Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

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ID: 114878
2020
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Abstract
Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination of titin are the most common genetic cause of dilated cardiomyopathy. Modifications of titin, which change protein length, and relative stiffness affect resting tension of the ventricle and are associated with acquired forms of heart failure. Transcriptional and post-translational changes that increase titin’s length and extensibility, making the sarcomere longer and softer, are associated with systolic dysfunction and left ventricular dilation. Modifications of titin that decrease its length and extensibility, making the sarcomere shorter and stiffer, are associated with diastolic dysfunction in animal models. There has been significant progress in understanding the mechanisms by which titin is modified. As molecular pathways that modify titin’s mechanical properties are elucidated, they represent therapeutic targets for treatment of both systolic and diastolic dysfunction. In this article, we review titin’s contribution to normal cardiac physiology, the pathophysiology of titin truncation variations leading to dilated cardiomyopathy, and transcriptional and post-translational modifications of titin. Emphasis is on how modification of titin can be utilized as a therapeutic target for treatment of heart failure.
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tharp2020journalmodifications Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Charles Tharp;Luisa Mestroni;Matthew Taylor;Tharp, Charles;Mestroni, Luisa;Taylor, Matthew;
Journal journal of clinical medicine
Year 2020
DOI
10.3390/jcm9092770
URL
https://www.mdpi.com/2077-0383/9/9/2770
Keywords
systolic dysfunction dilated cardiomyopathy phosphorylation titin rna binding motif protein 20 (rbm20) sarcomere diastolic dysfunction non-sense mrna decay mammalian target of rapamycin (mtor) complex-1

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