Biophysics of Titin in Cardiac Health and Disease

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Titin is a gigantic multifunctional filamentous protein that spans from the Z-disk to the M-band region of the cardiac sarcomere. The elastic I-band region of titin generates passive force during sarcomere stretch that plays important roles in maintaining the structural organization of the sarcomere and that contributes greatly to diastolic stiffness. Recent work has shown that to match hemodynamic demands the mechanical properties of titin can be finely tuned through differential expression of titin isoforms and phosphorylation of titin’s spring-like elements. Titin may also play a role in mechanically sensing sarcomere length changes due to its placement in the sarcomere and extensible, force-bearing I-band region. The precise ways in which titin behaves as a mechanosensor is not well established, but rapid progress is being made in our understanding of the various proteins involved in signaling pathways that interact with titin. Recent work also revealed mutations in the titin gene (TTN) as a major source of familial cardiomyopathies, including mutations in titin’s spring region linked to arrhythmogenic right ventricular dysplasia and mutations in titin’s A-band region responsible for ~30 % of dilated cardiomyopathy (DCM) cases. This chapter discusses the mechanical properties of titin and the role titin plays in cardiac health and disease.KeywordsPassive TensionArrhythmogenic Right Ventricular DysplasiaTitin KinasePEVK RegionN2BA TitinThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.