Abstract 11989: Cardiac Muscle-Specific Disruption of the Exocyst Trafficking Complex Results in Heart Failure

Abstract

Increased myocardial glycolysis is protective against ischemic injury. Glucose uptake via glucose transporter GLUT4 is the rate-limiting step of glycolysis in cardiomyocytes. GLUT4 delivery to the cardiomyocyte membrane can be triggered by insulin or by increased ATP-demand (i.e. during ischemia) via the AMP-activated protein kinase (AMPK). Previous studies of adipocytes and our recent study in skeletal muscle demonstrated that the exocyst trafficking complex is critical for GLUT4 exocytosis in response to insulin. But it is not known if the insulin-insulin receptor-exocyst-GLUT4 signaling axis is conserved in the cardiomyocytes, or if the exocyst also regulates cardiac glucose uptake via AMPK-induced GLUT4 translocation. Investigating glucose transporter trafficking in cardiomyocytes will be key to better understanding the mechanism of cardiac glucose metabolism under normal and disease conditions. We hypothesized that the exocyst is necessary for myocardial glucose uptake and metabolism and its activity protects the heart from ischemic injury. We have generated tamoxifen-inducible cardiac muscle-specific knockout mice of the central exocyst subunit Exoc5 (Exoc5-CMKO) to evaluate the role of the exocyst in cardiac fuel metabolism in vivo . Unexpectedly we found that cardiac muscle-specific Exoc5 knockout shortened the lifespan of Exoc5-CMKO mice (median survival after tamoxifen treatment was 60.5 days). Echocardiography showed cardiac dysfunction in Exoc5-CMKO mice, with reduced ejection fraction (Ctrl: 0.77; CMKO: 0.43; p<0.0001) and fractional shortening (Ctrl: 45.57; CMKO:21.62; p<0.0001), and increased systolic and diastolic LV diameters (LVID s (mm): Ctrl: 1.81; CMKO: 3.32; LVID d (mm): Ctrl: 3.47; CMKO:4.2; p<0.0001) compared to controls. Histological analysis revealed increased fibrosis in Exoc5-CMKO hearts, while isolated knockout primary cardiomyocytes showed decreased contractility and altered calcium handling. Our findings suggest that the exocyst is necessary for proper cardiac muscle function. Future studies will investigate how impaired exocyst-mediated membrane trafficking leads to heart failure in our Exoc5-CMKO mice.