Acute Optogenetic Modulation of Cardiac Twitch Dynamics Explored Through Modeling

Abstract

Optogenetic approaches allow cellular membrane potentials to be perturbed by light. When applied to muscle cells, mechanical events can be controlled through a process that could be termed “optomechanics.” Besides functioning as an optical on/off switch, we hypothesized that optomechanical control could include the ability to manipulate the strength and duration of contraction events. To explore this possibility, we constructed an electromechanical model of the human ventricular cardiomyocyte while adding a representation of channelrhodopsin-2 (ChR2), a light-activated channel commonly used in optogenetics. Two hybrid stimulus protocols were developed that combined light-based stimuli with traditional electrical current (all-or-none) excitation. The first protocol involved delivery of a subthreshold optical stimulus followed 50–90 ms later by an electrical stimulus. The result was a graded inhibition of peak cellular twitch force in concert with a prolongation of the intracellular Ca2+ transient. The second protocol was comprised of an electrical stimulus followed by a long light pulse (250–350 ms) that acted to prolong the cardiac action potential (AP). This created a pulse duration-dependent prolongation of the intracellular Ca2+ transient that in turn altered the rate of muscle relaxation without changing peak twitch force. These results illustrate the feasibility of acute, optomechanical manipulation of cardiomyocyte contraction and suggest that this approach could be used to probe the dynamic behavior of the cardiac sarcomere without altering its intrinsic properties. Other experimentally meaningful stimulus protocols could be designed by making use of the optomechanical cardiomyocyte model presented here.