Regulation of DMD pathology by an ankyrin-encoded miRNA

被引:77
作者
Alexander, Matthew S. [1 ,2 ]
Casar, Juan Carlos [1 ,2 ]
Motohashi, Norio [1 ,2 ]
Myers, Jennifer A. [1 ,2 ]
Eisenberg, Iris [1 ,2 ]
Gonzalez, Robert T. [1 ,2 ]
Estrella, Elicia A. [1 ,2 ]
Kang, Peter B. [1 ,2 ,6 ,7 ]
Kawahara, Genri [1 ,2 ]
Kunkel, Louis M. [1 ,2 ,3 ,4 ,5 ]
机构
[1] Childrens Hosp, Program Genom, Boston, MA 02115 USA
[2] Childrens Hosp, Div Genet, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA
[4] Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA
[5] Harvard Stem Cell Inst, Cambridge, MA 02138 USA
[6] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA
[7] Harvard Univ, Sch Med, Boston, MA 02115 USA
来源
SKELETAL MUSCLE | 2011年 / 1卷
基金
美国国家卫生研究院;
关键词
Duchenne Muscular Dystrophy; Tibialis Anterior; Duchenne Muscular Dystrophy Patient; Becker Muscular Dystrophy; Golden Retriever Muscular Dystrophy;
D O I
10.1186/2044-5040-1-27
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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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页数:17
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