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MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms
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MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms
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MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms
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Journal Article
MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms
2014
Overview
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.
Publisher
American Society for Clinical Investigation
Subject
/ Carrier Proteins - metabolism
/ Cellular signal transduction
/ Guanine Nucleotide Exchange Factors - genetics
/ Guanine Nucleotide Exchange Factors - metabolism
/ Humans
/ Male
/ Mice
/ MicroRNA
/ Muscle Fibers, Skeletal - metabolism
/ Muscle Fibers, Skeletal - pathology
/ Muscle, Skeletal - metabolism
/ Muscle, Skeletal - pathology
/ Muscular Dystrophy, Animal - genetics
/ Muscular Dystrophy, Animal - metabolism
/ Muscular Dystrophy, Animal - pathology
/ Muscular Dystrophy, Duchenne - genetics
/ Muscular Dystrophy, Duchenne - metabolism
/ Muscular Dystrophy, Duchenne - pathology
/ Mutation
/ Nerve Tissue Proteins - genetics
/ Nerve Tissue Proteins - metabolism
/ Proto-Oncogene Proteins c-akt - metabolism
/ PTEN Phosphohydrolase - metabolism
/ Rodents
