Enhancing diastolic function by strain-dependent detachment of cardiac myosin crossbridges

Bradley M. Palmer; Douglas M. Swank; Mark S. Miller; Bertrand C.W. Tanner; Markus Meyer; Martin M. LeWinter

doi:10.1085/jgp.201912484

Enhancing diastolic function by strain-dependent detachment of cardiac myosin crossbridges

Bradley M. Palmer, Douglas M. Swank, Mark S. Miller, Bertrand C.W. Tanner, Markus Meyer, Martin M. LeWinter

Medicine - Cardiology Division

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Abstract

The force response of cardiac muscle undergoing a quick stretch is conventionally interpreted to represent stretching of attached myosin crossbridges (phase 1) and detachment of these stretched crossbridges at an exponential rate (phase 2), followed by crossbridges reattaching in increased numbers due to an enhanced activation of the thin filament (phases 3 and 4). We propose that, at least in mammalian cardiac muscle, phase 2 instead represents an enhanced detachment rate of myosin crossbridges due to stretch, phase 3 represents the reattachment of those same crossbridges, and phase 4 is a passive-like viscoelastic response with power-law relaxation. To test this idea, we developed a two-state model of crossbridge attachment and detachment. Unitary force was assigned when a crossbridge was attached, and an elastic force was generated when an attached crossbridge was displaced. Attachment rate, f(x), was spatially distributed with a total magnitude f0. Detachment rate was modeled as g(x) = g0+ g1x, where g0 is a constant and g1 indicates sensitivity to displacement. The analytical solution suggested that the exponential decay rate of phase 2 represents (f0 + g0) and the exponential rise rate of phase 3 represents g0. The depth of the nadir between phases 2 and 3 is proportional to g1. We prepared skinned mouse myocardium and applied a 1% stretch under varying concentrations of inorganic phosphate (Pi). The resulting force responses fitted the analytical solution well. The interpretations of phases 2 and 3 were consistent with lower f0 and higher g0 with increasing Pi. This novel scheme of interpreting the force response to a quick stretch does not require enhanced thin-filament activation and suggests that the myosin detachment rate is sensitive to stretch. Furthermore, the enhanced detachment rate is likely not due to the typical detachment mechanism following MgATP binding, but rather before MgADP release, and may involve reversal of the myosin power stroke.

Original language	English (US)
Article number	e201912484
Journal	The Journal of general physiology
Volume	152
Issue number	4
DOIs	https://doi.org/10.1085/jgp.201912484
State	Published - Apr 6 2020

Bibliographical note

Funding Information:
This research was supported by grants from the National Institutes of Health (R01 HL-118524, M.M. LeWinter; R01 HL-122744, M. Meyer), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR064274, D.M. Swank), the American Heart Association (17SDG33370153, B.C.W. Tanner), and the National Science Foundation (1660908, B.M. Palmer; 1656450, B.C.W. Tanner). The authors declare no competing financial interests.

Publisher Copyright:
© 2020 Palmer et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1085/jgp.201912484

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title = "Enhancing diastolic function by strain-dependent detachment of cardiac myosin crossbridges",

