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Published on: May 19, 2021
Mathematical model for β1-adrenergic regulation of the mouse ventricular myocyte contraction
Paula D Mullins1,2, Vladimir E Bondarenko2
1Department of Mathematics, University of North Georgia, Blue Ridge, Georgia.
Insights
A new mathematical model simulates cardiac myocyte contraction, revealing β1-adrenergic receptor mechanisms. This tool aids in understanding heart function and disease, predicting drug effects on contractility.
Area of Science:
- Cardiovascular Physiology
- Computational Biology
- Pharmacology
Background:
- β1-adrenergic signaling regulates cardiac contraction, impacting heart rate and force.
- Chronic β1-adrenergic stimulation can lead to detrimental cardiac remodeling, including hypertrophy and heart failure.
- Understanding the precise molecular mechanisms of β1-adrenoceptor action is crucial for developing targeted therapies.
Purpose of the Study:
- To develop and validate a mathematical model of cardiac myocyte contraction incorporating the β1-adrenergic system.
- To elucidate the mechanisms underlying enhanced myocyte contraction upon β1-adrenergic receptor stimulation.
- To utilize the model for simulating drug effects and predicting cardiac function in disease states.
Main Methods:
- Development of a mathematical model of mouse ventricular myocyte contraction.
- Simulation of key experimental protocols: force-calcium relationships, cross-bridge kinetics, force-velocity relationships, and force redevelopment.
- Validation against experimental data for frequency and isoproterenol dependencies of Ca2+ transients and contraction parameters.
Main Results:
- The model accurately reproduced experimental data for various contraction parameters and β1-adrenergic stimulation effects.
- Model simulations suggested that phosphorylation of troponin I and myosin-binding protein C, along with increased intracellular Ca2+ transients, mediates enhanced contraction.
- The model successfully predicted the effects of 4-aminopyridine and tedisamil on myocyte contraction and allowed for work-loop simulations.
Conclusions:
- The developed mathematical model provides a robust platform for studying β1-adrenergic regulation of cardiac myocyte contraction.
- The model offers insights into the molecular mechanisms driving β1-adrenergic-mediated increases in cardiac contractility.
- This computational tool holds potential for future research involving genetically modified models and disease states.
Abstract:
The β1-adrenergic regulation of cardiac myocyte contraction plays an important role in regulating heart function. Activation of this system leads to an increased heart rate and stronger myocyte contraction. However, chronic stimulation of the β1-adrenergic signaling system can lead to cardiac hypertrophy and heart failure. To understand the mechanisms of action of β1-adrenoceptors, a mathematical model of cardiac myocyte contraction that includes the β1-adrenergic system was developed and studied. The model was able to simulate major experimental protocols for measurements of steady-state force-calcium relationships, cross-bridge release rate and force development rate, force-velocity relationship, and force redevelopment rate. It also reproduced quite well frequency and isoproterenol dependencies for intracellular Ca2+ concentration ([Ca2+]i) transients, total contraction force, and sarcomere shortening. The mathematical model suggested the mechanisms of increased contraction force and myocyte shortening on stimulation of β1-adrenergic receptors is due to phosphorylation of troponin I and myosin-binding protein C and increased [Ca2+]i transient resulting from activation of the β1-adrenergic signaling system. The model was used to simulate work-loop contractions and estimate the power during the cardiac cycle as well as the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The developed mathematical model can be used further for simulations of contraction of ventricular myocytes from genetically modified mice and myocytes from mice with chronic cardiac diseases.NEW & NOTEWORTHY A new mathematical model of mouse ventricular myocyte contraction that includes the β1-adrenergic system was developed. The model simulated major experimental protocols for myocyte contraction and predicted the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The model also allowed for simulations of work-loop contractions and estimation of the power during the cardiac cycle.
