Journal
SKELETAL MUSCLE
Volume 1, Issue -, Pages -Publisher
BMC
DOI: 10.1186/2044-5040-1-27
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Funding
- Bernard F and Alva B Gimbel Foundation
- National Institutes of Health (NIH) [P50 NS040828-10]
- Howard Hughes Medical Institute Exceptional Research Opportunities Program (EXROP)
- NIH through the Harvard Stem Cell Institute
- Muscular Dystrophy Association [MDA 186796, MDA 114353]
- Genise Goldenson Fund
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P50NS040828] Funding Source: NIH RePORTER
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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 beta, 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.
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