Autophagy as a new therapeutic target in Duchenne muscular dystrophy.
Autophagy as a new therapeutic target in Duchenne muscular dystrophy.
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DOI：
10.1038/cddis.2012.159
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发表时间：
2012-11-15
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
杜氏肌营养不良症是一种严重的骨骼肌退行性疾病，目前尚无有效的治疗方法。由于自噬已被证明在清除功能失调的细胞器和防止组织损伤方面至关重要，我们研究了其致病作用及其作为杜氏肌营养不良症（DMD）新治疗干预靶点的适用性。在这里，我们证明了DMD患者和mdx小鼠（该疾病的模型）的肌肉自噬严重受损，并伴有受损细胞器的积累。自噬缺陷伴随着Akt、哺乳动物雷帕霉素靶蛋白（mTOR）及其依赖的自噬抑制通路（包括翻译起始因子4e结合蛋白1和核糖体蛋白S6）的磷酸化和自噬诱导基因LC3、Atg12、Gabarapl1和Bnip3的下调而持续激活。mdx小鼠的缺陷自噬通过长期暴露于低蛋白饮食得以恢复。治疗导致Akt和mTOR信号通路正常化；它还能显著减少肌肉炎症、纤维化和肌纤维损伤，从而恢复肌肉功能。本研究强调了DMD的新致病方面，并提示自噬是一种新的有效治疗靶点。我们提出的治疗方法可以安全地应用，并立即在人体上进行疗效测试。
A resolutive therapy for Duchene muscular dystrophy, a severe degenerative disease of the skeletal muscle, is still lacking. Because autophagy has been shown to be crucial in clearing dysfunctional organelles and in preventing tissue damage, we investigated its pathogenic role and its suitability as a target for new therapeutic interventions in Duchenne muscular dystrophy (DMD). Here we demonstrate that autophagy is severely impaired in muscles from patients affected by DMD and mdx mice, a model of the disease, with accumulation of damaged organelles. The defect in autophagy was accompanied by persistent activation via phosphorylation of Akt, mammalian target of rapamycin (mTOR) and of the autophagy-inhibiting pathways dependent on them, including the translation-initiation factor 4E-binding protein 1 and the ribosomal protein S6, and downregulation of the autophagy-inducing genes LC3, Atg12, Gabarapl1 and Bnip3. The defective autophagy was rescued in mdx mice by long-term exposure to a low-protein diet. The treatment led to normalisation of Akt and mTOR signalling; it also reduced significantly muscle inflammation, fibrosis and myofibre damage, leading to recovery of muscle function. This study highlights novel pathogenic aspects of DMD and suggests autophagy as a new effective therapeutic target. The treatment we propose can be safely applied and immediately tested for efficacy in humans.
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影响因子：
158.5
作者：
Goemans, Nathalie M.;Tulinius, Mar;van Deutekom, Judith C.
通讯作者：
van Deutekom, Judith C.
DOI：
10.1097/nen.0b013e3181b7bfc8
发表时间：
2009-10-01
影响因子：
3.2
作者：
Francolini, Maura;Brunelli, Giorgio;Pizzi, Marina
通讯作者：
Pizzi, Marina
DOI：
10.1073/pnas.0805514105
发表时间：
2008-12-09
影响因子：
11.1
作者：
Colussi, Claudia;Mozzetta, Chiara;Gaetano, Carlo
通讯作者：
Gaetano, Carlo
影响因子：
7.8
作者：
Deponti, Daniela;Francois, Stephanie;Brunelli, Silvia
通讯作者：
Brunelli, Silvia
影响因子：
82.9
作者：
Grumati, Paolo;Coletto, Luisa;Bonaldo, Paolo
通讯作者：
Bonaldo, Paolo