abstract = "The force response of cardiac muscle undergoing a quick stretch is conventionally interpreted to represent stretching of attached myosin crossbridges (phase 1) and detachment of these stretched crossbridges at an exponential rate (phase 2), followed by crossbridges reattaching in increased numbers due to an enhanced activation of the thin filament (phases 3 and 4). We propose that, at least in mammalian cardiac muscle, phase 2 instead represents an enhanced detachment rate of myosin crossbridges due to stretch, phase 3 represents the reattachment of those same crossbridges, and phase 4 is a passive-like viscoelastic response with power-law relaxation. To test this idea, we developed a two-state model of crossbridge attachment and detachment. Unitary force was assigned when a crossbridge was attached, and an elastic force was generated when an attached crossbridge was displaced. Attachment rate, f(x), was spatially distributed with a total magnitude f0. Detachment rate was modeled as g(x) = g0+ g1x, where g0 is a constant and g1 indicates sensitivity to displacement. The analytical solution suggested that the exponential decay rate of phase 2 represents (f0 + g0) and the exponential rise rate of phase 3 represents g0. The depth of the nadir between phases 2 and 3 is proportional to g1. We prepared skinned mouse myocardium and applied a 1% stretch under varying concentrations of inorganic phosphate (Pi). The resulting force responses fitted the analytical solution well. The interpretations of phases 2 and 3 were consistent with lower f0 and higher g0 with increasing Pi. This novel scheme of interpreting the force response to a quick stretch does not require enhanced thin-filament activation and suggests that the myosin detachment rate is sensitive to stretch. Furthermore, the enhanced detachment rate is likely not due to the typical detachment mechanism following MgATP binding, but rather before MgADP release, and may involve reversal of the myosin power stroke.",

author = "Palmer, {Bradley M.} and Swank, {Douglas M.} and Miller, {Mark S.} and Tanner, {Bertrand C.W.} and Markus Meyer and LeWinter, {Martin M.}",

note = "Funding Information: This research was supported by grants from the National Institutes of Health (R01 HL-118524, M.M. LeWinter; R01 HL-122744, M. Meyer), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR064274, D.M. Swank), the American Heart Association (17SDG33370153, B.C.W. Tanner), and the National Science Foundation (1660908, B.M. Palmer; 1656450, B.C.W. Tanner). The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2020 Palmer et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).",

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AU - Meyer, Markus

AU - LeWinter, Martin M.

N1 - Funding Information: This research was supported by grants from the National Institutes of Health (R01 HL-118524, M.M. LeWinter; R01 HL-122744, M. Meyer), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR064274, D.M. Swank), the American Heart Association (17SDG33370153, B.C.W. Tanner), and the National Science Foundation (1660908, B.M. Palmer; 1656450, B.C.W. Tanner). The authors declare no competing financial interests. Publisher Copyright: © 2020 Palmer et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

PY - 2020/4/6

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N2 - The force response of cardiac muscle undergoing a quick stretch is conventionally interpreted to represent stretching of attached myosin crossbridges (phase 1) and detachment of these stretched crossbridges at an exponential rate (phase 2), followed by crossbridges reattaching in increased numbers due to an enhanced activation of the thin filament (phases 3 and 4). We propose that, at least in mammalian cardiac muscle, phase 2 instead represents an enhanced detachment rate of myosin crossbridges due to stretch, phase 3 represents the reattachment of those same crossbridges, and phase 4 is a passive-like viscoelastic response with power-law relaxation. To test this idea, we developed a two-state model of crossbridge attachment and detachment. Unitary force was assigned when a crossbridge was attached, and an elastic force was generated when an attached crossbridge was displaced. Attachment rate, f(x), was spatially distributed with a total magnitude f0. Detachment rate was modeled as g(x) = g0+ g1x, where g0 is a constant and g1 indicates sensitivity to displacement. The analytical solution suggested that the exponential decay rate of phase 2 represents (f0 + g0) and the exponential rise rate of phase 3 represents g0. The depth of the nadir between phases 2 and 3 is proportional to g1. We prepared skinned mouse myocardium and applied a 1% stretch under varying concentrations of inorganic phosphate (Pi). The resulting force responses fitted the analytical solution well. The interpretations of phases 2 and 3 were consistent with lower f0 and higher g0 with increasing Pi. This novel scheme of interpreting the force response to a quick stretch does not require enhanced thin-filament activation and suggests that the myosin detachment rate is sensitive to stretch. Furthermore, the enhanced detachment rate is likely not due to the typical detachment mechanism following MgATP binding, but rather before MgADP release, and may involve reversal of the myosin power stroke.

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Enhancing diastolic function by strain-dependent detachment of cardiac myosin crossbridges

Abstract

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