NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS
NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS
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DOI：
10.1172/jci30654
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发表时间：
2007-09-01
影响因子：
15.9
通讯作者：
Takeda, Shin'ichi
中科院分区：
文献类型：
--
作者：
Suzuki, Naoki;Motohashi, Norio;Takeda, Shin'ichi
叉头盒O（Foxo）转录因子通过上调肌肉特异性E3泛素连接酶MuRF-1和atrogin-1/MAFbx诱导肌肉萎缩，但除Akt外，Foxos在肌肉萎缩期间的上游调节因子在很大程度上是未知的。为了研究肌营养不良蛋白糖蛋白复合物（DGC）参与Foxo活性和肌肉萎缩的调节，我们分析了DGC成员在尾部悬吊（一种卸载诱导的肌肉萎缩模型）期间的表达。在几个DGC成员中，只有神经元型NOS（nNOS）在尾部悬吊期间迅速从肌膜移位到细胞质。电子顺磁共振光谱显示，在萎缩的肌肉中产生NO。nNOS基因敲除的小鼠在尾部悬吊后表现出比野生型小鼠轻得多的肌肉萎缩。重要的是，去磷酸化Foxo 3a的核积累在nNOS缺失的肌肉中并不明显，并且在尾部悬挂期间MuRF-1和atrogin-1/MAFbx都没有上调。此外，nNOS特异性抑制剂，7-硝基吲唑，显着防止悬浮诱导的肌肉萎缩。在尾部悬吊期间，野生型和nNOS缺失肌肉中的NF-κ B通路均被激活。我们还表明，nNOS参与失神经诱导萎缩的机制。我们的结论是，nNOS/NO介导的肌肉萎缩通过调节Foxo转录因子，是一个新的治疗靶点废用性肌肉萎缩。
Forkhead box O (Foxo) transcription factors induce muscle atrophy by upregulating the muscle-specific E3 ubiquitin ligases MuRF-1 and atrogin-1/MAFbx, but other than Akt, the upstream regulators of Foxos during muscle atrophy are largely unknown. To examine the involvement of the dystrophin glycoprotein complex (DGC) in regulation of Foxo activities and muscle atrophy, we analyzed the expression of DGC members during tail suspension, a model of unloading-induced muscle atrophy. Among several DGC members, only neuronal NOS (nNOS) quickly dislocated from the sarcolemma to the cytoplasm during tail suspension. Electron paramagnetic resonance spectrometry revealed production of NO in atrophying muscle. nNOS-null mice showed much milder muscle atrophy after tail suspension than did wild-type mice. Importantly, nuclear accumulation of dephosphorylated Foxo3a was not evident in nNOS-null muscle, and neither MuRF-1 nor atrogin-1/MAFbx were upregulated during tail suspension. Furthermore, an nNOS-specific inhibitor, 7-nitroindazole, significantly prevented suspension-induced muscle atrophy. The NF-kappa B pathway was activated in both wildtype and nNOS-null muscle during tail suspension. We also show that nNOS was involved in the mechanism of denervation-induced atrophy. We conclude that nNOS/NO mediates muscle atrophy via regulation of Foxo transcription factors and is a new therapeutic target for disuse-induced muscle atrophy.