Abstract
Inherited cardiomyopathies are a common form of heart disease that are caused by mutations in sarcomeric proteins with beta cardiac myosin (MYH7) being one of the most frequently affected genes. Since the discovery of the first cardiomyopathy associated mutation in beta-cardiac myosin, a major goal has been to correlate the in vitro myosin motor properties with the contractile performance of cardiac muscle. There has been substantial progress in developing assays to measure the force and velocity properties of purified cardiac muscle myosin but it is still challenging to correlate results from molecular and tissue-level experiments. Mutations that cause hypertrophic cardiomyopathy are more common than mutations that lead to dilated cardiomyopathy and are also often associated with increased isometric force and hyper-contractility. Therefore, the development of drugs designed to decrease isometric force by reducing the duty ratio (the proportion of time myosin spends bound to actin during its ATPase cycle) has been proposed for the treatment of hypertrophic cardiomyopathy. Para-Nitroblebbistatin is a small molecule drug proposed to decrease the duty ratio of class II myosins. We examined the impact of this drug on human beta cardiac myosin using purified myosin motor assays and studies of permeabilized muscle fiber mechanics. We find that with purified human beta-cardiac myosin para-Nitroblebbistatin slows actin-activated ATPase and in vitro motility without altering the ADP release rate constant. In permeabilized human myocardium, para-Nitroblebbistatin reduces isometric force, power, and calcium sensitivity while not changing shortening velocity or the rate of force development (ktr). Therefore, designing a drug that reduces the myosin duty ratio by inhibiting strong attachment to actin while not changing detachment can cause a reduction in force without changing shortening velocity or relaxation.
Highlights
Inherited cardiomyopathies caused by mutations in sarcomere protein-coding genes are a significant cause of cardiovascular diseases in people of all ages (Morimoto, 2007; Watkins et al, 2011)
We have examined the impact of pN-Bleb on the motor properties of recombinantly expressed human β-cardiac myosin subfragment 1 (M2β-S1) and the force and velocity properties of human myocardium
We examined the impact of pN-Bleb on the heavy meromyosin fragment of chicken skeletal muscle myosin (Sk HMM) with in vitro motility and actin-activated ATPase assays, which allowed a comparison of the specificity of pN-Bleb for these two myosin isoforms
Summary
Inherited cardiomyopathies caused by mutations in sarcomere protein-coding genes are a significant cause of cardiovascular diseases in people of all ages (Morimoto, 2007; Watkins et al, 2011). Hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiomyopathy, and the primary cause of sudden cardiac death in young adults (Maron, 2004; Efthimiadis et al, 2014; Maron et al, 2014). The latest revised HCM prevalence is about 1 in Inherited Cardiomyopathies and Cardiac Myosin. DCM is characterized by the thinning of one or both ventricular walls, an enlarged left ventricular chamber, and insufficient systolic contraction (Luk et al, 2009; Hershberger et al, 2010; McNally et al, 2013). Restrictive, arrhythmogenic right ventricular, left ventricular non-compaction, and other types of cardiomyopathies have been classified as well, but are less prevalent in the general population (Elliott et al, 2008; Watkins et al, 2011; Towbin, 2014)
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