relaxed muscle preparations. Comparison of the experimental images with images generated in silico, accounting for known binding partner interactions, suggests that the N-terminal domains of MyBP-C may bind to actin and possibly the myosin head but only when the myosin head is in the proximity of an actin filament. These physiologically relevant images help define the molecular mechanism by which the N-terminal domains of MyBP-C may search for, and capture, molecular binding partners to tune cardiac contractility.

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

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2021-0306 ◽

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.

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Cardiac myosin‐binding protein C as a candidate biomarker in heart failure: rational but not revolutionary

European Journal of Heart Failure ◽

10.1002/ejhf.2126 ◽

2021 ◽

Author(s):

A. Mark Richards

Keyword(s):

Heart Failure ◽

Protein C ◽

Binding Protein ◽

Cardiac Myosin ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

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The Interplay between S-glutathionylation and Phosphorylation of Cardiac Troponin I and Myosin Binding Protein C in End-Stage Human Failing Hearts

Antioxidants ◽

10.3390/antiox10071134 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1134

Author(s):

Heidi Budde ◽

Roua Hassoun ◽

Melina Tangos ◽

Saltanat Zhazykbayeva ◽

Melissa Herwig ◽

...

Keyword(s):

Oxidative Stress ◽

Protein C ◽

Troponin I ◽

Reduced Glutathione ◽

Binding Protein ◽

Enzyme Treatment ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding ◽

End Stage

Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca2+-activated tension and Ca2+ sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca2+ sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure.

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