Phosphorylation of Cardiac Myosin-Binding Protein-C Is a Critical Mediator of Diastolic Function. (May 2015)

• Record Type: Journal Article
• Authors: Rosas, Paola C.; Liu, Yang; Abdalla, Mohamed I.; Thomas, Candice M.; Kidwell, David T.; Dusio, Giuseppina F.; Mukhopadhyay, Dhriti; Kumar, Rajesh; Baker, Kenneth M.; Mitchell, Brett M.; Powers, Patricia A.; Fitzsimons, Daniel P.; Patel, Bindiya G.; Warren, Chad M.; Solaro, R. John; Moss, Richard L.; Tong, Carl W.
• Is Part Of: Circulation. Volume 8:Number 3(2015)
• Publication Date: 2015-05
• Subjects: Heart failure -- Periodicals; 616.129005
• DOI: 10.1161/CIRCHEARTFAILURE.114.001550
• Languages: English
• ISSNs: 1941-3289

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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.</p> </sec> <sec> <title>Methods and Results—</title> <p>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 (−d<italic>P</italic>/d<italic>t</italic><sub>min</sub>, pressure decay time constant <italic>τ</italic>-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<sup>2+</sup>]<sub>i</sub> 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<sup>2+</sup>]<sub>i</sub> handling, implicating that altered cross-bridge detachment rates mediate these changes in relaxation rates.</p> </sec> <sec> <title>Conclusions—</title> <p>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.</p> </sec> </abstract>