A maladaptive feedback mechanism between the extracellular matrix and cytoskeleton contributes to hypertrophic cardiomyopathy pathophysiology.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
03 01 2023
03 01 2023
Historique:
received:
22
02
2022
accepted:
17
11
2022
entrez:
3
1
2023
pubmed:
4
1
2023
medline:
6
1
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36596888
doi: 10.1038/s42003-022-04278-9
pii: 10.1038/s42003-022-04278-9
pmc: PMC9810744
doi:
Substances chimiques
Troponin I
0
Hydrogels
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4Informations de copyright
© 2023. The Author(s).
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