Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Sci Transl Med. 2012 Jul 25;4(144):144ra102. doi: 10.1126/scitranslmed.3003875.
Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause a diverse range of diseases collectively called laminopathies, the most common of which is dilated cardiomyopathy. Emerging evidence suggests that LMNA mutations cause disease by altering cell signaling pathways, but the specific mechanisms are poorly understood. We show that the AKT-mammalian target of rapamycin pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function. We also show defective autophagy in hearts of these mice and demonstrate that improvement in heart function induced by pharmacological interventions is correlated with enhanced autophagy. These findings provide a rationale for treatment of LMNA cardiomyopathy with rapalogs and implicate defective autophagy as a pathogenic mechanism of cardiomyopathy arising from LMNA mutation.
编码 A 型核纤层蛋白的核纤层蛋白 A/C 基因 (LMNA) 的突变导致了一系列被称为核纤层病的疾病，其中最常见的是扩张型心肌病。新出现的证据表明，LMNA 突变通过改变细胞信号通路导致疾病，但具体机制尚不清楚。我们表明，AKT-雷帕霉素哺乳动物靶蛋白通路在由 Lmna 突变引起的心肌病小鼠的心脏中过度激活，并且体内给予雷帕霉素类似物替西罗莫司可防止心脏功能恶化。我们还表明，这些小鼠的心脏中存在自噬缺陷，并证明药物干预诱导的心脏功能改善与增强的自噬相关。这些发现为使用雷帕霉素类似物治疗 LMNA 心肌病提供了依据，并表明自噬缺陷是由 LMNA 突变引起的心肌病的发病机制。
