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

Paola C Rosas1, Yang Liu1, Mohamed I Abdalla1

  • 1From the Department of Medical Physiology (P.C.R., Y.L., M.I.A., B.M.M., C.W.T.) and Division of Molecular Cardiology, Department of Medicine (C.M.T., R.K., K.M.B.), Texas A&M University Health Science Center, College of Medicine, Temple City; Internal Medicine/Division of Cardiology (D.T.K., C.W.T.) and Department of Surgery (G.F.D., D.M.), Baylor Scott & White Health-Central Texas, Temple City; Department of Cell and Regenerative Biology and Biotechnology Center, University of Wisconsin School of Medicine and Public Health, Madison (P.A.P., D.P.F., R.L.M.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago (B.G.P., C.M.W., R.J.S.).

Circulation. Heart Failure
|March 6, 2015
PubMed

Insights

Phosphorylation of cardiac myosin-binding protein-C (cMyBP-C) enhances heart muscle relaxation, crucial for treating heart failure with preserved ejection fraction (HFpEF). Deficient cMyBP-C phosphorylation leads to diastolic dysfunction, a hallmark of HFpEF.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Heart failure with preserved ejection fraction (HFpEF) affects nearly 50% of heart failure cases and lacks effective treatments.
  • Diastolic dysfunction is the primary mechanism underlying HFpEF, necessitating research into relaxation-mediating pathways.
  • Cardiac myosin-binding protein-C (cMyBP-C) is a key thick filament protein regulating cross-bridge cycling through its phosphorylation status.

Purpose of the Study:

  • To investigate the functional role of cMyBP-C phosphorylation in regulating myocardial relaxation and diastolic function.
  • To determine if alterations in cMyBP-C phosphorylation contribute to the development of HFpEF phenotypes.
  • To explore cMyBP-C as a potential therapeutic target for HFpEF.

Main Methods:

  • Comparison of mouse models with wild-type, phosphorylation-deficient (t3SA), and phosphomimetic (t3SD) cMyBP-C.
  • Assessment of cardiac function using echocardiography and pressure/volume measurements.
  • Analysis of myocardial relaxation rates and intracellular calcium handling via papillary muscle experiments.

Main Results:

  • Mice with phosphorylation-deficient cMyBP-C (t3SA) exhibited reduced running capacity, increased lung/body weight ratios, and elevated brain natriuretic peptide levels, indicative of heart failure.
  • Phosphorylation-deficient cMyBP-C (t3SA) mice showed impaired myocardial relaxation and diastolic dysfunction, consistent with HFpEF.
  • Phosphomimetic cMyBP-C (t3SD) mice demonstrated enhanced myocardial relaxation, while the underlying mechanism was attributed to altered cross-bridge detachment rates, not changes in calcium handling.

Conclusions:

  • cMyBP-C phosphorylation is essential for enhancing myocardial relaxation and maintaining diastolic function.
  • Deficient cMyBP-C phosphorylation leads to diastolic dysfunction and HFpEF-like phenotypes.
  • Targeting cMyBP-C phosphorylation presents a promising therapeutic strategy for treating HFpEF.
Abstract

Keywords:
diastoleheart failuremyocardial contractionmyocardiummyosin-binding protein C

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