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

Circ Heart Fail

From 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.).

Published: May 2015

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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447128PMC
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.114.001550DOI Listing

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