Cardiac myosin filaments are directly regulated by calcium

Ma, Weikang; Nag, Suman; Gong, Henry; Lin, Qingshan; Irving, Thomas C.

doi:10.1085/jgp.202213213

Cited by 31 publications

(41 citation statements)

References 54 publications

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“…Humane euthanasia and tissue collection procedures were approved by the Institutional Animal Care and Use Committees at Exemplar Genetics. Permeabilized tissues were prepared as described previously (50,51). Briefly, frozen left ventricle wall tissues (about 0.5 -1 cm 3 ) was defrosted at room temperature in skinning solution (in mM: 91 K+propionate, 3.5 MgCl 2 , 0.16 CaCl 2 , 7 EGTA, 2.5 Na 2 ATP, 15 Creatine phosphate, 20 Imidazole, 30 BDM, 1% Triton-X100 and 3% Dextran at pH 7) before dissecting into smaller strips (~5 -10 mm long and 1-2 mm wide).…”

Section: X-ray Diffractionmentioning

confidence: 99%

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

Kooiker

Mohran

Turner

et al. 2023

Preprint

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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.

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Section: X-ray Diffractionmentioning

confidence: 99%

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

Kooiker

Mohran

Turner

et al. 2023

Preprint

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“…The formation of the strong binding crossbridges will further activate the thin filament, which could be, at least partially, responsible for the increased calcium sensitivity, post EMD treatment. One recent study indicated that the myosin filaments can be directly regulated by calcium [ 47 ]. Calcium can turn the myosin filament ON in the absence of the thin-filament based activation, indicating that the calcium sensitivity might not be a exclusively a thin filament property.…”

Section: Discussionmentioning

confidence: 99%

EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments

Jani

Yuan

et al. 2022

IJMS

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Sufficient cardiac contractility is necessary to ensure the sufficient cardiac output to provide an adequate end-organ perfusion. Inadequate cardiac output and the diminished perfusion of vital organs from depressed myocardium contractility is a hallmark end-stage of heart failure. There are no available therapeutics that directly target contractile proteins to improve the myocardium contractility and reduce mortality. The purpose of this study is to present a proof of concept to aid in the development of muscle activators (myotropes) for augmenting the contractility in clinical heart failure. Here we use a combination of cardiomyocyte mechanics, the biochemical quantification of the ATP turnover, and small angle X-ray diffraction on a permeabilized porcine myocardium to study the mechanisms of EMD-57033 (EMD) for activating myosin. We show that EMD increases the contractility in a porcine myocardium at submaximal and systolic calcium concentrations. Biochemical assays show that EMD decreases the proportion of myosin heads in the energy sparing super-relaxed (SRX) state under relaxing conditions, which are less likely to interact with actin during contraction. Structural assays show that EMD moves the myosin heads in relaxed muscles from a structurally ordered state close to the thick filament backbone, to a disordered state closer to the actin filament, while simultaneously inducing structural changes in the troponin complex on the actin filament. The dual effects of EMD on activating myosin heads and the troponin complex provides a proof of concept for the use of small molecule muscle activators for augmenting the contractility in heart failure.

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“…The X-ray diffraction data presented here show that increasing [ADP] shifts a population of myosin heads from an ordered configuration near the thick-filament backbone to a less ordered configuration nearer to the thin-filament. It has been proposed that increased calcium sensitivity may not be solely a thin-filament-based phenomenon [ 31 ] and includes contributions from thick-filament-based activation processes. If so, our data showing an increase in thick-filament activation in the presence of elevated [ADP] ( Figure 2 and Figure 3 ) could provide at least a partial explanation for the increased calcium sensitivity observed under these conditions.…”

Section: Discussionmentioning

confidence: 99%

MgADP Promotes Myosin Head Movement toward Actin at Low [Ca2+] to Increase Force Production and Ca2+-Sensitivity of Contraction in Permeabilized Porcine Myocardial Strips

Awinda

Turner

et al. 2022

IJMS

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Myosin cross-bridges dissociate from actin following Mg2+-adenosine triphosphate (MgATP) binding. Myosin hydrolyses MgATP into inorganic phosphate (Pi) and Mg2+-adenosine diphosphate (ADP), and release of these hydrolysis products drives chemo-mechanical energy transitions within the cross-bridge cycle to power muscle contraction. Some forms of heart disease are associated with metabolic or enzymatic dysregulation of the MgATP-MgADP nucleotide pool, resulting in elevated cytosolic [MgADP] and impaired muscle relaxation. We investigated the mechanical and structural effects of increasing [MgADP] in permeabilized myocardial strips from porcine left ventricle samples. Sarcomere length was set to 2.0 µm at 28 °C, and all solutions contained 3% dextran T-500 to compress myofilament lattice spacing to near-physiological values. Under relaxing low [Ca2+] conditions (pCa 8.0, where pCa = −log10[Ca2+]), tension increased as [MgADP] increased from 0-5 mM. Complementary small-angle X-ray diffraction measurements show that the equatorial intensity ratio, I1,1/I1,0, also increased as [MgADP] increased from 0 to 5 mM, indicating myosin head movement away from the thick-filament backbone towards the thin-filament. Ca2+-activated force-pCa measurements show that Ca2+-sensitivity of contraction increased with 5 mM MgADP, compared to 0 mM MgADP. These data show that MgADP augments tension at low [Ca2+] and Ca2+-sensitivity of contraction, suggesting that MgADP destabilizes the quasi-helically ordered myosin OFF state, thereby shifting the cross-bridge population towards the disordered myosin ON state. Together, these results indicate that MgADP enhances the probability of cross-bridge binding to actin due to enhancement of both thick and thin filament-based activation mechanisms.

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Cardiac myosin filaments are directly regulated by calcium

Cited by 31 publications

References 54 publications

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

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

EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments

MgADP Promotes Myosin Head Movement toward Actin at Low [Ca2+] to Increase Force Production and Ca2+-Sensitivity of Contraction in Permeabilized Porcine Myocardial Strips

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