IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.
IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.
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DOI：
10.3410/f.1023760.282705
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发表时间：
2004
期刊：
影响因子：
64.5
通讯作者：
D. Cai;J. Frantz;N. Tawa;P. A. Meléndez;Byung-Chul Oh;H. Lidov;P. Hasselgren;W. Frontera;
中科院分区：
文献类型：
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作者：
D. Cai;J. Frantz;N. Tawa;P. A. Meléndez;Byung-Chul Oh;H. Lidov;P. Hasselgren;W. Frontera;
肌肉萎缩伴随着衰老和病理状况，从癌症、恶病质、糖尿病到去神经支配和固定。我们发现，通过激活 IkappaB 激酶 β (MIKK) 的肌肉特异性转基因表达，NF-kappaB 的激活会导致严重的肌肉萎缩，类似于临床恶病质。相比之下，通过 IkappaBalpha 超阻遏物 (MISR) 的表达对 NF-kappaB 进行肌肉特异性抑制时，没有观察到明显的表型。肌肉损失是由于泛素依赖性蛋白水解作用加速蛋白质分解所致。 MIKK 小鼠中 E3 连接酶 MuRF1（肌肉萎缩介质）的表达增加。 IKKbeta/NF-kappaB/MuRF1 通路的药理学或遗传抑制可逆转肌肉萎缩。在 MISR 小鼠中，通过抑制 NF-kappaB，显着减少去神经和肿瘤引起的肌肉损失，并提高存活率，这与 NF-kappaB 在肌肉萎缩病理学中的关键作用一致，并将其确立为治疗肌肉萎缩的重要临床靶点。
Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.