期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 6, 页码 2651-2667出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI73579
关键词
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资金
- Bernard F. and Alva B. Gimbel Foundation
- NIH [P50 NS040828-10, R01 NS080929, CHB IDDRC P30-HD 18655]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH [R01AR064300]
- Muscular Dystrophy Association (MDA) [MDA186796]
- MDA development grant [MDA255059, MDA202863]
Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which results in dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmd(mdx-scv) mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmd(mdx-scv) mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle-specific miR-486 overexpression in Dmd(mdx-5Cv) animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle.
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