Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle

Abstract

Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Detailed mechanism of action of these agents can help predict potential unwanted affects and identify patient populations that can benefit most from them. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking. Using porcine cardiac tissue and myofibrils we demonstrate that Danicamtiv increases force and calcium sensitivity via increasing the number of myosin in the on state and slowing cross bridge turnover. Our detailed analysis shows that inhibition of ADP release results in decreased cross bridge turnover with cross bridges staying on longer and prolonging myofibril relaxation. Using a mouse model of genetic dilated cardiomyopathy, we demonstrated that Danicamtiv corrected calcium sensitivity in demembranated and abnormal twitch magnitude and kinetics in intact cardiac tissue.

Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure

“…titin and MyBP-C) 22,23 . Other mechanisms regulate myosin heads in an SL-independent fashion, such as phosphorylation 35 or the external addition of pharmaceuticals that force myosin heads into OFF or ON states 10,17,33 . Importantly, without SL change, repositioning myosin heads into the ON state still elongates the thick filament 10,17,33 , most likely due to structural rearrangements within the thick filament backbone that are not yet understood 11 .…”

“…Importantly, the sarcomere length (SL)-dependent transition of myosin heads toward the ON state with increasing SL is considered the mechanical underpinning of length-dependence of calcium sensitivity (length-dependent activation) 15,16 . However, myosin heads may also transition between ON and OFF states by SL-independent mechanisms, leading to a basal transition of myosin heads towards ON or OFF states while maintaining their SL-dependent property 8,10,17,18 .…”

Danicamtiv Recruits Myosin Motors to Aid the Failing Heart

“…In this issue, Kooiker et al 5 investigate the mechanism of action of danicamtiv. Danicamtiv is another myotrope that has been proposed as treatment for heart failure, based on promising preclinical and early clinical studies in patients with heart failure with reduced ejection fraction.…”

“…Danicamtiv is another myotrope that has been proposed as treatment for heart failure, based on promising preclinical and early clinical studies in patients with heart failure with reduced ejection fraction. 6 Through a detailed assessment of tissue mechanics, X-ray diffraction, and myofibril measurements, the report by Kooiker et al 5 provides a comprehensive understanding of how danicamtiv modulates cardiac function at the molecular level and provides proof-of-concept for in vivo efficacy in a mouse model of dilated cardiomyopathy due to a thin filament mutation. 5 As illustrated in the Figure, the authors found that danicamtiv increases contractility by 2 separate mechanisms.…”

“…6 Through a detailed assessment of tissue mechanics, X-ray diffraction, and myofibril measurements, the report by Kooiker et al 5 provides a comprehensive understanding of how danicamtiv modulates cardiac function at the molecular level and provides proof-of-concept for in vivo efficacy in a mouse model of dilated cardiomyopathy due to a thin filament mutation. 5 As illustrated in the Figure, the authors found that danicamtiv increases contractility by 2 separate mechanisms. By reducing the rate of ADP release from myosin, danicamtiv increases the population of force-producing myosin heads rather than merely enhancing the force per myosin head.…”