title: Titin based viscosity in ventricular physiology: an integrative investigation of PEVK-actin interactions.
abstract: Viscosity is proposed to modulate diastolic function, but only limited understanding of the source(s) of viscosity exists. In vitro experiments have shown that the proline-glutamic acid-valine-lysine (PEVK) rich element of titin interacts with actin, causing a viscous force in the sarcomere. It is unknown whether this mechanism contributes to viscosity in vivo. We tested the hypothesis that PEVK-actin interaction causes cardiac viscosity and is important in vivo via an integrative physiological study on a unique PEVK knockout (KO) model. Both skinned cardiomyocytes and papillary muscle fibers were isolated from wildtype (WT) and PEVK KO mice and passive viscosity was examined using stretch-hold-release and sinusoidal analysis. Viscosity was reduced by ~60% in KO myocytes and ~50% in muscle fibers at room temperature. The PEVK-actin interaction was not modulated by temperature or diastolic calcium, but was increased by lattice compression. Stretch-hold and sinusoidal frequency protocols on intact isolated mouse hearts showed a smaller, 30-40% reduction in viscosity, possibly due to actomyosin interactions, and showed that microtubules did not contribute to viscosity. Transmitral Doppler echocardiography similarly revealed a 40% decrease in LV chamber viscosity in the PEVK KO in vivo. This integrative study is the first to quantify the influence of a specific molecular (PEVK-actin) viscosity in vivo and shows that PEVK-actin interactions are an important physiological source of viscosity.
authors.affiliation: Molecular Cardiovascular Research Program, Sarver Heart Center, Department of Physiology, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Chung
authors.forename: Methajit
authors.initials: M
authors.lastname: Methawasin
authors.forename: O Lynne
authors.initials: OL
authors.lastname: Nelson
authors.forename: Michael H
authors.initials: MH
authors.lastname: Radke
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Hidalgo
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Henk L
authors.initials: HL
authors.lastname: Granzier
mesh_terms: D000199:Actins / Q000378:metabolism*; D000205:Actomyosin / Q000037:antagonists & inhibitors; D000818:Animals; D064211:Connectin; D006352:Heart Ventricles / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism; D014783:Viscosity / Q000187:drug effects
chemical_list: D000199:Actins; D064211:Connectin; D006576:Heterocyclic Compounds, 4 or More Rings; D009124:Muscle Proteins; C472645:blebbistatin; D000205:Actomyosin; D011494:Protein Kinases