Role of microRNAs in Duchenne Muscular Dystrophy and in muscle differentiation
Year: 2011
Type: dissertation
Abstract: Duchenne Muscular Dystrophy (DMD), caused by mutations in the dystrophin gene, is one of the most severe myopathies. Among different therapeutic strategies, exon skipping allows the rescue of dystrophin synthesis through the production of a shorter but functional mRNA. Making use of exon skipping strategy we demonstrated that in DMD, the absence of dystrophin at the sarcolemma delocalizes and downregulates Nitric Oxide Synthase (nNOS); this alters HDAC2 S-nitrosylation and its chromatin association. We show that the differential HDAC2 nitrosylation state in Duchenne versus wild-type conditions deregulates the expression of a specific subset of microRNA genes crucial in DMD physiopathology.\nNamely, we identified miR-1 as regulator of the redox state of the cell through modulation of the G6PD enzyme while miR-29 controls the fibrotic process targeting extracellular matrix proteins.\nWe also show that, at variance with other myomiRs, miR-206 and miR-31 escape from the dystrophin-nNOS control being expressed in activated satellite cells before dystrophin expression. In these cells, miR-206 contributes to muscle regeneration through repression of the satellite specific factor Pax7, while miR-31 inhibits the early expression of dystrophin by directly repressing its mRNA.\nFinally, in human DMD myoblasts treated with exon skipping molecules, we demonstrate that miR-31 inhibition increases dystrophin rescue representing a new approach to coadiuvate the existing therapeutic strategies.\nWe conclude that:\n- the pathway activated by dystrophin/nNOS controls key\nmiRNA circuitries increasing the robustness of the muscle\ndifferentiation programme.\n- specific miRNAs are induced during muscle regeneration\ncontrolling the timing of mRNA expression during myoblasts\ndifferentiation.\n- the inhibition of specific miRNA extression enhances\ndystrophin rescue obtained through exon skipping treatments.
Author: CACCHIARELLI, DAVIDE
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7005720815