Paola C Rosas1, Yang Liu1, Mohamed I Abdalla1, Candice M Thomas1, David T Kidwell1, Giuseppina F Dusio1, Dhriti Mukhopadhyay1, Rajesh Kumar1, Kenneth M Baker1, Brett M Mitchell1, Patricia A Powers1, Daniel P Fitzsimons1, Bindiya G Patel1, Chad M Warren1, R John Solaro1, Richard L Moss1, Carl W Tong2. 1. 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.). 2. 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.). CTong@medicine.tamhsc.edu.
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.
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: Michael R Zile; John S Gottdiener; Scott J Hetzel; John J McMurray; Michel Komajda; Robert McKelvie; Catalin F Baicu; Barry M Massie; Peter E Carson Journal: Circulation Date: 2011-11-07 Impact factor: 29.690
Authors: Samantha P Harris; Christopher R Bartley; Timothy A Hacker; Kerry S McDonald; Pamela S Douglas; Marion L Greaser; Patricia A Powers; Richard L Moss Journal: Circ Res Date: 2002-03-22 Impact factor: 17.367
Authors: Sabine J van Dijk; E Rosalie Paalberends; Aref Najafi; Michelle Michels; Sakthivel Sadayappan; Lucie Carrier; Nicky M Boontje; Diederik W D Kuster; Marjon van Slegtenhorst; Dennis Dooijes; Cris dos Remedios; Folkert J ten Cate; Ger J M Stienen; Jolanda van der Velden Journal: Circ Heart Fail Date: 2011-12-16 Impact factor: 8.790
Authors: Weizhong Zhu; Natalia Petrashevskaya; Shuxun Ren; Aizhi Zhao; Khalid Chakir; Erhe Gao; J Kurt Chuprun; Yibin Wang; Mark Talan; Gerald W Dorn; Edward G Lakatta; Walter J Koch; Arthur M Feldman; Rui-Ping Xiao Journal: Circ Res Date: 2011-12-15 Impact factor: 17.367
Authors: Margaret M Redfield; Steven J Jacobsen; John C Burnett; Douglas W Mahoney; Kent R Bailey; Richard J Rodeheffer Journal: JAMA Date: 2003-01-08 Impact factor: 56.272
Authors: Brett A Colson; Andrew R Thompson; L Michel Espinoza-Fonseca; David D Thomas Journal: Proc Natl Acad Sci U S A Date: 2016-02-23 Impact factor: 11.205
Authors: Nathaniel C Napierski; Kevin Granger; Paul R Langlais; Hannah R Moran; Joshua Strom; Katia Touma; Samantha P Harris Journal: Circ Res Date: 2020-02-13 Impact factor: 17.367
Authors: Mark Y Jeong; Ying H Lin; Sara A Wennersten; Kimberly M Demos-Davies; Maria A Cavasin; Jennifer H Mahaffey; Valmen Monzani; Chandrasekhar Saripalli; Paolo Mascagni; T Brett Reece; Amrut V Ambardekar; Henk L Granzier; Charles A Dinarello; Timothy A McKinsey Journal: Sci Transl Med Date: 2018-02-07 Impact factor: 17.956
Authors: Dan F Smelter; Willem J de Lange; Wenxuan Cai; Ying Ge; J Carter Ralphe Journal: Am J Physiol Heart Circ Physiol Date: 2018-02-16 Impact factor: 4.733
Authors: K Elisabeth Runte; Stephen P Bell; Donald E Selby; Tim N Häußler; Takamuru Ashikaga; Martin M LeWinter; Bradley M Palmer; Markus Meyer Journal: Circ Heart Fail Date: 2017-08 Impact factor: 8.790