Abstract 3850: Cardiac Myosin Binding Protein C Regulates Cross-bridge Kinetics to Affect Diastolic Function
Cardiac Myosin Binding Protein C (cMyBP-C) is a thick filament accessory protein that acts as a repressive regulator of actin-myosin interactions. We hypothesized that cMyBP-C regulation of cross-bridge turnover kinetics affects the myocardial relaxation. Consistent with this idea, our recent simultaneous measurements of force and intracellular calcium [Ca2+]in in intact papillary muscles showed that (-dF/dt)max/(+dF/dt)max cannot be accelerated by β-adrenergic stimulation in myocardium from the cMyBP-C knock-out (KO) mouse despite a faster decay of [Ca2+]in. To determine whether our in vitro results apply on intact hearts, we performed echocardiography measurements in cMyBP-C(KO) and wild type (WT) mice. Observed increases in isovolumetric relaxation time and in the ratio of Doppler of mitral blood inflow to tissue Doppler (TD) of the mitral annulus (i.e., E/Ea) indicate that cMyBP-C(KO) hearts have diastolic dysfunction in comparison to WT hearts. Since the TD measurements of Ea and Sa represent the maximum velocities of myocardial relaxation and contraction, respectively, then ratio of Ea/Sa is an intact heart analog of (-dF/dt)max/(+dF/dt)max measurements in intact papillary muscle. Unlike the case in WT hearts, dobutamine treatment did not increase Ea/Sa in cMyBP-C(KO) hearts; therefore, our previous findings from isolated muscle also apply to the intact hearts. We then performed regression analysis on papillary muscle data to Weibull distribution. Weibull distribution scale factor (SF) quantifies the steepness of both rise and fall portions of a waveform; thus, (1/SF) equals rate constant for the entire time course of twitch (kforce) or [Ca2+]in transient (kca) of papillary muscle. cMyBP-C(KO) myocardium has 1.5-fold faster kforce than WT hearts, but this kforce cannot be accelerated with dobutamine despite acceleration of kCa. Together, these results indicate that cMyBP-C influences diastolic function by regulating cross-bridge kinetics.