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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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/20/12084 |
| _version_ | 1797472866213560320 |
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| author | Alf Månsson Dilson E. Rassier |
| author_facet | Alf Månsson Dilson E. Rassier |
| author_sort | Alf Månsson |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T20:07:13Z |
| format | Article |
| id | doaj.art-e12da89fef2947bcafe862e12c69d45e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T20:07:13Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e12da89fef2947bcafe862e12c69d45e2023-11-24T00:28:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123201208410.3390/ijms232012084Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating CompoundsAlf Månsson0Dilson E. Rassier1Department of Chemistry and Biomedical Sciences, Linnaeus University, 391 82 Kalmar, SwedenDepartment of Kinesiology and Physical Education, McGill University, Montreal, QC H2W 1S4, CanadaBottom-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.https://www.mdpi.com/1422-0067/23/20/12084myosinactinmyosin-active compoundsmuscle contractionmechanokinetic modelstatistical model |
| spellingShingle | Alf Månsson Dilson E. Rassier Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds International Journal of Molecular Sciences myosin actin myosin-active compounds muscle contraction mechanokinetic model statistical model |
| 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 | myosin actin myosin-active compounds muscle contraction mechanokinetic model statistical model |
| url | https://www.mdpi.com/1422-0067/23/20/12084 |
| work_keys_str_mv | AT alfmansson insightsintomusclecontractionderivedfromtheeffectsofsmallmolecularactomyosinmodulatingcompounds AT dilsonerassier insightsintomusclecontractionderivedfromtheeffectsofsmallmolecularactomyosinmodulatingcompounds |