LAMP2 Cardiomyopathy: Consequences of Impaired Autophagy in the Heart

作者：Ronny Alcalai, Michael Arad, Hiroko Wakimoto, Dor Yadin, Joshua Gorham, Libin Wang, Elia Burns, Barry J. Maron, William Clifford Roberts, Tetsuo Konno, David A. Conner, Antonio R. Pérez‐Atayde, Jon G. Seidman, Christine E. Seidman · 发表于：Journal of the American Heart Association · 年份：2021 · DOI：10.1161/jaha.120.018829 · 被引用次数：41 · 研究领域：Cardiomyopathy and Myosin Studies、Endoplasmic Reticulum Stress and Disease、RNA regulation and disease

Background Human mutations in the X‐linked lysosome‐associated membrane protein‐2 ( LAMP2 ) gene can cause a multisystem Danon disease or a primary cardiomyopathy characterized by massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. We introduced an in‐frame LAMP2 gene exon 6 deletion mutation (denoted L2 Δ6 ) causing human cardiomyopathy, into mouse LAMP2 gene, to elucidate its consequences on cardiomyocyte biology. This mutation results in in‐frame deletion of 41 amino acids, compatible with presence of some defective LAMP2 protein. Methods and Results Left ventricular tissues from L2 Δ6 and wild‐type mice had equivalent amounts of LAMP2 RNA, but a significantly lower level of LAMP2 protein. By 20 weeks of age male mutant mice developed left ventricular hypertrophy which was followed by left ventricular dilatation and reduced systolic function. Cardiac electrophysiology and isolated cardiomyocyte studies demonstrated ventricular arrhythmia, conduction disturbances, abnormal calcium transients and increased sensitivity to catecholamines. Myocardial fibrosis was strikingly increased in 40‐week‐old L2 Δ6 mice, recapitulating findings of human LAMP2 cardiomyopathy. Immunofluorescence and transmission electron microscopy identified mislocalization of lysosomes and accumulation of autophagosomes between sarcomeres, causing profound morphological changes disrupting the cellular ultrastructure. Transcription profile and protein expression ana...