Abstract 17124: Myoscape Controls Cardiomyocyte Calcium Cycling and Contractile Function in vivo via Regulation of L-type Calcium Channel Surface Expression

Alterations in cardiomyocyte calcium cycling have been shown to play a major role in the pathophysiology of contractile dysfunction, hypertrophy and the progression of heart failure. 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 (LTCC) and cardiac Alpha-Actinin 2. Knockdown of Myoscape in adult rat ventricular cardiomyocytes (ARVCMs) leads to a decrease in global calcium transients, with smaller Ca2+ amplitudes (n=4, p<0.001), lower diastolic Ca2+content and a prolonged time to peak. Consistently, analysis of single LTCC currents in ARVCM confirmed a significant reduction upon Myoscape ablation. Conversely, overexpression of Myoscape significantly increases global Ca2+transients and enhances LTCC currents. Moreover, overexpression of Myoscape almost completely restores decreased LTCC currents in failing ARVCMs. As a fun...