title: Gigantic business: titin properties and function through thick and thin.
abstract: The giant protein titin forms a unique filament network in cardiomyocytes, which engages in both mechanical and signaling functions of the heart. TTN, which encodes titin, is also a major human disease gene. In this review, we cover the roles of cardiac titin in normal and failing hearts, with a special emphasis on the contribution of titin to diastolic stiffness. We provide an update on disease-associated titin mutations in cardiac and skeletal muscles and summarize what is known about the impact of protein-protein interactions on titin properties and functions. We discuss the importance of titin-isoform shifts and titin phosphorylation, as well as titin modifications related to oxidative stress, in adjusting the diastolic stiffness of the healthy and the failing heart. Along the way we distinguish among titin alterations in systolic and in diastolic heart failure and ponder the evidence for titin stiffness as a potential target for pharmacological intervention in heart disease.
authors.affiliation: From the Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
mesh_terms: D000818:Animals; D003187:Compliance; D064211:Connectin / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D003971:Diastole; D004195:Disease Models, Animal; D004548:Elasticity; D006331:Heart Diseases / Q000235:genetics / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology / Q000648:ultrastructure; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000502:physiology; D011499:Protein Processing, Post-Translational; D012518:Sarcomeres / Q000648:ultrastructure; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D059289:Vascular Stiffness
chemical_list: D064211:Connectin; D020033:Protein Isoforms
keywords: heart failure