Modulation of Cardiac Twitch Dynamics by the Troponin I Inhibitory Region

Abstract

We have created a computational model of cardiac thin filament regulation that includes a representation of the troponin I inhibitory region (or inhibitory peptide, IP) and its binding interactions with actin. According to a canonical view of thin filament activation, IP-actin binding prevents movement of tropomyosin out of its blocked position under low Ca^(2+) conditions. Ca^(2+) binding to troponin C (TnC) causes dissociation of the IP from actin, and permits tropomyosin transition. Instead of assuming that IP-actin interactions are infinitely strong in the absence of Ca^(2+), our model allows some spontaneous IP-actin dissociation. We have used the energetic cost of Ca^(2+)-free dissociation (ΔG) as a free parameter to determine whether the model can recapitulate changes to the IP. For instance, lowering ΔG while keeping all other model parameters constant increases the Ca^(2+) sensitivity of steady-state force in model simulations. These model results closely resemble experiments in which the IP is mutated (T144P; Tachampa et al., Circ Res 101:1081, 2007). We hypothesize that alterations to the IP in the form of cardiomyopathic mutations or phosphorylation have the ability to tune the dynamic Ca^(2+) sensitivity of cardiac muscle, altering the magnitude and time course of twitches. Twitch simulations demonstrate that lowering ΔG from infinity to 6.75 kJ/mol increases the magnitude and duration of contraction by 17 and 20%, respectively. These results suggest that twitch dynamics can be modified substantially by the energy of IP-actin binding. They further suggest that the model can be used to explore the effects of IP mutations and posttranslational modifications.