ReviewJournal of molecular and cellular cardiology2010
The molecular basis of the steep force-calcium relation in heart muscle.
Review in Journal of molecular and cellular cardiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- CaJournal of molecular and cellular cardiology · 2025Article
- Molecular determinants of skeletal muscle force loss in response to 5 days of dry immersion in human.Journal of cachexia, sarcopenia and muscle · 2024Article
- Using a Failing Human Ventricular Cardiomyocyte Model to Re-Evaluate CaBiomolecules · 2024Article
- Exosomal Preconditioning of Human iPSC-Derived Cardiomyocytes Beneficially Alters Cardiac Electrophysiology and Micro RNA Expression.International journal of molecular sciences · 2024Article
- Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects.Acta neuropathologica · 2024Article
- AnBioMed research international · 2024Article
- Advancing clinical translation of cardiac biomechanics models: a comprehensive review, applications and future pathways.Frontiers in physics · 2023Article
- Local Control Model of a Human Ventricular Myocyte: An Exploration of Frequency-Dependent Changes and Calcium Sparks.Biomolecules · 2023Article
- The Role of CaBiomolecules · 2022Article
- Monoclonal Antibodies as Probes to Study Ligand-Induced Conformations of Troponin Subunits.Frontiers in physiology · 2022Article
- Functional and Molecular Characterisation of Heart Failure Progression in Mice and the Role of Myosin Regulatory Light Chains in the Recovery of Cardiac Muscle Function.International journal of molecular sciences · 2021Article
- In-silico human electro-mechanical ventricular modelling and simulation for drug-induced pro-arrhythmia and inotropic risk assessment.Progress in biophysics and molecular biology · 2021Article
- Computationally efficient model of myocardial electromechanics for multiscale simulations.PloS one · 2021Article
- Omecamtiv Mecarbil: A Novel Mechanistic and Therapeutic Approach to Chronic Heart Failure Management.Cureus · 2021Review
- Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients.American journal of medical genetics. Part A · 2018Article
- Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil.Drugs in context · 2018Review
- Functional significance of C-terminal mobile domain of cardiac troponin I.Archives of biochemistry and biophysics · 2017Article
- A Spatially Detailed Model of Isometric Contraction Based on Competitive Binding of Troponin I Explains Cooperative Interactions between Tropomyosin and Crossbridges.PLoS computational biology · 2015Article
- Pathomechanisms in heart failure: the contractile connection.Journal of muscle research and cell motility · 2015Review
- Mechanical aberrations in hypetrophic cardiomyopathy: emerging concepts.Frontiers in physiology · 2015Article
Corrections and comments
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Authors and funding
2 authors.
Funding
Abstract
Contraction of heart muscle is regulated by binding of Ca(2+) ions to troponin in the muscle thin filaments, causing a change in filament structure that allows myosin binding and force generation. The steady-state relationship between force and Ca(2+) concentration in demembranated ventricular trabeculae is well described by the Hill equation, with parameters EC(50), the Ca(2+) concentration that gives half the maximum force, and n(H), the Hill coefficient describing the steepness of the Ca(2)(+) dependence. Although each troponin molecule has a single regulatory Ca(2+) site, n(H) is typically around 3, indicating co-operativity in the regulatory mechanism. This review focuses on the molecular basis of this co-operativity, and in particular on the popular hypothesis that force-generating myosin cross-bridges are responsible for the effect. Although cross-bridges can switch on thin filaments at low MgATP concentrations, we argue that the evidence from contracting heart muscle cells shows that this mechanism does not operate in more physiological conditions, and would not play a significant role in the intact heart. Interventions that alter maximum force and EC(50) do not in general produce a significant change in n(H). Complete abolition of force generation by myosin inhibitors does not affect the n(H) values for either Ca(2+) binding to the thin filaments or changes in troponin structure, and both values match that for force generation in the absence of inhibitors. These results provide strong evidence that the co-operative mechanism underlying the high value of n(H) is not due to force-generating cross-bridges but is rather an intrinsic property of the thin filaments.
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