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

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 Angelis, Christophe Heymes, Wolfgang Rottbauer, Patrick Most, Franz Hofmann and Norbert Frey ()
Additional contact information
Matthias Eden: University Hospital Schleswig-Holstein, Campus Kiel
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
Franz Hofmann: University of Technology Munich
Norbert Frey: University Hospital Schleswig-Holstein, Campus Kiel

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11317

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