The Role of Titin Phosphorylation in Changes in Myocardial Stiffness in Cardiomyopathies

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Abstract

The review provides a brief analysis of current knowledge about such post-translational modification of titin as phosphorylation, with an emphasis on the changes that occur during the development of heart diseases. Studies conducted using animal models of heart disease, as well as using biomaterial from cardiac tissue from patients with various pathologies, show changes in the level of titin phosphorylation in comparison with healthy controls. As a rule, hyperphosphorylation of the S11878 site and hypophosphorylation of the S12022 site in the PEVK sequence of titin are observed, as well as changes in the level of phosphorylation of sites in the N2B sequence of this protein during the development of pathological changes. The functional effect of these changes is an increase in the stiffness of cardiomyocytes and cardiac muscle as a whole, which is based on the viscoelastic properties of titin, changes in which, in turn, are observed due to hypo- or hyperphosphorylation of certain sites of this protein. The review also provides a description of a number of therapeutic interventions aimed at changing the level of titin phosphorylation, which are considered as a way to change the viscoelastic properties of pathological myocardium in order to normalize its contractility.

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About the authors

G. Z. Mikhailova

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: ivanvikhlyantsev@gmail.com
Russian Federation, Pushchino, Moscow Region

I. M. Vikhlyantsev

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Author for correspondence.
Email: ivanvikhlyantsev@gmail.com
Russian Federation, Pushchino, Moscow Region

V. L. Lakomkin

National Cardiology Research Center

Email: ivanvikhlyantsev@gmail.com
Russian Federation, Moscow

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2. Fig. 1. The layout of titin in the sarcomere and its domain structure. (a) is a schematic representation of the location of titin molecules in the sarcomere. Full-sized titin molecules, called T1, overlap the distance from the M-line to the Z-disk in the sarcomeres of striated vertebrate muscles. The part of the titine molecule located in the A-zone is called T2. For each myosin strand in half of the sarcomere, there are presumably six full-sized titin molecules. (b) is the domain structure of titin. Titin domains (N2B, N2A, PEVK, kinase domain), as well as phosphorylation sites of the titin molecule located in the M-line, I-zone and Z-disk are indicated. Adapted from [3].

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