Molecular mechanism regulating myosin and cardiac functions by ELC

Janine Lossie, Clemens Köhncke, Shokoufeh Mahmoodzadeh, Walter Steffen, Monica Canepari, Manuela Maffei, Martin Taube, Oriane Larchevêque, Philipp Baumert, Hannelore Haase, Roberto Bottinelli, Vera Regitz-Zagrosek, Ingo Morano

Research output: Contribution to journalArticle

Abstract

The essential myosin light chain (ELC) is involved in modulation of force generation of myosin motors and cardiac contraction, while its mechanism of action remains elusive. We hypothesized that ELC could modulate myosin stiffness which subsequently determines its force production and cardiac contraction. Therefore, we generated heterologous transgenic mouse (TgM) strains with cardiomyocyte-specific expression of ELC with human ventricular ELC (hVLC-1; TgMhVLC-1) or E56G-mutated hVLC-1 (hVLC-1E56G; TgM E56G). hVLC-1 or hVLC-1E56G expression in TgM was around 39% and 41%, respectively of total VLC-1. Laser trap and in vitro motility assays showed that stiffness and actin sliding velocity of myosin with hVLC-1 prepared from TgMhVLC-1 (1.67 pN/nm and 2.3 μm/s, respectively) were significantly higher than myosin with hVLC-1E56G prepared from TgME56G (1.25 pN/nm and 1.7 μm/s, respectively) or myosin with mouse VLC-1 (mVLC-1) prepared from C57/BL6 (1.41 pN/nm and 1.5 μm/s, respectively). Maximal left ventricular pressure development of isolated perfused hearts in vitro prepared from TgMhVLC-1 (80.0 mmHg) were significantly higher than hearts from TgME56G (66.2 mmHg) or C57/BL6 (59.3 ± 3.9 mmHg). These findings show that ELCs decreased myosin stiffness, in vitro motility, and thereby cardiac functions in the order hVLC-1 > hVLC-1E56G ≈ mVLC-1. They also suggest a molecular pathomechanism of hypertrophic cardiomyopathy caused by hVLC-1 mutations.

Original languageEnglish
Pages (from-to)464-469
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume450
Issue number1
DOIs
Publication statusPublished - Jul 18 2014

Keywords

  • Essential myosin light chains
  • In vitro motility
  • Mutations
  • Myosin
  • Stiffness

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Molecular mechanism regulating myosin and cardiac functions by ELC'. Together they form a unique fingerprint.

  • Cite this

    Lossie, J., Köhncke, C., Mahmoodzadeh, S., Steffen, W., Canepari, M., Maffei, M., Taube, M., Larchevêque, O., Baumert, P., Haase, H., Bottinelli, R., Regitz-Zagrosek, V., & Morano, I. (2014). Molecular mechanism regulating myosin and cardiac functions by ELC. Biochemical and Biophysical Research Communications, 450(1), 464-469. https://doi.org/10.1016/j.bbrc.2014.05.142