Phase Dependent Mechanosensitivity in Cardiomyocytes

Abstract

Cardiomyocytes are mechanosensitive. In the functioning heart, discrete sets of cardiac oscillators maintain stable relative phase dynamics and mechanical coupling between each other through the elastic tissue. A few questions that remains elusive to date are, how strong is the coupling and how tunable is their dynamics, whether this coupling is phase dependent, and if so, at what phase of cardiac dynamics is the coupling most dominant. In other words, at which phase of its dynamics a cardiac cell is most sensitive to forces and deformations induced by its neighbors. Here we address these questions by culturing rat cardiomyocytes on a stretchable substrate. We apply cyclic stretch on the substrate with a range of frequencies in the vicinity of the intrinsic beating frequency of the cell cluster. We find that the cell cluster can synchronize its dynamics with that of the substrate within 25% of its intrinsic frequency in less than a minute. However, it takes much longer time to return to its intrinsic frequency after removal of substrate stretch. With increasing substrate frequency, the cluster tends to catch up, and beats with a range of frequencies between the intrinsic and the applied with wide variation in relative phases. This allows us to measure phase dependent mechano-sensitivity of the cardiac cluster to the periodic deformation of the substrate that is critical to produce stable relative phase dynamics. We find that cardiac cells are most mechano sensitive when they are at 1/2 of their phase. This phase dependence might be mediated by the ion channels active at this phase of the dynamics. This study identifies a functional output of sub-second scale mechanotransduction with the potential to enhance or reinforce cardiac contractile dynamics.