Mechanical competition leads to dynamic instabilities and heterogeneity in stem-cell derived cardiomyocytes

Cooperative and synchronized contraction of sarcomeres is important for the optimal function of cardiomyocytes. Theories of collective molecular motor dynamics, however, predict the possibility of emergent phenomena such as dynamic instabilities and spontaneous oscillatory motion due to non-monotonic force-velocity relations. We have tracked the contractions of individual sarcomeres in stem-cell derived cardiomyocytes by endogenous fluorescent labeling of α-actinin 2 using CRISPR/Cas9 technology. Cardiomyocytes were attached to micro-patterned elastic substrates with various Young’s moduli between 7 and 60 kPa. On soft substrates, sarcomeres in one cell contracted coherently, whereas contractions became increasingly incoherent and heterogeneous with increasing substrate stiffness. These findings suggest that competition between sarcomeres, enforced by rigid mechanical boundary conditions, perturbs dynamic coherence. Using a simple dynamic model, we show that elastic coupling of z-lines to the substrate in conjunction with a non-monotonic force-velocity relation can account for many of the observed features.