Novel myosin-based therapies for congenital cardiac and skeletal myopathies

Ochala, Julien; Sun, Yin-Biao

doi:10.1136/jmedgenet-2016-103881

Cited by 13 publications

(10 citation statements)

References 42 publications

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“…Recently, the discovery of small molecules able to modulate the activity of βcardiac myosin have provided new pharmaceutical perspectives for treatment of cardiac diseases 8,9,10,11 . The mechanism of action of a cardiac myosin activator, Omecamtiv mecarbil (OM) has been elucidated: OM favors the PPS conformation and thus increases the number of heads able to participate in force production upon the systole on-set 11 .…”

Section: Implications For Future Treatmentsmentioning

confidence: 99%

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Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

Robert-Paganin

Auguin²,

Houdusse³

2018

Preprint

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Abstract:Hypertrophic cardiomyopathies (HCM) result from distinct single-point mutations in sarcomeric proteins that lead to muscle hypercontractility. While different models account for a pathological increase in the power output, clear understanding of the molecular basis of dysfunction in HCM is the mandatory next step to improve current treatments. An optimized quasi-atomic model of the sequestered state of cardiac myosin coupled to X-ray crystallography and in silico analysis of the mechanical compliance of the lever arm allowed us to perform a systematic study for a large set of HCM mutations. We define different classes of mutations depending on their effects on lever arm compliance, sequestered state stability and motor functions. This work reconciles previous models and explains how distinct HCM mutations can have disparate effects on the motor mechano-chemical parameters and yet lead to the same disease. The framework presented here can guide future investigations aiming at finding HCM treatments.

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Section: Implications For Future Treatmentsmentioning

confidence: 99%

“…To date, the effects of HCM mutations on motor activity have not been precisely predicted 7 . While recent advances give hope in future treatments of such a disease with small molecule modulators of myosin function 8,9,10,11,12 , it is essential to progress in understanding of the impact of β-cardiac myosin mutations to guide future therapeutic strategies.…”

mentioning

confidence: 99%

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

Robert-Paganin

Auguin²,

Houdusse³

2018

Preprint

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“…An additional issue that is pertinent to consider is effects of non-uniform sarcomere properties along a muscle cell [ 262 , 263 ] or myofibril [ 264 ]. These issues may, not the least be important to consider in future studies of cardiomyopathies and other diseases [ 265 , 266 , 267 , 268 , 269 ].…”

Section: Top-down and Bottom-up Modelsmentioning

confidence: 99%

Do Actomyosin Single-Molecule Mechanics Data Predict Mechanics of Contracting Muscle?

Månsson

Ušaj

Moretto

et al. 2018

IJMS

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In muscle, but not in single-molecule mechanics studies, actin, myosin and accessory proteins are incorporated into a highly ordered myofilament lattice. In view of this difference we compare results from single-molecule studies and muscle mechanics and analyze to what degree data from the two types of studies agree with each other. There is reasonable correspondence in estimates of the cross-bridge power-stroke distance (7–13 nm), cross-bridge stiffness (~2 pN/nm) and average isometric force per cross-bridge (6–9 pN). Furthermore, models defined on the basis of single-molecule mechanics and solution biochemistry give good fits to experimental data from muscle. This suggests that the ordered myofilament lattice, accessory proteins and emergent effects of the sarcomere organization have only minor modulatory roles. However, such factors may be of greater importance under e.g., disease conditions. We also identify areas where single-molecule and muscle data are conflicting: (1) whether force generation is an Eyring or Kramers process with just one major power-stroke or several sub-strokes; (2) whether the myofilaments and the cross-bridges have Hookean or non-linear elasticity; (3) if individual myosin heads slip between actin sites under certain conditions, e.g., in lengthening; or (4) if the two heads of myosin cooperate.

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“…Additionally, nonmuscle myosin II and actin have pivotal roles in cell motility and thereby in functions associated with the immune system, synaptic plasticity, and cell division (1). Therefore, disturbed myosin II function is central to a range of diseases (2, 3, 4) as well as to functional decline during aging (5). Such characteristics have motivated the development of myosin-active small molecular compounds for therapeutic use (2, 3, 6, 7, 8).…”

Section: Introductionmentioning

confidence: 99%

Blebbistatin Effects Expose Hidden Secrets in the Force-Generating Cycle of Actin and Myosin

Rahman

Ušaj

Rassier

et al. 2018

Biophysical Journal

130

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Cyclic interactions between myosin II motors and actin filaments driven by ATP turnover underlie muscle contraction and have key roles in the motility of nonmuscle cells. A remaining enigma in the understanding of this interaction is the relationship between the force-generating structural change and the release of the ATP-hydrolysis product, inorganic phosphate (Pi), from the active site of myosin. Here, we use the small molecular compound blebbistatin to probe otherwise hidden states and transitions in this process. Different hypotheses for the Pi release mechanism are tested by interpreting experimental results from in vitro motility assays and isolated muscle fibers in terms of mechanokinetic actomyosin models. The data fit with ideas that actomyosin force generation is preceded by Pi release, which in turn is preceded by two serial transitions after/coincident with cross-bridge attachment. Blebbistatin changes the rate limitation of the cycle from the first to the second of these transitions, uncovering functional roles of an otherwise short-lived pre-power stroke state that has been implicated by structural data.

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Novel myosin-based therapies for congenital cardiac and skeletal myopathies

Cited by 13 publications

References 42 publications

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

Do Actomyosin Single-Molecule Mechanics Data Predict Mechanics of Contracting Muscle?

Blebbistatin Effects Expose Hidden Secrets in the Force-Generating Cycle of Actin and Myosin

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