MicroRNAs involved in molecular circuitries relevant for the duchenne muscular dystrophy pathogenesis are controlled by the dystrophin/nNOS pathway

Davide Cacchiarelli, Julie Martone, Erika Girardi, Marcella Cesana, Tania Incitti, Mariangela Morlando, Carmine Nicoletti, Tiziana Santini, Olga Sthandier, Laura Barberi, Alberto Auricchio, Antonio Musar, Irene Bozzoni

Research output: Contribution to journalArticlepeer-review

208 Scopus citations

Abstract

In Duchenne muscular dystrophy (DMD) the absence of dystrophin at the sarcolemma delocalizes and downregulates nitric oxide synthase (nNOS); this alters S-nitrosylation of HDAC2 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. Several circuitries controlled by the identified microRNAs, such as the one linking miR-1 to the G6PD enzyme and the redox state of cell, or miR-29 to extracellular proteins and the fibrotic process, explain some of the DMD pathogenetic traits. We also show that, at variance with other myomiRs, miR-206 escapes from the dystrophin-nNOS control being produced in activated satellite cells before dystrophin expression; in these cells, it contributes to muscle regeneration through repression of the satellite specific factor, Pax7. We conclude that the pathway activated by dystrophin/nNOS controls several important circuitries increasing the robustness of the muscle differentiation program.

Original languageEnglish (US)
Pages (from-to)341-351
Number of pages11
JournalCell Metabolism
Volume12
Issue number4
DOIs
StatePublished - Oct 6 2010
Externally publishedYes

Bibliographical note

Funding Information:
We thank Prof. A. Riccio, Dr. M. Mora, Prof. P. Paggi, and Dr. L. Lombardi for providing material; Dr. De Angelis for helpful discussion; and Marcella Marchioni for technical support. D.C. is a recipient of a Microsoft research PhD fellowship. This work was partially supported by grants from Telethon (GGP07049 to I.B. and GGP06119 to A.M.); Parent Project Italia, EU project SIROCCO (LSHG-CT-2006-037900); ESF project “NuRNASu,” IIT “SEED,” PRIN, and BEMM; Fondazione Roma, EU project-Myoage, AFM (to A.M.); and AFM and EU projects Clinigene and DiMi (to A.A.).

Keywords

  • DEVBIO
  • DNA
  • HUMDISEASE

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