Abstract 16588: Myoscape (Muscle Enriched Calcium-Channel Associated Protein), Stabilizes Cav1.2 Surface Expression and Controls Calcium Cycling and Contractile Function in vivo
Heart failure is still a major cause of death and mortality. Alterations in cardiomyocyte calcium cycling have been shown to play a major role in the pathophysiology of contractile dysfunction. The L-type Ca2+channel controls calcium entry and subsequent calcium-induced calcium release. Here we report a novel muscle enriched protein termed Myoscape which directly interacts with the distal C terminus of the L-type Ca2+channel. Adenoviral knockdown of Myoscape in adult rat ventricular cardiomyocytes (ARVCMs) leads to a decrease in global calcium transients, with smaller Ca2+ amplitudes (1.38±0.06 vs. 1.08±0.09120 cells, n=4, p<0.001), lower diastolic Ca2+content and a prolonged time to peak. Consistently, analysis of L-Type Ca2+channel currents in ARVCM confirmed a significant reduction upon Myoscape ablation. Conversely, adenoviral overexpression of Myoscape significantly increases global Ca2+transients and enhances L-Type Ca2+channel currents. Moreover, overexpression of Myoscape is able to restore decreased L-Type Ca2+channel currents in failing ARVCMs. As a functional consequence, knockdown of Myoscape significantly reduced contractility of ARVCM, as assessed by fractional shortening measurements (21%±1% vs. 14%±1%, 60 cells, n=3, p<0.001). In vivo antisense-morpholino based knockdown of the Myoscape orthologue in zebrafish (n=60) led to severe cardiomyopathy with impaired contractile function, pericardial edema and premature death. Finally, Myoscape knockout mice develop reduced fractional shortening after 8 weeks which progresses to advanced cardiomyopathy after one year follow up (FS 51.7% ±4.2. vs. 33.3%±3.7, n=10). Myoscape KO mice showed significantly reduced L-Type Ca2+currents, cell capacity and current densities (pA/pF 3.72±0.4 vs. 2.48±0.2) without alteration of t-tubule architecture. Interestingly, myocardial Myoscape protein abundance is markedly reduced in patients with cardiomyopathy compared to control individuals (n=8; P<0.01).Taken together, we have identified a novel modulator of cardiomyocyte L-type calcium channels and contractile function. Future studies will have to show whether this new mechanism can be exploited therapeutically
- © 2013 by American Heart Association, Inc.