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In Vitro Assessment of Cardiac Function Using Skinned Cardiomyocytes
Published on: June 22, 2020
Cardiac titin and heart disease
Martin M LeWinter1, Henk L Granzier
1*Cardiology Unit, Fletcher Allen Health Care, Department of Medicine, University of Vermont, Burlington, VT; and †Sarver Molecular Cardiovascular Research Program, and ‡Department of Physiology, University of Arizona, Tucson, AZ.
Journal of Cardiovascular Pharmacology
|September 28, 2013
Summary
Titin, a giant protein, influences heart stiffness and signaling. Mutations and altered modifications in titin are linked to heart diseases like dilated cardiomyopathy, with potential for future therapies.
Area of Science:
- Biochemistry
- Cardiology
- Molecular Biology
Background:
- Titin is a crucial sarcomeric protein regulating myocardial passive stiffness and cellular signaling.
- Titin's mechanical properties are influenced by isoforms, post-translational modifications (e.g., phosphorylation, oxidation), and its interactions with other proteins.
- Titin is increasingly recognized as a significant gene in human cardiac diseases.
Purpose of the Study:
- To review the role of titin in myocardial mechanics and its implications in various heart conditions.
- To explore how titin's structure and function are altered in diseases such as dilated cardiomyopathy (DCM) and heart failure.
- To discuss the genetic basis of titin-related cardiomyopathies and potential therapeutic strategies.
Main Methods:
- Review of existing literature on titin's structure, function, and role in cardiac pathology.
- Analysis of studies investigating titin isoform variation, post-translational modifications, and mutations in heart disease.
- Examination of genetic data linking titin and related protein mutations to cardiomyopathies.
Main Results:
- Altered titin isoforms and hypophosphorylation contribute to altered passive stiffness and resting tension in heart failure.
- Titin mutations are a leading cause of inherited dilated cardiomyopathy (DCM) and also implicated in hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia.
- Mutations in titin-binding proteins and the splice factor RBM20 are associated with DCM and hypertrophic cardiomyopathy.
Conclusions:
- Titin plays a central role in cardiac mechanics and its dysfunction is a significant factor in various cardiomyopathies.
- Genetic variations and post-translational modifications of titin are key contributors to inherited heart muscle diseases.
- Therapeutic strategies targeting titin's isoforms, modifications, or expression levels represent a promising, albeit nascent, approach for treating titin-related cardiomyopathies.
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