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Cardiomyocytes Sense Matrix Rigidity through a Combination of Muscle and Non-muscle Myosin Contractions

Pragati Pandey, William Hawkes, Junquiang Hu, William Valentine Megone, Julien Gautrot, Narayana Anilkumar, Min Zhang, Liisa Hirvonen, Susan Cox, Elisabeth Ehler, James Hone, Michael Sheetz and Thomas Iskratsch

Abstract

Mechanical properties are cues for many biological processes in health or disease. In the heart, changes to the extracellular matrix composition and crosslinking result in stiffening of the cellular microenvironment during development. Moreover, myocardial infarction and cardiomyopathies lead to fibrosis and a stiffer environment, affecting cardiomyocyte behavior. Here, we identify that single cardiomyocyte adhesions sense simultaneous (fast oscillating) cardiac and (slow) non-muscle myosin contractions. Together, these lead to oscillating tension on the mechanosensitive adaptor protein talin on substrates with a stiffness of healthy adult heart tissue, compared with no tension on embryonic heart stiff-ness and continuous stretching on fibrotic stiffness. Moreover, we show that activation of PKC leads to the induction of cardiomyocyte hypertrophy in a stiffness-dependent way, through activation of non-muscle myosin. Finally, PKC and non-muscle myosin are upregulated at the costameres in heart disease, indicating aberrant mechanosensing as a contributing factor to long-term remodeling and heart failure.

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