Simulating Cardiac Muscle Mutations in a Compliant Lattice with Commonly Used Assays

Abstract

Cardiac muscle cells consist of a highly organized filament lattice with repetitive structure. Both inter- and intra-filament interactions control muscle activation and relaxation, and even small perturbations of these interactions can result in the development of cardiomyopathies. Building on an existing spatially explicit computational model of muscle contraction at the half-sarcomere level, we simulated different mutations by changing model parameters using published biochemical or biomechanical data. Importantly, we added the ability to specify profiles of protein properties and their frequency (penetrance) within the model. We assigned the mutant properties to a portion of the proteins, with the remainder retaining wildtype properties. The current model consists of 8 thin filaments, with a four state cardiac troponin-tropomyosin regulation cycle, determining accessibility of actin binding sites for myosin motor heads arising from the 4 thick filaments. Upon binding, the myosin motors follow a three-state model of the crossbridge cycle to generate axial tension. We simulated the cardiac troponin c (cTnC) mutation L48Q, which has increased calcium binding affinity, and the non-functional cTnC mutation D65A, which prevents calcium from binding at site II (contraction trigger site). Additionally, we co-varied cross-bridge cycle transition rates, increasing the attachment rate and decreasing the detachment rates to simulate the effect of myosin mutations, to study how this affected contraction with different dosages of L48Q. We simulated isometric twitch force, the force-pCa relationship, and filament material properties assays. For the isometric twitches, we specified a calcium transient derived from published intra-lattice measurements. Our results show emergent contractile dynamics similar to the respective experimental phenotypes. L48Q, with increasing penetrance, increases calcium sensitivity and linearly increases maximum tension, as well as time at maximum tension. D65A decreases maximum tension, and our myosin treatment increases maximum tension, and slows relaxation.