scholarly journals Phosphorylation of cardiac myosin–binding protein-C contributes to calcium homeostasis

2020 ◽  
Vol 295 (32) ◽  
pp. 11275-11291 ◽  
Author(s):  
Mohit Kumar ◽  
Kobra Haghighi ◽  
Evangelia G. Kranias ◽  
Sakthivel Sadayappan
Keyword(s):  
Heart Failure ◽  
Protein C ◽  
Contractile Function ◽  
Binding Protein ◽  
Stress Conditions ◽  
Calcium Handling ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Cardiac myosin–binding protein-C (cMyBP-C) is highly phosphorylated under basal conditions. However, its phosphorylation level is decreased in individuals with heart failure. The necessity of cMyBP-C phosphorylation for proper contractile function is well-established, but the physiological and pathological consequences of decreased cMyBP-C phosphorylation in the heart are not clear. Herein, using intact adult cardiomyocytes from mouse models expressing phospho-ablated (AAA) and phosphomimetic (DDD) cMyBP-C as well as controls, we found that cMyBP-C dephosphorylation is sufficient to reduce contractile parameters and calcium kinetics associated with prolonged decay time of the calcium transient and increased diastolic calcium levels. Isoproterenol stimulation reversed the depressive contractile and Ca2+-kinetic parameters. Moreover, caffeine-induced calcium release yielded no difference between AAA/DDD and controls in calcium content of the sarcoplasmic reticulum. On the other hand, sodium–calcium exchanger function and phosphorylation levels of calcium-handling proteins were significantly decreased in AAA hearts compared with controls. Stress conditions caused increases in both spontaneous aftercontractions in AAA cardiomyocytes and the incidence of arrhythmias in vivo compared with the controls. Treatment with omecamtiv mecarbil, a positive cardiac inotropic drug, rescued the contractile deficit in AAA cardiomyocytes, but not the calcium-handling abnormalities. These findings indicate a cascade effect whereby cMyBP-C dephosphorylation causes contractile defects, which then lead to calcium-cycling abnormalities, resulting in aftercontractions and increased incidence of cardiac arrhythmias under stress conditions. We conclude that improvement of contractile deficits alone without improving calcium handling may be insufficient for effective management of heart failure.

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

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

Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure

2007 ◽  
Vol 43 (2) ◽  
pp. 223-229 ◽  
Author(s):  
Ali El-Armouche ◽  
Lutz Pohlmann ◽  
Saskia Schlossarek ◽  
Jutta Starbatty ◽  
Yung-Hsin Yeh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Experimental Heart Failure ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals An Endogenously Produced Fragment of Cardiac Myosin-Binding Protein C Is Pathogenic and Can Lead to Heart Failure

2013 ◽  
Vol 113 (5) ◽  
pp. 553-561 ◽  
Author(s):  
Md. Abdur Razzaque ◽  
Manish Gupta ◽  
Hanna Osinska ◽  
James Gulick ◽  
Burns C. Blaxall ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Double Transgenic Mice

Rationale : A stable 40-kDa fragment is produced from cardiac myosin-binding protein C when the heart is stressed using a stimulus, such as ischemia-reperfusion injury. Elevated levels of the fragment can be detected in the diseased mouse and human heart, but its ability to interfere with normal cardiac function in the intact animal is unexplored. Objective : To understand the potential pathogenicity of the 40-kDa fragment in vivo and to investigate the molecular pathways that could be targeted for potential therapeutic intervention. Methods and Results : We generated cardiac myocyte–specific transgenic mice using a Tet-Off inducible system to permit controlled expression of the 40-kDa fragment in cardiomyocytes. When expression of the 40-kDa protein is induced by crossing the responder animals with tetracycline transactivator mice under conditions in which substantial quantities approximating those observed in diseased hearts are reached, the double-transgenic mice subsequently experience development of sarcomere dysgenesis and altered cardiac geometry, and the heart fails between 12 and 17 weeks of age. The induced double-transgenic mice had development of cardiac hypertrophy with myofibrillar disarray and fibrosis, in addition to activation of pathogenic MEK–ERK pathways. Inhibition of MEK–ERK signaling was achieved by injection of the mitogen-activated protein kinase (MAPK)/ERK inhibitor U0126. The drug effectively improved cardiac function, normalized heart size, and increased probability of survival. Conclusions : These results suggest that the 40-kDa cardiac myosin-binding protein C fragment, which is produced at elevated levels during human cardiac disease, is a pathogenic fragment that is sufficient to cause hypertrophic cardiomyopathy and heart failure.

scholarly journals Cardiac myosin binding protein-C phosphorylation regulates the super-relaxed state of myosin

2019 ◽  
pp. 201821660 ◽  
Author(s):  
James W. McNamara ◽  
Rohit R. Singh ◽  
Sakthivel Sadayappan
Keyword(s):  
Protein C ◽  
Contractile Function ◽  
Binding Protein ◽  
Critical Role ◽  
Cardiac Contractility ◽  
Detectable Effect ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) accelerates cardiac contractility. However, the mechanisms by which cMyBP-C phosphorylation increases contractile kinetics have not been fully elucidated. In this study, we tested the hypothesis that phosphorylation of cMyBP-C releases myosin heads from the inhibited super-relaxed state (SRX), thereby determining the fraction of myosin available for contraction. Mice with various alanine (A) or aspartic acid (D) substitutions of the three main phosphorylatable serines of cMyBP-C (serines 273, 282, and 302) were used to address the association between cMyBP-C phosphorylation and SRX. Single-nucleotide turnover in skinned ventricular preparations demonstrated that phosphomimetic cMyBP-C destabilized SRX, whereas phospho-ablated cMyBP-C had a stabilizing effect on SRX. Strikingly, phosphorylation at serine 282 site was found to play a critical role in regulating the SRX. Treatment of WT preparations with protein kinase A (PKA) reduced the SRX, whereas, in nonphosphorylatable cMyBP-C preparations, PKA had no detectable effect. Mice with stable SRX exhibited reduced force production. Phosphomimetic cMyBP-C with reduced SRX exhibited increased rates of tension redevelopment and reduced binding to myosin. We also used recombinant myosin subfragment-2 to disrupt the endogenous interaction between cMyBP-C and myosin and observed a significant reduction in the population of SRX myosin. This peptide also increased force generation and rate of tension redevelopment in skinned fibers. Taken together, this study demonstrates that the phosphorylation-dependent interaction between cMyBP-C and myosin is a determinant of the fraction of myosin available for contraction. Furthermore, the binding between cMyBP-C and myosin may be targeted to improve contractile function.

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