title: Targeting Mitogen-Activated Protein Kinase Signaling in Mouse Models of Cardiomyopathy Caused by Lamin A/C Gene Mutations.
abstract: 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.
authors.affiliation: Center of Research in Myology, UPMC-Inserm UMR974, CNRS FRE3617, Institut de Myologie, G.H. Pitie Salpetriere, Paris Cedex, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
authors.affiliation: 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. Electronic address: hjw14@columbia.edu.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation
chemical_list: D034904:Lamin Type A; C440308:lamin C
keywords: Emery–Dreifuss muscular dystrophy; Heart; Lamin; Laminopathy; Mitogen-activated protein kinase inhibitors; Nuclear envelope