Titin based viscosity in ventricular physiology: An integrative investigation of PEVK-actin interactions

Charles S. Chung, Methajit Methawasin, O. Lynne Nelson, Michael H. Radke, Carlos G. Hidalgo, Michael Gotthardt, Henk L. Granzier

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)428-434
Number of pages7
JournalJournal of Molecular and Cellular Cardiology
Volume51
Issue number3
DOIs
StatePublished - Sep 2011

Keywords

  • Actin
  • Diastole
  • In vivo
  • Passive force
  • Titin/connectin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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