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Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds

Bottom-up mechanokinetic models predict ensemble function of actin and myosin based on parameter values derived from studies using isolated proteins. To be generally useful, e.g., to analyze disease effects, such models must also be able to predict ensemble function when actomyosin interaction kinet...

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Detalles Bibliográficos
Autores principales: Månsson, Alf, Rassier, Dilson E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9603234/
https://www.ncbi.nlm.nih.gov/pubmed/36292937
http://dx.doi.org/10.3390/ijms232012084
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author Månsson, Alf
Rassier, Dilson E.
author_facet Månsson, Alf
Rassier, Dilson E.
author_sort Månsson, Alf
collection PubMed
description Bottom-up mechanokinetic models predict ensemble function of actin and myosin based on parameter values derived from studies using isolated proteins. To be generally useful, e.g., to analyze disease effects, such models must also be able to predict ensemble function when actomyosin interaction kinetics are modified differently from normal. Here, we test this capability for a model recently shown to predict several physiological phenomena along with the effects of the small molecular compound blebbistatin. We demonstrate that this model also qualitatively predicts effects of other well-characterized drugs as well as varied concentrations of MgATP. However, the effects of one compound, amrinone, are not well accounted for quantitatively. We therefore systematically varied key model parameters to address this issue, leading to the increased amplitude of the second sub-stroke of the power stroke from 1 nm to 2.2 nm, an unchanged first sub-stroke (5.3–5.5 nm), and an effective cross-bridge attachment rate that more than doubled. In addition to better accounting for the effects of amrinone, the modified model also accounts well for normal physiological ensemble function. Moreover, a Monte Carlo simulation-based version of the model was used to evaluate force–velocity data from small myosin ensembles. We discuss our findings in relation to key aspects of actin–myosin operation mechanisms causing a non-hyperbolic shape of the force–velocity relationship at high loads. We also discuss remaining limitations of the model, including uncertainty of whether the cross-bridge elasticity is linear or not, the capability to account for contractile properties of very small actomyosin ensembles (<20 myosin heads), and the mechanism for requirements of a higher cross-bridge attachment rate during shortening compared to during isometric contraction.
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spelling pubmed-96032342022-10-27 Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds Månsson, Alf Rassier, Dilson E. Int J Mol Sci Article Bottom-up mechanokinetic models predict ensemble function of actin and myosin based on parameter values derived from studies using isolated proteins. To be generally useful, e.g., to analyze disease effects, such models must also be able to predict ensemble function when actomyosin interaction kinetics are modified differently from normal. Here, we test this capability for a model recently shown to predict several physiological phenomena along with the effects of the small molecular compound blebbistatin. We demonstrate that this model also qualitatively predicts effects of other well-characterized drugs as well as varied concentrations of MgATP. However, the effects of one compound, amrinone, are not well accounted for quantitatively. We therefore systematically varied key model parameters to address this issue, leading to the increased amplitude of the second sub-stroke of the power stroke from 1 nm to 2.2 nm, an unchanged first sub-stroke (5.3–5.5 nm), and an effective cross-bridge attachment rate that more than doubled. In addition to better accounting for the effects of amrinone, the modified model also accounts well for normal physiological ensemble function. Moreover, a Monte Carlo simulation-based version of the model was used to evaluate force–velocity data from small myosin ensembles. We discuss our findings in relation to key aspects of actin–myosin operation mechanisms causing a non-hyperbolic shape of the force–velocity relationship at high loads. We also discuss remaining limitations of the model, including uncertainty of whether the cross-bridge elasticity is linear or not, the capability to account for contractile properties of very small actomyosin ensembles (<20 myosin heads), and the mechanism for requirements of a higher cross-bridge attachment rate during shortening compared to during isometric contraction. MDPI 2022-10-11 /pmc/articles/PMC9603234/ /pubmed/36292937 http://dx.doi.org/10.3390/ijms232012084 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Månsson, Alf
Rassier, Dilson E.
Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds
title Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds
title_full Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds
title_fullStr Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds
title_full_unstemmed Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds
title_short Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds
title_sort insights into muscle contraction derived from the effects of small-molecular actomyosin-modulating compounds
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9603234/
https://www.ncbi.nlm.nih.gov/pubmed/36292937
http://dx.doi.org/10.3390/ijms232012084
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