Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Fatiha Elhamine, Michael H. Radke, Gabriele Pfitzer, Henk Granzier, Michael Gotthardt, Robert Stehle

Research output: Contribution to journalArticle

4 Scopus citations

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 Ca2++-induced force development (rate constant kACT), myofibrils from knockout, heterozygous and wildtype mice were stretched to the same sarcomere length (2.3 μm) and rapidly activated with Ca2++. Additionally, mechanically induced force-redevelopment kinetics (rate constant kTR) were determined by slackening and re-stretching myofibrils during Ca2++-mediated activation. Myofibrils from knockout mice exhibited significantly higher kACT, kTR and maximum Ca2++-activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca2++] 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 crossbridges without decelerating relaxation.

Original languageEnglish (US)
Pages (from-to)3666-3674
Number of pages9
JournalJournal of Cell Science
Volume127
Issue number17
DOIs
StatePublished - 2014

Keywords

  • Crossbridge kinetics
  • Diastolic dysfunction
  • Muscle relaxation
  • Passive tension
  • Titin genotype effects

ASJC Scopus subject areas

  • Cell Biology

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