title: Titin-based mechanical signalling in normal and failing myocardium.
abstract: Nodal points of mechanotransduction are found along the cardiac sarcomere, notably in the Z-disc/I-band and M-band regions. A major integrating component of these mechanosensitive complexes is the giant protein titin, which is anchored at the Z-disc, spans the I-band as an elastic spring and enters the A-band bound to myosin, then reaching all the way to the M-band. Passive-force generation and transmission of stress via the titin filaments may be central to the mechanosensory function of the myofibrillar signalosome complexes. This review discusses recent findings shedding light on mechanisms by which titin elasticity is regulated dynamically. Adjustment of titin stiffness occurs during heart development and disease through a shift in the expression ratio of the two main titin isoforms in cardiac sarcomeres, N2BA (compliant) and N2B (stiffer). Titin-isoform switching in favor of the stiffer N2B-titin can be triggered by thyroid hormone (T3)activating the phosphatidylinositol-3-kinase (PI3K)/AKT pathway. Conversely, low T3 promotes the compliant N2BA-titin. In addition, titin stiffness can be tuned acutely by protein kinase (PK)A-or PKG-mediated phosphorylation of a cardiac-specific I-band titin segment, the N2-B domain. Beta-adrenergic agonists, nitric oxide, or natriuretic peptides thus trigger a softening of the titin springs, thereby modulating diastolic function. Failing human hearts can have elevated passive stiffness in part because of a titin phosphorylation deficit, which may contribute to mechanical dysfunction. Altered titin phosphorylation could also affect protein-protein interactions in the mechanosensory complexes associated with the sarcomere. In this context, the review highlights novel links between titin and stress-signalling pathways in the cardiomyocyte.
authors.affiliation: Physiology and Biophysics Unit, University of Muenster, Schlossplatz 5, D-48149 Muenster, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Krüger
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
mesh_terms: D064211:Connectin; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D008465:Mechanoreceptors / Q000502:physiology*; D009124:Muscle Proteins / Q000737:chemistry / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology*; D020033:Protein Isoforms; D011494:Protein Kinases / Q000737:chemistry / Q000502:physiology*; D012518:Sarcomeres / Q000502:physiology; D015398:Signal Transduction
chemical_list: D064211:Connectin; D009124:Muscle Proteins; D020033:Protein Isoforms; C577285:TTN protein, human; D011494:Protein Kinases