Phosphorylation of cardiac Myosin-binding protein-C is a critical mediator of diastolic function.

Abstract

BACKGROUND:

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for ≈50% of all cases of HF and currently has no effective treatment. Diastolic dysfunction underlies HFpEF; therefore, elucidation of the mechanisms that mediate relaxation can provide new potential targets for treatment. Cardiac myosin-binding protein-C (cMyBP-C) is a thick filament protein that modulates cross-bridge cycling rates via alterations in its phosphorylation status. Thus, we hypothesize that phosphorylated cMyBP-C accelerates the rate of cross-bridge detachment, thereby enhancing relaxation to mediate diastolic function.

METHODS AND RESULTS:

We compared mouse models expressing phosphorylation-deficient cMyBP-C(S273A/S282A/S302A)-cMyBP-C(t3SA), phosphomimetic cMyBP-C(S273D/S282D/S302D)-cMyBP-C(t3SD), and wild-type-control cMyBP-C(tWT) to elucidate the functional effects of cMyBP-C phosphorylation. Decreased voluntary running distances, increased lung/body weight ratios, and increased brain natriuretic peptide levels in cMyBP-C(t3SA) mice demonstrate that phosphorylation deficiency is associated with signs of HF. Echocardiography (ejection fraction and myocardial relaxation velocity) and pressure/volume measurements (-dP/dtmin, pressure decay time constant τ-Glantz, and passive filling stiffness) show that cMyBP-C phosphorylation enhances myocardial relaxation in cMyBP-C(t3SD) mice, whereas deficient cMyBP-C phosphorylation causes diastolic dysfunction with HFpEF in cMyBP-C(t3SA) mice. Simultaneous force and [Ca(2+)]i measurements on intact papillary muscles show that enhancement of relaxation in cMyBP-C(t3SD) mice and impairment of relaxation in cMyBP-C(t3SA) mice are not because of altered [Ca(2+)]i handling, implicating that altered cross-bridge detachment rates mediate these changes in relaxation rates.

CONCLUSIONS:

cMyBP-C phosphorylation enhances relaxation, whereas deficient phosphorylation causes diastolic dysfunction and phenotypes resembling HFpEF. Thus, cMyBP-C is a potential target for treatment of HFpEF.

• Authors: Paola C Rosas, Yang Liu, Mohamed I Abdalla, Candice M Thomas, David T Kidwell, Giuseppina F Dusio, Dhriti Mukhopadhyay, Rajesh Kumar, Kenneth M Baker, Brett M Mitchell, Patricia A Powers, Daniel P Fitzsimons, Bindiya G Patel, Chad M Warren, R John Solaro, Richard L Moss, Carl W Tong
• Journal: Circulation. Heart failure (Circ Heart Fail) Vol. 8 Issue 3 Pg. 582-94 (May 2015) ISSN: 1941-3297 [Electronic] United States
• PMID: 25740839 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Carrier Proteins
• myosin-binding protein C
• Cyclic AMP-Dependent Protein Kinases

Topics

• Animals
• Blood Pressure
• Carrier Proteins (genetics, metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Diastole
• Genotype
• Heart Failure (genetics, metabolism, physiopathology)
• Kinetics
• Mice, Transgenic
• Mutation
• Phenotype
• Phosphorylation
• Protein Processing, Post-Translational
• Ventricular Dysfunction, Left (genetics, metabolism, physiopathology)
• Ventricular Function, Left