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

Circ Heart Fail. 2015 May;8(3):582-94. doi: 10.1161/CIRCHEARTFAILURE.114.001550. Epub 2015 Mar 4.

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.

Keywords: diastole; heart failure; myocardial contraction; myocardium; myosin-binding protein C.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

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