Mechano-Chemical Interactions in the Isotonic Twitch: A Modeling Study

Lauren Dupuis, Joost Lumens, Theo Arts, Tammo Delhaas
Maastricht University


Abstract

Sarcomeres, the most basic functional unit of cardiac contraction, are com-posed of thick and thin filaments. Calcium ions bind to troponin complexes on thin filaments, triggering conformational changes that unblock binding sites. Myosin heads protruding from thick filaments can bind to unblocked sites, forming cross-bridges (XB) that can generate force. Relatively small increases in intracellular calcium concentration result in disproportionately large increases in muscle force, implying cooperativity. We have previously proposed an intrinsic chemical cooperativity in the thin filament that is boosted by mechanical tension due to its hindering effect on the release of calcium from the troponin complex, thereby delaying relaxation. With the MechChem model of mechano-chemical interactions in cardiac sarcomere contractions, developed based on our proposed cooperativity mechanism, we could simulate steady-state isometric twitch experiments. In the current study, we have further developed the MechChem model to simulate isotonic twitch experiments in which the sarcomere can contract and shorten against an afterload. The model comprises of a two-state thin filament activation model and a two-state XB cycle model, whereas the sarcomere is represented as two elements, a series elastic element and a contractile element that changes in length. The MechChem model-generated tension traces mimicked experimental results in duration of contraction, whereas simulated sarcomere length curves reproduced the degree of experimental sarcomere shortening. The longest isotonic twitch duration was observed in the sarcomere contracting against the largest afterload due to the tension-dependent cooperativity mechanism in the MechChem model, i.e. high tension hindering relaxation. Our simulations demonstrate that the MechChem model successfully generates isotonic twitches, and therefore offers a relatively fast and realistic physiology-based computational description of sarcomere contraction.