Interconnection between molecular regulators in LMNA related muscular dystrophy

Abstract

Nuclear lamina is composed of different A-type and B-type lamin proteins and acts as major regulator of DNA replication, transcription, heterochromatin-euchromatin machinery. The majority of mutations in A type lamin are associated with some forms of muscular dystrophies,that majorly distinguishable by a common clinical feature : progressive skeletal muscle wasting. This speculates impaired skeletal muscle differentiation during development and after injury with the influence of myriad of signalling pathways. The molecular mechanism behind phenotypes of lamin A associated muscular dystrophies are still elusive . Here, we used genome wide expression analysis platform during the differentiation of murine C2C12 skeletal muscle cells to investigate the factors have been attributed to the disease. We compared the expression levels of the components of pathways that indicates important role of skeletal muscle as well as identified gene regulatory networks at two different time points of muscle differentiation in wild type and mutant cells. We also report significant perturbations in the expression and activation of Wnt signalling pathway in mutant cells among 40 dysregulated signalling pathways , presenting pronounced regulation of normal downstream myogenic signalling . Finally, with this largest data sets we evaluate in depth characterization of molecular effectors for myogenic differentiation, which could allow greater insight into development of therapeutic strategies for the remission of patients with LMNA linked muscle - related pathologies.