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Regulation of DMD pathology by an ankyrin-encoded miRNA

DOI: 10.1186/2044-5040-1-27

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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.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.Duchenne muscular dystrophy (DMD) is a progressive, X-linked, muscle-wasting disease that occurs in 1 in 3,500 live male births [1]. Males with inactivating mutations in the DMD (dystrophin) gene make a nonfunctional protein which results in degenerating skeletal muscles, severely elevated creatine kinase (CK) levels, cardiac arrhythmias and secondary infections and subsequent respiratory failure due to the degeneration of the diaphragm muscles [2,3]. By contrast, patients with Becker muscular dystrophy (BMD) also have mutations in the DMD gene, but produce a partially functional dystrophin protein [3]. Patients with BMD have mildly progressive muscle weakness and elevated CK serum levels as well as variable longevity and mobility [3]. While the genetic mutations that cause DMD are now well established, the subsequent steps that lead to the disease pathogenesis are still emerging [4]. In dystrophin-deficient muscles, it has been demonstrated that the platelet-derived growth factor (PDGF) receptor (PDGFR) signaling pathway is signif


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