How Localized Z-Disc Damage Affects Force Generation and Gene Expression in Cardiomyocytes.

The proper function of cardiomyocytes (CMs) is highly related to the Z-disc, which has a pivotal role in orchestrating the sarcomeric cytoskeletal function. To better understand Z-disc related cardiomyopathies, novel models of Z-disc damage have to be developed. Human pluripotent stem cell (hPSC)-derived CMs can serve as an in vitro model to better understand the sarcomeric cytoskeleton. A femtosecond laser system can be applied for localized and defined damage application within cells as single Z-discs can be removed. We have investigated the changes in force generation via traction force microscopy, and in gene expression after Z-disc manipulation in hPSC-derived CMs. We observed a significant weakening of force generation after removal of a Z-disc. However, no significant changes of the number of contractions after manipulation were detected. The stress related gene NF-kB was significantly upregulated. Additionally, α-actinin (ACTN2) and filamin-C (FLNc) were upregulated, pointing to remodeling of the Z-disc and the sarcomeric cytoskeleton. Ultimately, cardiac troponin I (TNNI3) and cardiac muscle troponin T (TNNT2) were significantly downregulated. Our results allow a better understanding of transcriptional coupling of Z-disc damage and the relation of damage to force generation and can therefore finally pave the way to novel therapies of sarcomeric disorders.

Citation

Dominik Müller, Sören Donath, Emanuel Georg Brückner, Santoshi Biswanath Devadas, Fiene Daniel, Lara Gentemann, Robert Zweigerdt, Alexander Heisterkamp, Stefan Michael Klaus Kalies. How Localized Z-Disc Damage Affects Force Generation and Gene Expression in Cardiomyocytes. Bioengineering (Basel, Switzerland). 2021 Dec 14;8(12)

PMID: 34940366

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