Throttling back the heart's molecular motor

Warshaw, David M.

doi:10.1126/science.aaf1636

Cited by 9 publications

(10 citation statements)

References 15 publications

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“…As described in section III, HCM is characterized by preserved or even increased contractility (hypercontractility). Recently, a small molecule, MYK-461, has been identified that reduces contractility by decreasing the ATPase activity of the cardiac MHC (142) [see also the accompanying edi-torial (464)]. These authors demonstrated that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human MYH7 mutations.…”

Section: Small Molecule Myosin Activators and Inhibitorsmentioning

confidence: 99%

Cardiac Disorders and Pathophysiology of Sarcomeric Proteins

Velden

Stienen

2019

Physiological Reviews

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The sarcomeric proteins represent the structural building blocks of heart muscle, which are essential for contraction and relaxation. During recent years, it has become evident that posttranslational modifications of sarcomeric proteins, in particular phosphorylation, tune cardiac pump function at rest and during exercise. This delicate, orchestrated interaction is also influenced by mutations, predominantly in sarcomeric proteins, which cause hypertrophic or dilated cardiomyopathy. In this review, we follow a bottom-up approach starting from a description of the basic components of cardiac muscle at the molecular level up to the various forms of cardiac disorders at the organ level. An overview is given of sarcomere changes in acquired and inherited forms of cardiac disease and the underlying disease mechanisms with particular reference to human tissue. A distinction will be made between the primary defect and maladaptive/adaptive secondary changes. Techniques used to unravel functional consequences of disease-induced protein changes are described, and an overview of current and future treatments targeted at sarcomeric proteins is given. The current evidence presented suggests that sarcomeres not only form the basis of cardiac muscle function but also represent a therapeutic target to combat cardiac disease.

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Section: Small Molecule Myosin Activators and Inhibitorsmentioning

confidence: 99%

Cardiac Disorders and Pathophysiology of Sarcomeric Proteins

Velden

Stienen

2019

Physiological Reviews

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“…Such intervention could simplify treatment and become a generalized approach to control many contractile protein mutations that lead to HCM, or the use of myosin activators for dilated cardiomyopathy. (Adapted with permission from Warshaw, 7 Copyright Ó The American Association for the Advancement of Science.) The Journal of Thoracic and Cardiovascular Surgery c October 2016 identification of HCM patients before their clinical presentation.…”

Section: Myk-461 As a Cure For Hcm?mentioning

confidence: 99%

Hypertrophic cardiomyopathy: New approaches and a time to reappraise older approaches

Takayama

Chung

Maurer

et al. 2016

The Journal of Thoracic and Cardiovascular Surgery

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“…Thus, their motion is approximated by an overdamped stochastic process. Important examples include myosin [7], responsible for muscle contraction in cardiac and skeleton muscles, or kinesin/dynein for pulling cargos (e.g., organelles). They have the capability of producing force directly rather than via an intermediate energy, by converting chemical energy, e.g., adenosine triphosphate (ATP), to kinetic energy.…”

Section: Introductionmentioning

confidence: 99%

Exact Time-Dependent Solutions and Information Geometry of a Rocking Ratchet

Kim

Hollerbach

2022

Symmetry

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The noise-induced transport due to spatial symmetry-breaking is a key mechanism for the generation of a uni-directional motion by a Brownian motor. By utilising an asymmetric sawtooth periodic potential and three different types of periodic forcing G(t) (sinusoidal, square and sawtooth waves) with period T and amplitude A, we investigate the performance (energetics, mean current, Stokes efficiency) of a rocking ratchet in light of thermodynamic quantities (entropy production) and the path-dependent information geometric measures. For each G(t), we calculate exact time-dependent probability density functions under different conditions by varying T, A and the strength of the stochastic noise D in an unprecedentedly wide range. Overall similar behaviours are found for different cases of G(t). In particular, in all cases, the current, Stokes efficiency and the information rate normalised by A and D exhibit one or multiple local maxima and minima as A increases. However, the dependence of the current and Stokes efficiency on A can be quite different, while the behaviour of the information rate normalised by A and D tends to resemble that of the Stokes efficiency. In comparison, the irreversibility measured by a normalised entropy production is independent of A. The results indicate the utility of the information geometry as a proxy of a motor efficiency.

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Throttling back the heart's molecular motor

Abstract: A small molecule inhibits mutated forms of myosin that cause cardiac hypertrophy [Also see Report by Green et al. ]

Cited by 9 publications

References 15 publications

Cardiac Disorders and Pathophysiology of Sarcomeric Proteins

Cardiac Disorders and Pathophysiology of Sarcomeric Proteins

Hypertrophic cardiomyopathy: New approaches and a time to reappraise older approaches

Exact Time-Dependent Solutions and Information Geometry of a Rocking Ratchet

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