Investigating the deregulation and bio-functional relevance of caveolin-1 in muscular laminopathies -

Abstract

Laminopathies comprise a heterogeneous group of disorders arising from mutations or altered post translational processing of nuclear envelope (NE)-lamina proteins. The majority of these disorders are caused by inherited or de novo mutations in the LMNA gene and are manifested as diverse pathologies affecting a wide range of tissues including skeletal and cardiac muscle. To date, the molecular mechanisms underlying the phenotypic diversity and disease pathogenesis in laminopathies have not been deciphered. Our objective is to gain a better understanding of the mechanisms by which distinct mutations in the ubiquitously expressed LMNA gene contribute to the tissue specific phenotypes that result in muscular laminopathies including Emery-Dreifuss Muscular Dystrophy (EDMD) and Dilated Cardiomyopathy (DCM). We hypothesize that complete loss of or specific mutations in LMNA associated with muscular laminopathies exert differential effects on the expression and-or intra-cellular distribution of caveolins which by lieu of their association with the cell membrane caveolae, orchestrate many signaling pathways in response to changes in the cell’s biochemical or mechanical environment. Of particular interest to us is caveolin-1, a product of the Cav-1 mechanosensitive gene (encodes for α and β isoforms of caveolin-1) which has been shown to be implicated in muscle repair and regeneration. In this study, we assessed the transcript and protein expression of Cav-1 (both α and β isoforms) in mouse embryo fibroblast (MEF) lines derived from mice lacking either A-type lamin (Lmna---) or emerin (Emd --Y) which have the EDMD phenotype or mice homozygous for the N195K mutant (Lmna N195K-N195K) which have the DCM phenotype versus wild-type (WT) controls under baseline and oxidative stress conditions. Real-Time PCR quantification of Cav-1 under baseline conditions showed a reduction in the Cav-1α transcript in Lmna--- MEFs and a significant elevation in the Cav-1α transcript in Lmna N195K-N195K and