Abstract 85: Interactions Between Cardiac Myosin Binding Protein C and Actin Contribute to the Regulation of Cardiac Contraction

• Published in: Circulation research Vol. 119; no. suppl_1
• Main Authors: van Dijk, Sabine J, Bezold Kooiker, Kristina, Harris, Samantha P
• Format: Journal Article
• Language: English
• Published: 22.07.2016
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.119.suppl_1.85

Abstract only Cardiac myosin binding protein C (cMyBP-C) is a regulatory muscle protein that is essential for proper cardiac contraction, and mutations in cMyBP-C are commonly associated with hypertrophic cardiomyopathy. cMyBP-C not only interacts with myosin, but with actin as well. In vitro studies have demonstrated that multiple functions of cMyBP-C could readily be explained by an interaction between cMyBP-C and actin, but the in vivo significance of cMyBP-C binding to either myosin or actin is not well understood. Here we created transgenic mice with a single point mutation (L348P) in a key binding domain of cMyBP-C that enhances the binding affinity of cMyBP-C for actin in vitro (Bezold et al , JBC 2013) to gain insights into the relevance of cMyBP-C binding to actin in working hearts. Echocardiograms from 3 month old male L348P-Tg mice (N=23) and non-transgenic (nTg, N=17) controls were used to assess systolic and diastolic function. Results showed significantly prolonged isovolumetric relaxation time (L348P-Tg: 18.5±0.6 vs nTg: 10.2±0.3 ms) and slower movement of the mitral valve annulus (E’: -17.2±1.5 vs -32.2±1.6 and A’: -9.1±1.7 vs -17.6±1.0 mm/s, p<0.05), accompanied by slower inflow of blood into the left ventricle (reduced E and A, prolonged mitral valve deceleration time). Pressure-volume measurements showed significantly reduced rates of pressure decay in L348P-Tg mice (Tau Glantz: 39.1±2.6 vs 12.7±0.9 ms) and an increased end-diastolic pressure volume relationship (0.13±0.02 vs 0.07±0.01). We challenged mice with acute beta-adrenergic stimulation (isoprenaline injection) to determine whether the L348P mutation affected contractile reserve. Isoprenaline had little effect on diastolic parameters, but revealed systolic dysfunction in L348P-Tg mice as evident from a blunted increase in contraction (e.g. fractional shortening after isoprenaline: 38.5±1.3 vs 44.2±1.7%). Taken together our results show for the first time that interactions between cMyBP-C and actin are relevant for functioning of the whole heart. Increasing the cMyBP-C-actin interaction by the L348P mutation caused increased stiffness of the left ventricle, slowed relaxation and diastolic dysfunction. Results also suggested that the L348P mutation reduces contractile reserve.