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MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms
Matthew S. Alexander, … , Jeffrey J. Widrick, Louis M. Kunkel
Matthew S. Alexander, … , Jeffrey J. Widrick, Louis M. Kunkel
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(6):2651-2667. https://doi.org/10.1172/JCI73579.
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Research Article Muscle biology

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

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Abstract

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 (Dmdmdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmdmdx-5Cv 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 Dmdmdx-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.

Authors

Matthew S. Alexander, Juan Carlos Casar, Norio Motohashi, Natássia M. Vieira, Iris Eisenberg, Jamie L. Marshall, Molly J. Gasperini, Angela Lek, Jennifer A. Myers, Elicia A. Estrella, Peter B. Kang, Frederic Shapiro, Fedik Rahimov, Genri Kawahara, Jeffrey J. Widrick, Louis M. Kunkel

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Figure 1

Overexpression of miR-486 in dystrophic Dmdmdx-5Cv mouse muscles reduces dystrophic disease histopathology.

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Overexpression of miR-486 in dystrophic Dmdmdx-5Cv mouse muscles reduces...
(A) H&E staining of adult TA and diaphragm muscles from WT, Tg(Cmk-Mir486), Dmdmdx-5Cv, and Dmdmdx-5Cv Tg(Cmk-Mir486) mice. Arrowheads demarcate centralized nuclei, a classic finding in dystrophic disease and regenerating skeletal muscle. Scale bars: 50 μm. (B) Summary graphs of centralized nuclei counted from the TA and diaphragm muscles of adult Dmdmdx-5Cv and Dmdmdx-5Cv Tg(Cmk-Mir486) mice. (C) Fiber type cross-section area analysis of the TA muscles of WT, Tg(Cmk-Mir486), Dmdmdx-5Cv, and Dmdmdx-5Cv Tg(Cmk-Mir486) adult mice. Six-hundred fibers from 5 separate mice per cohort were used for analysis. *P < 0.005; **P < 0.05. The mean and SEM values for the 4 genotype cohorts are as follows: WT (773 ± 27), Tg(Cmk-Mir486) (907 ± 19), Dmdmdx-5Cv(691 ± 42), and Dmdmdx-5Cv Tg(Cmk-Mir486) (815 ± 36) measured in μm2.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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