Cardiac hypertrophy is associated with diastolic heart failure (DHF), a syndrome in which systolic function is preserved but cardiac filling dynamics are depressed. The molecular mechanisms underlying DHF and the potential role of altered cross-bridge cycling are poorly understood. Accordingly, chronic pressure overload was induced by surgically banding the thoracic ascending aorta (AOB) in ∼400 g female Dunkin Hartley guinea pigs (AOB); Sham-operated age-matched animals served as controls. Guinea pigs were chosen to avoid the confounding impacts of altered myosin heavy chain (MHC) isoform expression seen in other small rodent models. In vivo cardiac function was assessed by echocardiography; cardiac hypertrophy was confirmed by morphometric analysis. AOB resulted in left ventricle (LV) hypertrophy and compromised diastolic function with normal systolic function. Biochemical analysis revealed exclusive expression of β-MHC isoform in both sham control and AOB LVs. Myofilament function was assessed in skinned multicellular preparations, skinned single myocyte fragments, and single myofibrils prepared from frozen (liquid N2) LVs. The rates of force-dependent ATP consumption (tension-cost) and force redevelopment (Ktr), as well as myofibril relaxation time (Timelin) were significantly blunted in AOB, indicating reduced cross-bridge cycling kinetics. Maximum Ca2+ activated force development was significantly reduced in AOB myocytes, while no change in myofilament Ca2+ sensitivity was observed. Our results indicate blunted cross-bridge cycle in a β-MHC small animal DHF model. Reduced cross-bridge cycling kinetics may contribute, at least in part, to the development of DHF in larger mammals, including humans.
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5 June 2023
Article|
Myofilament Function 2022|
April 27 2023
Depressed myocardial cross-bridge cycling kinetics in a female guinea pig model of diastolic heart failure
Sukriti Dewan
,
Sukriti Dewan
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Software, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Physiology and Biophysics,
College of Medicine, University of Illinois at Chicago
, Chicago, IL, USA
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
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Namthip Witayavanitkul
,
Namthip Witayavanitkul
(Conceptualization, Formal analysis, Investigation, Validation)
1Department of Physiology and Biophysics,
College of Medicine, University of Illinois at Chicago
, Chicago, IL, USA
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
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Mohit Kumar
,
Mohit Kumar
(Formal analysis, Investigation)
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
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Beth J. Mayer
,
Beth J. Mayer
(Data curation)
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
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Lauren Betancourt
,
Lauren Betancourt
(Formal analysis)
3
Phymedexp INSERM, CNRS, University of Montpellier
, Montpellier, France
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Olivier Cazorla
,
Olivier Cazorla
(Writing - original draft, Writing - review & editing)
3
Phymedexp INSERM, CNRS, University of Montpellier
, Montpellier, France
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Pieter P. de Tombe
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Physiology and Biophysics,
College of Medicine, University of Illinois at Chicago
, Chicago, IL, USA
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
3
Phymedexp INSERM, CNRS, University of Montpellier
, Montpellier, France
Correspondence to Pieter P. de Tombe: pdetombe@uic.edu
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Sukriti Dewan
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Physiology and Biophysics,
College of Medicine, University of Illinois at Chicago
, Chicago, IL, USA
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
Namthip Witayavanitkul
Conceptualization, Formal analysis, Investigation, Validation
1Department of Physiology and Biophysics,
College of Medicine, University of Illinois at Chicago
, Chicago, IL, USA
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
Mohit Kumar
Formal analysis, Investigation
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
Beth J. Mayer
Data curation
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
Lauren Betancourt
Formal analysis
3
Phymedexp INSERM, CNRS, University of Montpellier
, Montpellier, France
Olivier Cazorla
Writing - original draft, Writing - review & editing
3
Phymedexp INSERM, CNRS, University of Montpellier
, Montpellier, France
Pieter P. de Tombe
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Physiology and Biophysics,
College of Medicine, University of Illinois at Chicago
, Chicago, IL, USA
2Department of Cell and Molecular Physiology,
Stritch School of Medicine, Loyola University Chicago
, Maywood, IL, USA
3
Phymedexp INSERM, CNRS, University of Montpellier
, Montpellier, France
Correspondence to Pieter P. de Tombe: pdetombe@uic.edu
Disclosures: The authors declare no competing interests exist.
This work is part of a special issue on Myofilament Function 2022.
Received:
October 28 2022
Revision Received:
February 10 2023
Accepted:
April 17 2023
Online ISSN: 1540-7748
Print ISSN: 0022-1295
Funding
Funder(s):
National Institutes of Health
- Award Id(s): P01-HL062426
© 2023 Dewan et al.
2023
Dewan 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/).
J Gen Physiol (2023) 155 (6): e202213288.
Article history
Received:
October 28 2022
Revision Received:
February 10 2023
Accepted:
April 17 2023
Citation
Sukriti Dewan, Namthip Witayavanitkul, Mohit Kumar, Beth J. Mayer, Lauren Betancourt, Olivier Cazorla, Pieter P. de Tombe; Depressed myocardial cross-bridge cycling kinetics in a female guinea pig model of diastolic heart failure. J Gen Physiol 5 June 2023; 155 (6): e202213288. doi: https://doi.org/10.1085/jgp.202213288
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