Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes

Abstract

Reversible post-translational modifications of various cardiac proteins regulate the mechanical properties of the cardiomyocytes and thus modulate the contractile performance of the heart. The giant protein titin forms a continuous filament network in the sarcomeres of striated muscle cells, where it determines passive tension development and modulates active contraction. These mechanical properties of titin are altered through post-translational modifications, particularly phosphorylation. Titin contains hundreds of potential phosphorylation sites, the functional relevance of which is only beginning to emerge. Here, we provide a state-of-the-art summary of the phosphorylation sites in titin, with a particular focus on the elastic titin spring segment. We discuss how phosphorylation at specific amino acids can reduce or increase the stretch-induced spring force of titin, depending on where the spring region is phosphorylated. We also review which protein kinases phosphorylate titin and how this phosphorylation affects titin-based passive tension in cardiomyocytes. A comprehensive overview is provided of studies that have measured altered titin phosphorylation and titin-based passive tension in myocardial samples from human heart failure patients and animal models of heart disease. As our understanding of the broader implications of phosphorylation in titin progresses, this knowledge could be used to design targeted interventions aimed at reducing pathologically increased titin stiffness in patients with stiff hearts.Electronic supplementary materialThe online version of this article (doi:10.1007/s12551-017-0263-9) contains supplementary material, which is available to authorized users.

Extensive eccentric contractions in intact cardiac trabeculae: revealing compelling differences in contractile behaviour compared to skeletal muscles

“…For instance, phosphorylation of the cardiac N2B region increases the persistence length of the elastic titin spring, which results in reduced overall titin-based stiffness and force. By contrast, phosphorylation of the PEVK region reduces the effective free spring length yielding increased stretch-dependent stiffness and force [76]. Hence, it is expected that titin makes a complex contribution to several phases of the cardiac cycle.…”

End‐diastolic force pre‐activates cardiomyocytes and determines contractile force: role of titin and calcium

“…Levels of N2BA and N2B in the heart are regulated by splicing factors (Labeit & Kolmerer, 1995;Freiburg et al 2000;Bang et al 2001). Another mechanism to decrease passive stiffness is increasing protein kinase A/protein kinase G/extracellular signal-regulated kinase 2 phosphorylation or decreasing protein kinase C phosphorylation (Hamdani et al 2017). The in vivo consequences of decreasing titin stiffness have been extensively studied since the finding from Greaser et al (2008) who identified a rat model that expressed a large highly compliant isoform.…”

Contractile Function of Isolated Hearts With Preserved and Reduced Ejection Fraction In Vivo

“…Нормальное соотношение N2BA и N2B в миокарде человека составляет примерно 30:70 [19]. Это соотношение регулируется протеинкиназами А и G, а также кальцийкальмодулинкиназой (CaMKII), снижающими упругость титина [20], и протеинфосфатазами, осуществляющими дефосфорилирование и повышающими его упругость. Дефосфорилирование титина происходит при ограни-чении ресинтеза АТФ, в результате повышаются упругость миофибрилл и диастолическая упругость миокарда в целом.…”

“…Дефосфорилирование титина происходит при ограни-чении ресинтеза АТФ, в результате повышаются упругость миофибрилл и диастолическая упругость миокарда в целом. Сниженное отношение N2BA:N2B представляет общий признак ХСН у людей с сохраненной ФИ [19,20]. Упругость титина может также возрастать при действии активных форм кислорода, когда в молекуле титина образуются дисульфидные связи, они разрушаются при глутатионилировании [20].…”