title: Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics.
abstract: Cardiac titin is the main determinant of sarcomere stiffness during diastolic relaxation. To explore whether titin stiffness affects the kinetics of cardiac myofibrillar contraction and relaxation, we used subcellular myofibrils from the left ventricles of homozygous and heterozygous N2B-knockout mice which express truncated cardiac titins lacking the unique elastic N2B region. Compared with myofibrils from wild-type mice, myofibrils from knockout and heterozygous mice exhibit increased passive myofibrillar stiffness. To determine the kinetics of Ca(2+)-induced force development (rate constant kACT), myofibrils from knockout, heterozygous and wild-type mice were stretched to the same sarcomere length (2.3 µm) and rapidly activated with Ca(2+). Additionally, mechanically induced force-redevelopment kinetics (rate constant kTR) were determined by slackening and re-stretching myofibrils during Ca(2+)-mediated activation. Myofibrils from knockout mice exhibited significantly higher kACT, kTR and maximum Ca(2+)-activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca(2+)] were not significantly different among the three genotypes. These results indicate that increased titin stiffness promotes myocardial contraction by accelerating the formation of force-generating cross-bridges without decelerating relaxation.
authors: Institute of Vegetative Physiology, University of Cologne, Robert Koch Str. 39, D-50931 Köln, Germany.
authors: Fatiha
authors: F
authors: Elhamine
authors: Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, D-13125 Berlin, Germany.
authors: Michael H
authors: MH
authors: Radke
authors: Institute of Vegetative Physiology, University of Cologne, Robert Koch Str. 39, D-50931 Köln, Germany.
authors: Gabriele
authors: G
authors: Pfitzer
authors: Sarver Molecular Cardiovascular Research and Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA.
authors: Henk
authors: H
authors: Granzier
authors: Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, D-13125 Berlin, Germany.
authors: Michael
authors: M
authors: Gotthardt
authors: Institute of Vegetative Physiology, University of Cologne, Robert Koch Str. 39, D-50931 Köln, Germany Robert.Stehle@Uni-Koeln.de.
authors: Robert
authors: R
authors: Stehle
mesh_terms: D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D064211:Connectin / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D009126:Muscle Relaxation / Q000502:physiology*; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism* / Q000502:physiology; D012518:Sarcomeres / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D064211:Connectin; D002118:Calcium
keywords: Crossbridge kinetics; Diastolic dysfunction; Muscle relaxation; Passive tension; Titin genotype effects