Cardiovascular disease is one of the commonest causes of death in the Western world. It is triggered by a number of factors: circulatory disorders, inflammation or inherited conditions can all act to weaken the pumping action of the heart muscle. At the molecular level, one thing is common to all forms of heart failure: a disruption to the calcium metabolism of heart muscle cells. And this is the exact interaction site for the “Myoscape” protein newly discovered by Kiel cardiologists Dr Matthias Eden and Professor Norbert Frey.
Working together with researchers from Munich, Heidelberg and Paris, they were able to show that Myoscape binds to a specific calcium channel on the heart muscle and thus has a significant effect on its function. “In the absence of Myoscape, heart muscle cells in the model system develop a serious impairment of calcium channel metabolism, ultimately leading to progressive heart failure,” comments Frey. Conversely, the researchers were able to show that calcium channel currents increase significantly if levels of Myoscape protein in heart muscle cells are artificially increased. In such cases, the increased level of Myoscape is then even capable of restoring previously decreased calcium currents in failing heart muscle cells.
In further experiments, the researchers were ultimately able to elucidate the exact mechanism by which Myoscape influences calcium metabolism and the pumping ability of the heart muscle cell. “To function properly, the calcium channel needs to be located at the right position in the heart muscle cell,” Eden explains. This is because the binding of Myoscape and another protein called actinin 2 stabilises the calcium channel in the heart muscle cell at the correct position in the cell membrane. In the absence of Myoscape, the calcium channel is removed from the cell membrane and heart failure then develops. “Since patients with severe heart failure also exhibit reduced levels of Myoscape protein in the heart, we believe that we have here discovered a critical new mechanism for the genesis of heart failure,” says Frey. In the future, this could lead to the development of innovative forms of treatment.
Matthias Eden, Benjamin Meder, Mirko Völkers, Montatip Poomvanicha, Katrin Domes, M. Branchereau, P. Marck, Rainer Will, Alexander Bernt, Ashraf Rangrez, Matthias Busch, German Mouse Clinic Consortium, Martin Hrabe de Angelis, Christophe Heymes, Wolfgang Rottbauer, Patrick Most, Franz Hofmann & Norbert Frey: Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression, Nature Communications, doi:15.13155/ncomms11317
Prof. Norbert Frey, Klinik für Innere Medizin III, phone: 0431/597-1440, mail: norbert.frey(at)uksh.de
Source: press release