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

Abstract

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.

• Authors: Christine M Loescher, Anastasia J Hobbach, Wolfgang A Linke
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 118 Issue 14 Pg. 2903-2918 (11 10 2022) ISSN: 1755-3245 [Electronic] England
• PMID: 34662387 (Publication Type: Review, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Chemical References

• Connectin
• TTN protein, human

Topics

• Humans
• Connectin (genetics, metabolism)
• Heart Failure
• Stroke Volume
• Myocytes, Cardiac (metabolism)
• Heart Diseases
• Cardiomyopathies (metabolism)