Control of In Vivo Contraction/Relaxation Kinetics by Myosin Binding Protein C

Abstract

Background— Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament protein whose presence and phosphorylation by protein kinase A (PKA) regulates cross-bridge formation and kinetics in isolated myocardium. We tested the influence of cMyBP-C and its PKA-phosphorylation on contraction/relaxation kinetics in intact hearts and revealed its essential role in several classic properties of cardiac function. Methods and Results— Comprehensive in situ cardiac pressure–volume analysis was performed in mice harboring a truncation mutation of cMyBP-C (cMyBP-C (t/t) ) that resulted in nondetectable protein versus hearts re-expressing solely wild-type (cMyBP-C WT:(t/t) ) or mutated protein in which known PKA-phosphorylation sites were constitutively suppressed (cMyBP-C AllP-:(t/t) ). Hearts lacking cMyBP-C had faster early systolic activation, which then terminated prematurely, limiting ejection. Systole remained short at faster heart rates; thus, cMyBP-C (t/t) hearts displayed minimal rate-dependent decline in diastolic time and cardiac preload. Furthermore, prolongation of pressure relaxation by afterload was markedly blunted in cMyBP-C (t/t) hearts. All 3 properties were similarly restored to normal in cMyBP-C WT:(t/t) and cMyBP-C AllP-:(t/t) hearts, which supports independence of PKA-phosphorylation. However, the dependence of peak rate of pressure rise on preload was specifically depressed in cMyBP-C AllP-:(t/t) hearts, whereas cMyBP-C (t/t) and cMyBP-C AllP-:(t/t) hearts had similar blunted adrenergic and rate-dependent contractile reserve, which supports linkage of these behaviors to PKA-cMyBP-C modification. Conclusions— cMyBP-C is essential for major properties of cardiac function, including sustaining systole during ejection, the heart-rate dependence of the diastolic time period, and relaxation delay from increased arterial afterload. These are independent of its phosphorylation by PKA, which more specifically modulates early pressure rise rate and adrenergic/heart rate reserve.