MicroRNA-486 dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy-associated symptoms
MicroRNA-486 dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy-associated symptoms
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DOI：
10.1172/jci73579
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发表时间：
2014-06-01
影响因子：
15.9
通讯作者：
Kunkel, Louis M.
中科院分区：
文献类型：
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作者：
Alexander, Matthew S.;Carlos Casar, Juan;Kunkel, Louis M.
Duchenne肌营养不良症(DMD)是由编码dystrophin的基因突变引起的，该基因导致肌肉内信号通路功能障碍。此前，我们发现microRNA-486(miR-486)是一种肌肉丰富的microRNA，在DMD(MDX-SCV)小鼠的肌肉中显著减少，在DMD患者的肌肉中显著减少。在这里，我们确定了肌肉特异的miR-486转基因在DMD(MDX-SCV)小鼠肌肉中的过表达导致血清肌酸激酶水平降低，肌膜完整性改善，集中肌核减少，肌纤维尺寸增加，肌肉生理和性能改善。此外，我们还发现DOCK3在骨骼肌中作为miR-486的靶标，并确定DOCK3在营养不良的肌肉中被诱导表达。DOCK3在人肌管中过表达可调节PTEN/AKT信号通路，从而调节肌肉肥大和生长，并诱导细胞凋亡。此外，在dystrophin缺乏的肌肉中，PTEN/AKT通路的几个组成部分被miR-486显著调节。在DMD(MDX-5CV)动物中，骨骼肌特异性miR-486的过表达降低了DOCK3的水平，降低了PTEN的表达，随后增加了磷酸化的AKT的水平，这导致了总体上的有益效果。总之，这些研究表明，miR-486的稳定过表达可以改善dystrophin缺陷性骨骼肌的疾病进展。
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.