Involvement of adiponectin in the pathogenesis of dystrophinopathy.
Involvement of adiponectin in the pathogenesis of dystrophinopathy.
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DOI：
10.1186/s13395-015-0051-9
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发表时间：
2015
期刊：
影响因子：
4.9
通讯作者：
Brichard SM
中科院分区：
文献类型：
--
作者：
Abou-Samra M;Lecompte S;Schakman O;Noel L;Many MC;Gailly P;Brichard SM
激素脂联素（ApN）在代谢综合征中下降，在代谢综合征中起关键的致病作用。ApN对急性或慢性炎症小鼠骨骼肌也有一定的抗炎作用。在这里，我们研究ApN是否能够足够有效地对抗严重的退行性肌肉疾病，包括炎症成分，如杜氏肌营养不良（DMD）。将Mdx小鼠（肌营养不良蛋白突变引起的DMD模型）与过表达ApN的小鼠杂交，生成Mdx -ApN小鼠；只使用了同窝的同伴。研究了炎症/氧化应激的不同标志物和信号通路的组成部分。通过体内功能测试和Evans蓝染料（EBD）的肌肉损伤来评估全局力。最后，使用了人肌管的原代培养物。mdx小鼠循环ApN明显减少。在mdx-ApN小鼠中，补充ApN显著减少了肌肉炎症、氧化应激，并增强了肌源性分化标志物和肌营养蛋白A（一种肌营养不良蛋白类似物）的表达。因此，mdx-ApN小鼠表现出更高的整体力量和耐力，并通过减少EBD在肌纤维中的外渗来量化肌肉损伤。ApN的这些有益作用在人肌管中得到了再现。ApN通过脂联素受体1 （AdipoR1，肌肉中主要的ApN受体）和AMPK-SIRT1-PGC-1α信号通路介导其保护作用，导致核因子κB （NF-κB）和炎症基因下调，并上调utrophin。脂联素被证明是一种非常强大的激素，能够保护骨骼肌免受炎症和损伤，从而为肌营养不良症提供新的治疗前景。本文的在线版本（doi:10.1186/s13395-015-0051-9）包含补充材料，可供授权用户使用。
The hormone adiponectin (ApN) is decreased in the metabolic syndrome, where it plays a key pathogenic role. ApN also exerts some anti-inflammatory effects on skeletal muscles in mice exposed to acute or chronic inflammation. Here, we investigate whether ApN could be sufficiently potent to counteract a severe degenerative muscle disease, with an inflammatory component such as Duchenne muscular dystrophy (DMD). Mdx mice (a DMD model caused by dystrophin mutation) were crossed with mice overexpressing ApN in order to generate mdx-ApN mice; only littermates were used. Different markers of inflammation/oxidative stress and components of signaling pathways were studied. Global force was assessed by in vivo functional tests, and muscle injury with Evans Blue Dye (EBD). Eventually, primary cultures of human myotubes were used. Circulating ApN was markedly diminished in mdx mice. Replenishment of ApN strikingly reduced muscle inflammation, oxidative stress, and enhanced the expression of myogenic differentiation markers along with that of utrophin A (a dystrophin analog) in mdx-ApN mice. Accordingly, mdx-ApN mice exhibited higher global force and endurance as well as decreased muscle damage as quantified by curtailed extravasation of EBD in myofibers. These beneficial effects of ApN were recapitulated in human myotubes. ApN mediates its protection via the adiponectin receptor 1 (AdipoR1, the main ApN receptor in muscle) and the AMPK-SIRT1-PGC-1α signaling pathway, leading to downregulation of the nuclear factor kappa B (NF-κB) and inflammatory genes, together with upregulation of utrophin. Adiponectin proves to be an extremely powerful hormone capable of protecting the skeletal muscle against inflammation and injury, thereby offering novel therapeutic perspectives for dystrophinopathies. The online version of this article (doi:10.1186/s13395-015-0051-9) contains supplementary material, which is available to authorized users.