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- Title
A maladaptive feedback mechanism between the extracellular matrix and cytoskeleton contributes to hypertrophic cardiomyopathy pathophysiology.
- Authors
Viola, Helena M.; Richworth, Caitlyn; Solomon, Tanya; Chin, Ian L.; Szappanos, Henrietta Cserne; Sundararaj, Srinivasan; Shishmarev, Dmitry; Casarotto, Marco G.; Choi, Yu Suk; Hool, Livia C.
- 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. An in vitro model of hypertrophic cardiomyopathy is developed and used to identify a structural-functional link between the L-type calcium channel, mitochondria and the extracellular matrix.
- Subjects
HYPERTROPHIC cardiomyopathy; EXTRACELLULAR matrix; CALCIUM channels; SUDDEN death; HYPERTROPHIC scars; YOUNG'S modulus; PATHOLOGICAL physiology; CYTOSKELETON
- Publication
Communications Biology, 2023, Vol 6, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-04278-9