Loss of mXin α , an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects

The intercalated disk protein Xin was originally discovered in chicken striated muscle and implicated in cardiac morphogenesis. In the mouse, there are two homologous genes, mXin α and mXin β . The human homolog of mXin α , Cmya1 , maps to chromosomal region 3p21.2–21.3, near a dilated cardiomyopathy with conduction defect-2 locus. Here we report that mXin α -null mouse hearts are hypertrophied and exhibit fibrosis, indicative of cardiomyopathy. A significant upregulation of mXin β likely provides partial compensation and accounts for the viability of the mXin α -null mice. Ultrastructural studies of mXin α -null mouse hearts reveal intercalated disk disruption and myofilament disarray. In mXin α -null mice, there is a significant decrease in the expression level of p120-catenin, β -catenin, N-cadherin, and desmoplakin, which could compromise the integrity of the intercalated disks and functionally weaken adhesion, leading to cardiac defects. Additionally, altered localization and decreased expression of connexin 43 are observed in the mXin α -null mouse heart, which, together with previously observed abnormal electrophysiological properties of mXin α deficient mouse ventricular myocytes, could potentially lead to conduction defects. Indeed, ECG recordings on isolated, perfused hearts (Langendorff preparations) show a significantly prolonged QT interval in mXin α -deficient hearts. Thus mXin α functions in regulating the hypertrophic response and maintaining the structural integrity of the intercalated disk in normal mice, likely through its association with adherens junctional components and actin cytoskeleton. The mXin α -knockout mouse line provides a novel model of cardiac hypertrophy and cardiomyopathy with conduction defects. and connexin 43, but not α -catenin or plakoglobin, are decreased significantly in mXin α -null mice. These data suggest that mXin α plays an important role in regulating the hypertrophic response and maintaining the tightly associated intercalated disk membrane and myofilament organization in normal mice. a patch-clamp of and α -deficient we significant reductions in transient outward K + currents ( I to ) and Ba 2+ -sensitive inward rectifier K + currents ( I k1 ) in mXin α − / − myocytes which are important components for repolarizing cardiomyocytes. An optical mapping technique has been used to compare the conduction velocity on the front surface of ventricles of wild-type and mXin α -null hearts with the MED64 recording system (MED-P515A, Panasonic). The results revealed that the conduction velocity in mXin α -null ventricles was significantly slower than that in wild-type ventricles This slower conduction velocity together with the depressed I to and I k1 detected in ventricular myocytes is consistent with a prolonged QT period in mXin α -null ECG. Although the mechanism causing a wider P wave in mXin α -null ECG remains unclear, MED64 recording studies on left atrial-pulmonary vein myocardium preparations and connexin 40 studies on its expression and localization may provide evidence to support a wider P wave in the mXin α -null heart. Together, these data demonstrate that mXin α -knockout mice represent a novel model for the study of cardiomyopathy with conduction defects.