Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy.
Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy.
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DOI：
10.1016/j.neuron.2009.07.019
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发表时间：
2009-08-13
期刊：
影响因子：
16.2
通讯作者：
Pennuto, Maria
中科院分区：
文献类型：
--
作者：
Palazzolo, Isabella;Stack, Conor;Kong, Lingling;Musaro, Antonio;Adachi, Hiroaki;Katsuno, Masahisa;Sobue, Gen;Taylor, J. Paul;Sumner, Charlotte J.;Fischbeck, Kenneth H.;Pennuto, Maria
雄激素受体（AR）中多聚谷氨酰胺束的扩张导致脊髓和延髓肌萎缩（SBMA）。我们以前已经表明，Akt介导的AR磷酸化减少配体结合，减弱突变体AR的毒性。在这里，我们表明，在培养的细胞中，胰岛素样生长因子1（IGF-1）减少AR聚集和增加AR清除通过泛素-蛋白酶体系统通过Akt的AR磷酸化。为了评估外源性IGF-1在体内的潜在益处，我们将SBMA小鼠与在骨骼肌中选择性过表达IGF-1的肌肉特异性亚型的小鼠杂交。在由此产生的后代中，我们发现Akt活化和AR磷酸化增加以及AR聚集减少的证据。IGF-1/Akt信号的增强挽救了SBMA小鼠的行为和组织病理学异常，延长了寿命并减少了肌肉和脊髓病理学。这项研究建立了IGF-1/Akt介导的突变型AR失活作为体内对抗疾病的策略，并首次证明骨骼肌是SBMA治疗干预的可行靶组织。
Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We have previously shown that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the toxicity of mutant AR. Here we show that in cultured cells insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. To evaluate the potential benefit of exogenous IGF-1 in vivo, we crossed SBMA mice with mice that overexpress a muscle-specific isoform of IGF-1 selectively in skeletal muscle. In the resulting offspring, we found evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescued behavioral and histopathological abnormalities, extended the life span and reduced both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates for the first time that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA.
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