Inherent Force-Dependent Properties of β Cardiac Myosin Contribute to the Force-Velocity Relationship of Cardiac Muscle

Abstract

The cardiac cycle is a tightly regulated process in which the heart generates power during systole and relaxes during diastole. Appropriate power must be generated to effectively pump blood against cardiac afterload. Dysfunction of this cycle has devastating consequences for affected individuals. Cardiac power output is regulated by several feedback mechanisms (e.g. neuronal, hormonal, mechanical) which ultimately lead to changes in the force and power output of the molecular motor, β-cardiac myosin (βCM). Despite its importance in driving and regulating cardiac power output, the effect of force on the contractility of a single βCM has not been measured at physiological [ATP]. Using optical trapping techniques, we found that similar to some other myosins, βCM has a two-substep working stroke where the second mechanical substep is associated with ADP release. At saturating [ATP] (4 mM), forces that resist the power stroke slow myosin-driven contraction, suggesting that the inherent properties of myosin contribute to the force-velocity relationship in muscle and play an important role in the regulation of cardiac power output. Based on our results and kinetic modeling, we propose that force inhibits the mechanical transition associated with ADP release, leading to slowing of the rate of ADP release, the same kinetic step that limits muscle shortening. These results have important implications for cardiac diseases which affect power output, such as heart failure and cardiomyopathies. This work was supported by the American Heart Association (14SDG18850009 to M.J.G.) and National Institutes of Health (R01GM057247 to E.M.O. and K99HL123623 to M.J.G.).