Stochastic tug-of-war among sarcomeres mediates cardiomyocyte response to environmental stiffness


Haertter D, Hauke L, Driehorst T, Nishi K, Zimmermann WH, Schmidt CF




bioRxiv 2024.05.28.596183.


Cardiac muscle function emerges from the coordinated contraction of sarcomeres in cardiomyocytes. Sarcomere dynamics are usually inferred from whole-cell or myofibril observations, assuming synchronized, uniform behavior. Here, we investigated how different mechanical properties of the cell environment affect contraction at both the sarcomere and cell level. Human induced pluripotent stem cell-derived cardiomyocytes with fluorescently labeled Z-bands were cultured individually on patterned elastic substrates (5 – 85 kPa). Sarcomere dynamics were precisely tracked and analyzed using SarcAsM, a machine learning algorithm we developed. Increasingly stiff substrates inhibited overall cardiomyocyte contraction, but, surprisingly, did not diminish individual sarcomere dynamics. Instead, sarcomeres competed in a tug-of-war with increasing heterogeneity, exhibiting rich dynamic phenomena such as rapid length oscillations and overextensions (popping). Statistical analysis showed that the heterogeneous dynamics were not caused by static structural differences, but were largely stochastic. This stochastic heterogeneity is thus an intrinsic property of cardiac sarcomere dynamics and is likely to be crucial for the adaptation of emergent cardiomyocyte contractility to mechanical constraints from its environment.Competing Interest StatementWHZ is an uncompensated member of the boards of directors of Repairon GmbH and ksilink. WHZ is founder and holds equity of myriamed GmbH and Repairon GmbH. No research funding has been provided by these companies for the reported work.