A maladaptive feedback mechanism between the extracellular matrix and cytoskeleton contributes to hypertrophic cardiomyopathy pathophysiology

Viola, Helena M. and Richworth, Caitlyn and Solomon, Tanya and Chin, Ian L. and Szappanos, Henrietta Cserne and Sundararaj, Srinivasan and Shishmarev, Dmitry and Casarotto, Marco G. and Choi, Yu Suk and Hool, Livia C. (2023) A maladaptive feedback mechanism between the extracellular matrix and cytoskeleton contributes to hypertrophic cardiomyopathy pathophysiology. Communications Biology, 6 (1). ISSN 2399-3642

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Link to published document: http://doi.org/10.1038/s42003-022-04278-9

Abstract

Hypertrophic cardiomyopathy is an inherited disorder due to mutations in contractile proteins that results in a stiff, hypercontractile myocardium. To understand the role of cardiac stiffness in disease progression, here we create an in vitro model of hypertrophic cardiomyopathy utilizing hydrogel technology. Culturing wild-type cardiac myocytes on hydrogels with a Young's Moduli (stiffness) mimicking hypertrophic cardiomyopathy myocardium is sufficient to induce a hypermetabolic mitochondrial state versus myocytes plated on hydrogels simulating healthy myocardium. Significantly, these data mirror that of myocytes isolated from a murine model of human hypertrophic cardiomyopathy (cTnI-G203S). Conversely, cTnI-G203S myocyte mitochondrial function is completely restored when plated on hydrogels mimicking healthy myocardium. We identify a mechanosensing feedback mechanism between the extracellular matrix and cytoskeletal network that regulates mitochondrial function under healthy conditions, but participates in the progression of hypertrophic cardiomyopathy pathophysiology resulting from sarcomeric gene mutations. Importantly, we pinpoint key 'linker' sites in this schema that may represent potential therapeutic targets.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 06 Mar 2023 05:04
Last Modified: 10 Mar 2023 06:29
URI: http://eprints.victorchang.edu.au/id/eprint/1360

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