Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression.
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.
Department of Internal Medicine III (Cardiology and Angiology), University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.|German Centre for Cardiovascular Research, partner site 20246 Hamburg/24105 Kiel/23562 Lübeck, Germany.
Matthias
M
Eden
Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany.
Benjamin
B
Meder
Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany.
Mirko
M
Völkers
Department of Pharmacology, University of Technology Munich, 80333 Munich, Germany.
Montatip
M
Poomvanicha
Department of Pharmacology, University of Technology Munich, 80333 Munich, Germany.
Katrin
K
Domes
Inserm U1048 - Institut des Maladies Métaboliques et Cardiovasculaires (I2MC)/Equipe 13, Bat L4 1er étage C.H.U Rangueil 1 av Jean Poulhès - BP 84225 31432 Toulouse Cedex 4, France.
M
M
Branchereau
Inserm U1048 - Institut des Maladies Métaboliques et Cardiovasculaires (I2MC)/Equipe 13, Bat L4 1er étage C.H.U Rangueil 1 av Jean Poulhès - BP 84225 31432 Toulouse Cedex 4, France.
P
P
Marck
Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany.
Rainer
R
Will
German Centre for Cardiovascular Research, partner site 20246 Hamburg/24105 Kiel/23562 Lübeck, Germany.
Alexander
A
Bernt
German Centre for Cardiovascular Research, partner site 20246 Hamburg/24105 Kiel/23562 Lübeck, Germany.
Ashraf
A
Rangrez
Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany.
Matthias
M
Busch
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Martin
M
Hrabě de Angelis
Inserm U1048 - Institut des Maladies Métaboliques et Cardiovasculaires (I2MC)/Equipe 13, Bat L4 1er étage C.H.U Rangueil 1 av Jean Poulhès - BP 84225 31432 Toulouse Cedex 4, France.
Christophe
C
Heymes
Department of Internal Medicine III, Cardiology and Angiology, University Hospital of Ulm, 89081 Ulm, Germany.
Wolfgang
W
Rottbauer
Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany.|German Centre for Cardiovascular Research, partner site 69120 Heidelberg/68167 Mannheim, Germany.
Patrick
P
Most
Department of Pharmacology, University of Technology Munich, 80333 Munich, Germany.
Franz
F
Hofmann
Department of Internal Medicine III (Cardiology and Angiology), University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.|German Centre for Cardiovascular Research, partner site 20246 Hamburg/24105 Kiel/23562 Lübeck, Germany.
Norbert
N
Frey
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000597218:STRIP2 protein, human; D002118:Calcium