title: Regulation of DMD pathology by an ankyrin-encoded miRNA.
abstract: BACKGROUND
  Duchenne muscular dystrophy (DMD) is an X-linked myopathy resulting from the production of a nonfunctional dystrophin protein. MicroRNA (miRNA) are small 21- to 24-nucleotide RNA that can regulate both individual genes and entire cell signaling pathways. Previously, we identified several mRNA, both muscle-enriched and inflammation-induced, that are dysregulated in the skeletal muscles of DMD patients. One particularly muscle-enriched miRNA, miR-486, is significantly downregulated in dystrophin-deficient mouse and human skeletal muscles. miR-486 is embedded within the ANKYRIN1(ANK1) gene locus, which is transcribed as either a long (erythroid-enriched) or a short (heart muscle- and skeletal muscle-enriched) isoform, depending on the cell and tissue types.
  
  
  RESULTS
  Inhibition of miR-486 in normal muscle myoblasts results in inhibited migration and failure to repair a wound in primary myoblast cell cultures. Conversely, overexpression of miR-486 in primary myoblast cell cultures results in increased proliferation with no changes in cellular apoptosis. Using bioinformatics and miRNA reporter assays, we have identified platelet-derived growth factor receptor β, along with several other downstream targets of the phosphatase and tensin homolog deleted on chromosome 10/AKT (PTEN/AKT) pathway, as being modulated by miR-486. The generation of muscle-specific transgenic mice that overexpress miR-486 revealed that miR-486 alters the cell cycle kinetics of regenerated myofibers in vivo, as these mice had impaired muscle regeneration.
  
  
  CONCLUSIONS
  These studies demonstrate a link for miR-486 as a regulator of the PTEN/AKT pathway in dystrophin-deficient muscle and an important factor in the regulation of DMD muscle pathology.
authors.affiliation: Program in Genomics and Division of Genetics, Children's Hospital Boston, 3 Blackfan Circle, CLS15024, Boston, MA 02115, USA. kunkel@enders.tch.havard.edu.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Alexander
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Casar
authors.forename: Norio
authors.initials: N
authors.lastname: Motohashi
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Myers
authors.forename: Iris
authors.initials: I
authors.lastname: Eisenberg
authors.forename: Robert T
authors.initials: RT
authors.lastname: Gonzalez
authors.forename: Elicia A
authors.initials: EA
authors.lastname: Estrella
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kang
authors.forename: Genri
authors.initials: G
authors.lastname: Kawahara
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel