Muchir Antoine, Worman Howard J
Center of Research in Myology, UPMC-Inserm UMR974, CNRS FRE3617, Institut de Myologie, G.H. Pitie Salpetriere, Paris Cedex, France.
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA; Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, USA.
Methods Enzymol. 2016;568:557-80. doi: 10.1016/bs.mie.2015.07.028. Epub 2015 Oct 24.
The most frequently occurring mutations in the gene encoding nuclear lamin A and nuclear lamin C cause striated muscle diseases virtually always involving the heart. In this review, we describe the approaches and methods used to discover that cardiomyopathy-causing lamin A/C gene mutations increase MAP kinase signaling in the heart and that this plays a role in disease pathogenesis. We review different mouse models of cardiomyopathy caused by lamin A/C gene mutations and how transcriptomic analysis of one model identified increased cardiac activity of the ERK1/2, JNK, and p38α MAP kinases. We describe methods used to measure the activity of these MAP kinases in mouse hearts and then discuss preclinical treatment protocols using pharmacological inhibitors to demonstrate their role in pathogenesis. Several of these kinase inhibitors are in clinical development and could potentially be used to treat human subjects with cardiomyopathy caused by lamin A/C gene mutations.
编码核纤层蛋白A和核纤层蛋白C的基因中最常见的突变几乎总会导致累及心脏的横纹肌疾病。在本综述中，我们描述了用于发现导致心肌病的核纤层蛋白A/C基因突变会增加心脏中的丝裂原活化蛋白激酶（MAP激酶）信号传导，且这在疾病发病机制中起作用的方法。我们综述了由核纤层蛋白A/C基因突变引起的心肌病的不同小鼠模型，以及对其中一个模型的转录组分析如何确定细胞外信号调节激酶1/2（ERK1/2）、应激活化蛋白激酶（JNK）和p38α MAP激酶的心脏活性增加。我们描述了用于测量小鼠心脏中这些MAP激酶活性的方法，然后讨论了使用药理学抑制剂的临床前治疗方案，以证明它们在发病机制中的作用。其中几种激酶抑制剂正处于临床开发阶段，有可能用于治疗由核纤层蛋白A/C基因突变引起的心肌病的人类患者。
