Regulation of DMD pathology by an ankyrin-encoded miRNA

Matthew S. Alexander, Juan C. Casar, Norio Motohashi, Jennifer A. Myers, Iris Eisenberg, Robert T. Gonzalez, Elicia A. Estrella, Peter B. Kang, Genri Kawahara, Louis M. Kunkel

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


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.

Original languageEnglish (US)
Article number27
JournalSkeletal muscle
Issue number1
StatePublished - Aug 8 2011
Externally publishedYes

Bibliographical note

Funding Information:
Funding for this work was generously provided by the Bernard F and Alva B Gimbel Foundation (to LMK) and through National Institutes of Health (NIH) grant P50 NS040828-10. RTG was funded by the Howard Hughes Medical Institute Exceptional Research Opportunities Program (EXROP). MSA was funded by a traineeship awarded by the NIH through the Harvard Stem Cell Institute. PBK is supported by the Muscular Dystrophy Association (MDA 186796 and MDA 114353) and the Genise Goldenson Fund. The authors express their gratitude toward the families and patients who donated their biopsies and time for these experiments.


Dive into the research topics of 'Regulation of DMD pathology by an ankyrin-encoded miRNA'. Together they form a unique fingerprint.

Cite this