Optogenetic actuation in ChR2-transduced fibroblasts alter excitation-contraction coupling and mechano-electric feedback in coupled cardiomyocytes: a computational modeling study

Abstract

With the help of the conventional electrical method and the growing optogenetic technology, cardiac fibroblasts (Fbs) have been verified to couple electrically with working myocytes and bring electrophysiological remodeling changes in them. The intrinsic properties of cardiac functional autoregulation represented by excitation-contraction coupling (ECC) and mechano-electric feedback (MEF) have also been extensively studied. However, the roles of optogenetic stimulation on the characteristics of ECC and MEF in cardiomyocytes (CMs) coupled with Fbs have been barely investigated. In this study, we proposed a combined model composed of three modules to explore these influences. Simulation results showed that (1) during ECC, an increased light duration (LD) strengthened the inflow of ChR2 current and prolonged action potential duration (APD), and extended durations of twitch and internal sarcomere deformation through the decreased dissociation of calcium with troponin C (CaTnC) complexes and the prolonged duration of Xb attachment-detachment; (2) during MEF, an increased LD was followed by a longer muscle twitch and deformation, and led to APD prolongation through the inward ChR2 current and its inward rectification kinetics, which far outweighed the effects of the delaying dissociation of CaTnC complexes and the prolonged reverse mode of Na+-Ca2+ exchange on AP shortening; (3) due to the ChR2 current's rectification feature, enhancing the light irradiance (LI) brought slight variations in peak or valley values of electrophysiological and mechanical parameters while did not change durations of AP and twitch and muscle deformation in both ECC and MEF. In conclusion, the inward ChR2 current and its inward rectification feature were found to affect significantly the durations of AP and twitch in both ECC and MEF. The roles of optogenetic actuation on both ECC and MEF should be considered in future cardiac computational optogenetics at the tissue and organ scale.

Keywords

• optogenetics
• cardiomyocyte
• fibroblast
• excitation-contraction coupling
• mechano- electric feedback
• computational modeling