Cardiac muscle regulatory units are predicted to interact stronger than neighboring cross-bridges
Mari Kalda, Marko Vendelin
Sci Rep, 2020 Mar 26; 10(1): 5530.
- PMID: 32218497
- DOI: 10.1038/s41598-020-62452-7
Significance
Heart muscle cells respond steeply to small increases in calcium, allowing the heart to regulate its force of contraction. This published paper developed a thermodynamically consistent computer model to identify which molecular interactions produce that cooperative response. The model shows that interactions between neighboring regulatory units have about five times the effect on the energy landscape of contraction as interactions between cross-bridges. By reproducing force, shortening, and ATP-use measurements, the model provides a framework for studying how molecular changes in cardiac muscle can affect the whole heart.
Abstract
Strong interactions between cross-bridges (XB) and regulatory units (RU) lead to a steep response of cardiac muscle to an increase in intracellular calcium. We developed a model to quantitatively assess the influence of different types of interactions within the sarcomere on the properties of cardiac muscle. In the model, the ensembles consisting of cross-bridge groups connected by elastic tropomyosin are introduced, and their dynamics is described by a set of partial differential equations. Through large scans in the free energy landscape, we demonstrate the different influence of RU-RU, XB-XB, and XB-RU interactions on the cooperativity coefficient of calcium binding, developed maximal force, and calcium sensitivity. The model solution was fitted to reproduce experimental data on force development during isometric contraction, shortening in physiological contraction, and ATP consumption by acto-myosin. On the basis of the fits, we quantified the free energy change introduced through RU-RU and XB-XB interactions and showed that RU-RU interaction leads to ~ 5 times larger change in the free energy profile of the reaction than XB-XB interaction. Due to the deterministic description of muscle contraction and its thermodynamic consistency, we envision that the developed model can be used to study heart muscle biophysics on tissue and organ levels.