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Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

Author

Listed:
  • Matthias Eden

    (University Hospital Schleswig-Holstein, Campus Kiel
    German Centre for Cardiovascular Research)

  • Benjamin Meder

    (University of Heidelberg)

  • Mirko Völkers

    (University of Heidelberg)

  • Montatip Poomvanicha

    (University of Technology Munich)

  • Katrin Domes

    (University of Technology Munich)

  • M. Branchereau

    (Inserm U1048 - Institut des Maladies Métaboliques et Cardiovasculaires (I2MC)/Equipe 13)

  • P. Marck

    (Inserm U1048 - Institut des Maladies Métaboliques et Cardiovasculaires (I2MC)/Equipe 13)

  • Rainer Will

    (University of Heidelberg)

  • Alexander Bernt

    (German Centre for Cardiovascular Research)

  • Ashraf Rangrez

    (German Centre for Cardiovascular Research)

  • Matthias Busch

    (University of Heidelberg)

  • Martin Hrabě de Angelis

    (German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health)

  • Christophe Heymes

    (Inserm U1048 - Institut des Maladies Métaboliques et Cardiovasculaires (I2MC)/Equipe 13)

  • Wolfgang Rottbauer

    (Cardiology and Angiology, University Hospital of Ulm)

  • Patrick Most

    (University of Heidelberg
    German Centre for Cardiovascular Research)

  • Franz Hofmann

    (University of Technology Munich)

  • Norbert Frey

    (University Hospital Schleswig-Holstein, Campus Kiel
    German Centre for Cardiovascular Research)

Abstract

Calcium signalling plays a critical role in the pathogenesis of heart failure. Here we describe a cardiac protein named Myoscape/FAM40B/STRIP2, which directly interacts with the L-type calcium channel. Knockdown of Myoscape in cardiomyocytes decreases calcium transients associated with smaller Ca2+ amplitudes and a lower diastolic Ca2+ content. Likewise, L-type calcium channel currents are significantly diminished on Myoscape ablation, and downregulation of Myoscape significantly reduces contractility of cardiomyocytes. Conversely, overexpression of Myoscape increases global Ca2+ transients and enhances L-type Ca2+ channel currents, and is sufficient to restore decreased currents in failing cardiomyocytes. In vivo, both Myoscape-depleted morphant zebrafish and Myoscape knockout (KO) mice display impairment of cardiac function progressing to advanced heart failure. Mechanistically, Myoscape-deficient mice show reduced L-type Ca2+currents, cell capacity and calcium current densities as a result of diminished LTCC surface expression. Finally, Myoscape expression is reduced in hearts from patients suffering of terminal heart failure, implying a role in human disease.

Suggested Citation

  • Matthias Eden & Benjamin Meder & Mirko Völkers & Montatip Poomvanicha & Katrin Domes & M. Branchereau & P. Marck & Rainer Will & Alexander Bernt & Ashraf Rangrez & Matthias Busch & Martin Hrabě de Ang, 2016. "Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression," Nature Communications, Nature, vol. 7(1), pages 1-16, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11317
    DOI: 10.1038/ncomms11317
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