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The actomyosin cortex is an active material that provides animal cells with a strong but flexible exterior whose mechanics, including non-Gaussian fluctuations and occasional large displacements or cytoquakes, have defied explanation. We study the active fluctuations of the cortex using nanoscale tracking of arrays of flexible microposts adhered to multiple cultured cell types. When the confounding effects of static heterogeneity and tracking error are removed, the fluctuations are found to be heavy tailed and well described by a truncated Lévy α-stable distribution over a wide range of timescales, in multiple cell types. The largest random displacements closely resemble the earlier-reported cytoquakes, but notably, we find these cytoquakes are not due to earthquakelike cooperative rearrangement of many cytoskeletal elements. Rather, they are indistinguishable from chance large excursions of a superdiffusive random process driven by heavy-tailed noise. The noncooperative microscopic events driving these fluctuations need not be larger than the expected elastic energy of single tensed cortical actin filaments, and the implied distribution of microscopic event energies will need to be accounted for by future models of the cytoskeleton.

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder responsible for nearly a quarter of sports-related sudden cardiac deaths. ACM cases caused by mutations in desmosome proteins lead to right ventricular enlargement, the loss of cardiomyocytes, and fibrofatty tissue replacement, disrupting electrical and mechanical stability. It is currently unknown how paracrine factors secreted by infiltrating fatty tissues affect ACM cardiomyocyte electrophysiology. Methods: A normal and a PKP2 mutant (c.971_972InsT) ACM hiPSC line were cultivated and differentiated into cardiomyocytes (CMs). Adipocytes were differentiated from human adipose stem cells, and adipocyte conditioned medium (AdCM) was collected. Optical mapping and phenotypic analyses were conducted on human iPSC-cardiomyocytes (hiPSC-CMs) cultured in cardiac maintenance medium (CMM) and either with AdCM or specific cytokines. Results: Significant differences were observed in voltage parameters such as the action potential duration (APD80, APD30), conduction velocity (CV), and CV heterogeneity. When cultured in AdCM relative to CMM, the APD80 increased and the CV decreased significantly in both groups; however, the magnitudes of changes often differed significantly between 1 and 7 days of cultivation. Cytokine exposure (IL-6, IL-8, MCP-1, CFD) affected the APD and CV in both the normal and PKP2 mutant hiPSC-CMs, with opposite effects. NF-kB signaling was also found to differ between the normal and PKP2 mutant hiPSC-CMs in response to AdCM and IL-6. Conclusions: Our study shows that hiPSC-CMs from normal and mPKP2 ACM lines exhibit distinct molecular and functional responses to paracrine factors, with differences in RNA expression and electrophysiology. These different responses to paracrine factors may contribute to arrhythmogenic propensity.