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Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics

Rapid myocardial relaxation is essential in maintaining cardiac output, and impaired relaxation is an early indicator of diastolic dysfunction. While the biochemical modifiers of relaxation are well known to include calcium handling, thin filament activation, and myosin kinetics, biophysical and bio...

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Autores principales: Schick, Brianna M., Dlugas, Hunter, Czeiszperger, Teresa L., Matus, Alexandra R., Bukowski, Melissa J., Chung, Charles S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635462/
https://www.ncbi.nlm.nih.gov/pubmed/34015323
http://dx.doi.org/10.1016/j.abb.2021.108909
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author Schick, Brianna M.
Dlugas, Hunter
Czeiszperger, Teresa L.
Matus, Alexandra R.
Bukowski, Melissa J.
Chung, Charles S.
author_facet Schick, Brianna M.
Dlugas, Hunter
Czeiszperger, Teresa L.
Matus, Alexandra R.
Bukowski, Melissa J.
Chung, Charles S.
author_sort Schick, Brianna M.
collection PubMed
description Rapid myocardial relaxation is essential in maintaining cardiac output, and impaired relaxation is an early indicator of diastolic dysfunction. While the biochemical modifiers of relaxation are well known to include calcium handling, thin filament activation, and myosin kinetics, biophysical and biomechanical modifiers can also alter relaxation. We have previously shown that the relaxation rate is increased by an increasing strain rate, not a reduction in afterload. The slope of the relaxation rate to strain rate relationship defines Mechanical Control of Relaxation (MCR). To investigate MCR further, we performed in vitro experiments and computational modeling of preload-adjustment using intact rat cardiac trabeculae. Trabeculae studies are often performed using isometric (fixed-end) muscles at optimal length (Lo, length producing maximal developed force). We determined that reducing muscle length from Lo increased MCR by 20%, meaning that reducing preload could substantially increase the sensitivity of the relaxation rate to the strain rate. We subsequently used computational modeling to predict mechanisms that might underlie this preload-dependence. Computational modeling was not able to fully replicate experimental data, but suggested that thin-filament properties are not sufficient to explain preload-dependence of MCR because the model required the thin-filament to become more activated at reduced preloads. The models suggested that myosin kinetics may underlie the increase in MCR at reduced preload, an effect that can be enhanced by force-dependence. Relaxation can be modified and enhanced by reduced preload. Computational modeling implicates myosin-based targets for treatment of diastolic dysfunction, but further model refinements are needed to fully replicate experimental data.
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spelling pubmed-86354622021-12-01 Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics Schick, Brianna M. Dlugas, Hunter Czeiszperger, Teresa L. Matus, Alexandra R. Bukowski, Melissa J. Chung, Charles S. Arch Biochem Biophys Article Rapid myocardial relaxation is essential in maintaining cardiac output, and impaired relaxation is an early indicator of diastolic dysfunction. While the biochemical modifiers of relaxation are well known to include calcium handling, thin filament activation, and myosin kinetics, biophysical and biomechanical modifiers can also alter relaxation. We have previously shown that the relaxation rate is increased by an increasing strain rate, not a reduction in afterload. The slope of the relaxation rate to strain rate relationship defines Mechanical Control of Relaxation (MCR). To investigate MCR further, we performed in vitro experiments and computational modeling of preload-adjustment using intact rat cardiac trabeculae. Trabeculae studies are often performed using isometric (fixed-end) muscles at optimal length (Lo, length producing maximal developed force). We determined that reducing muscle length from Lo increased MCR by 20%, meaning that reducing preload could substantially increase the sensitivity of the relaxation rate to the strain rate. We subsequently used computational modeling to predict mechanisms that might underlie this preload-dependence. Computational modeling was not able to fully replicate experimental data, but suggested that thin-filament properties are not sufficient to explain preload-dependence of MCR because the model required the thin-filament to become more activated at reduced preloads. The models suggested that myosin kinetics may underlie the increase in MCR at reduced preload, an effect that can be enhanced by force-dependence. Relaxation can be modified and enhanced by reduced preload. Computational modeling implicates myosin-based targets for treatment of diastolic dysfunction, but further model refinements are needed to fully replicate experimental data. 2021-05-18 2021-08-15 /pmc/articles/PMC8635462/ /pubmed/34015323 http://dx.doi.org/10.1016/j.abb.2021.108909 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Schick, Brianna M.
Dlugas, Hunter
Czeiszperger, Teresa L.
Matus, Alexandra R.
Bukowski, Melissa J.
Chung, Charles S.
Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics
title Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics
title_full Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics
title_fullStr Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics
title_full_unstemmed Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics
title_short Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics
title_sort reduced preload increases mechanical control (strain-rate dependence) of relaxation by modifying myosin kinetics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635462/
https://www.ncbi.nlm.nih.gov/pubmed/34015323
http://dx.doi.org/10.1016/j.abb.2021.108909
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