High tension in sarcomeres hinders myocardial relaxation: A computational study

• Published in: PloS one Vol. 13; no. 10; p. e0204642
• Main Authors: Dupuis, Lauren J, Lumens, Joost, Arts, Theo, Delhaas, Tammo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.10.2018; Public Library of Science (PLoS)
• Subjects: Animals; Binding; Biology and Life Sciences; Biomedical engineering; Biophysics; Calcium; Calcium (intracellular); Calcium - metabolism; Calcium content; Calcium ions; Calcium-binding protein; Care and treatment; Computation; Computer applications; Computer Simulation; Contraction; Deactivation; Engineering; Engineering and Technology; Health aspects; Heart; Heart - physiology; Heart function; Humans; Hypotheses; Intracellular; Isometric; Medicine and Health Sciences; Molecular biology; Muscle contraction; Muscle Contraction - physiology; Muscle Relaxation - physiology; Muscles; Myocardial Contraction - physiology; Myocardial diseases; Myocardium - metabolism; Physical Sciences; Physiology; Prolongation; Research and Analysis Methods; Rodents; Sarcomeres; Sarcomeres - physiology; Stress (Psychology); Tension; Time dependence; Troponin; Troponin - metabolism; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0204642

Experiments have shown that the relaxation phase of cardiac sarcomeres during an isometric twitch is prolonged in muscles that reached a higher peak tension. However, the mechanism is not completely understood. We hypothesize that the binding of calcium to troponin is enhanced by the tension in the thin filament, thus contributing to the prolongation of contraction upon higher peak tension generation. To test this hypothesis, we developed a computational model of sarcomere mechanics that incorporates tension-dependence of calcium binding. The model was used to simulate isometric twitch experiments with time dependency in the form of a two-state cross-bridge cycle model and a transient intracellular calcium concentration. In the simulations, peak isometric twitch tension appeared to increase linearly by 51.1 KPa with sarcomere length from 1.9 μm to 2.2 μm. Experiments showed an increase of 47.3 KPa over the same range of sarcomere lengths. The duration of the twitch also increased with both sarcomere length and peak intracellular calcium concentration, likely to be induced by the inherently coupled increase of the peak tension in the thin filament. In the model simulations, the time to 50% relaxation (tR50) increased over the range of sarcomere lengths from 1.9 μm to 2.2 μm by 0.11s, comparable to the increased duration of 0.12s shown in experiments. Model simulated tR50 increased by 0.12s over the range of peak intracellular calcium concentrations from 0.87 μM to 1.45 μM. Our simulation results suggest that the prolongation of contraction at higher tension is a result of the tighter binding of Ca2+ to troponin in areas under higher tension, thus delaying the deactivation of the troponin.