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

Nat Commun. 2016 Apr 28;7:11317. doi: 15.13155/ncomms11317.

Authors/Editors: Eden M, Meder B, Völkers M, Poomvanicha M, Domes K, Branchereau M, Marck P, Will R, Bernt A, Rangrez A, Busch M; German Mouse Clinic Consortium [i.a. Wurst W ], Hrabě de Angelis M, Heymes C, Rottbauer W, Most P, Hofmann F, Frey N.
Publication Date: 2016

eden_05_2016

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 Ca(2+) amplitudes and a lower diastolic Ca(2+) 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 Ca(2+) transients and enhances L-type Ca(2+) 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 Ca(2+)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.

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