Titin (TTN): from molecule to modifications, mechanics, and medical significance

The giant sarcomere protein titin is a major determinant of cardiomyocyte stiffness and contributor to cardiac strain sensing. Titin-based forces are highly regulated in health and disease, which aids in the regulation of myocardial function, including cardiac filling and output. Due to the enormous...

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Bibliographic Details
Published in:Cardiovascular research 2022-11, Vol.118 (14), p.2903-2918
Main Authors: Loescher, Christine M, Hobbach, Anastasia J, Linke, Wolfgang A
Format: Article
Language:English
Subjects:
Cardiomyopathies - metabolism
Connectin - genetics
Connectin - metabolism
Editor's Choice
Heart Diseases
Heart Failure
Humans
Myocytes, Cardiac - metabolism
Review
Stroke Volume
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Summary:The giant sarcomere protein titin is a major determinant of cardiomyocyte stiffness and contributor to cardiac strain sensing. Titin-based forces are highly regulated in health and disease, which aids in the regulation of myocardial function, including cardiac filling and output. Due to the enormous size, complexity, and malleability of the titin molecule, titin properties are also vulnerable to dysregulation, as observed in various cardiac disorders. This review provides an overview of how cardiac titin properties can be changed at a molecular level, including the role isoform diversity and post-translational modifications (acetylation, oxidation, and phosphorylation) play in regulating myocardial stiffness and contractility. We then consider how this regulation becomes unbalanced in heart disease, with an emphasis on changes in titin stiffness and protein quality control. In this context, new insights into the key pathomechanisms of human cardiomyopathy due to a truncation in the titin gene (TTN) are discussed. Along the way, we touch on the potential for titin to be therapeutically targeted to treat acquired or inherited cardiac conditions, such as HFpEF or TTN-truncation cardiomyopathy.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvab328