Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-κB activation in response to tumor necrosis factor α
Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-κB activation in response to tumor necrosis factor α
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DOI：
10.1096/fasebj.12.10.871
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发表时间：
1998-07-01
期刊：
影响因子：
4.8
通讯作者：
Reid, MB
中科院分区：
文献类型：
--
作者：
Li, YP;Schwartz, RJ;Reid, MB
骨骼肌萎缩和无力被认为是由肿瘤坏死因子α(TNF-α)在各种慢性病中刺激的。然而，关于肿瘤坏死因子-α对分化的骨骼肌细胞的直接作用及其信号转导机制的研究还很少，我们测试了肿瘤坏死因子-α对小鼠来源的C2C12肌肉细胞系和大鼠骨骼肌原代培养细胞的影响。分化肌管经肿瘤坏死因子-α处理后，总蛋白含量呈时间和浓度依赖性降低，成体肌球蛋白重链(MHCf)含量减少；低浓度(1-3 ng/ml)的肿瘤坏死因子-α不改变肌肉DNA含量，与肌球蛋白重链(MHCf)合成减少无关。肿瘤坏死因子-α激活核因子-kappaB与其靶DNA序列的结合，并刺激核因子-kappa B抑制蛋白I-kappa Bα的降解。2 6S蛋白酶体抑制剂(MG132 10~40mU M)可阻断NF-kappa B的激活，过氧化氢酶1 kU/ml可抑制由TNF-α激活的NF-kappaB，外源性过氧化氢200 mU M可激活NF-kappaB并促进I-kappa B的降解。这些数据表明，在分化的骨骼肌细胞中，肿瘤坏死因子-α直接诱导骨骼肌蛋白质丢失，核因子-kappaB被迅速激活，并且骨骼肌中的肿瘤坏死因子-α/核因子-kappaB信号受内源性活性氧的调节。
Skeletal muscle atrophy and weakness are thought to be stimulated by tumor necrosis factor a (TNF-alpha) in a variety of chronic diseases. However, little is known about the direct effects of TNF-alpha on differentiated skeletal muscle cells or the signaling mechanisms involved, We have tested the effects of TNF-alpha on the mouse-derived C2C12 muscle cell line and on primary cultures from rat skeletal muscle. TNF-alpha treatment of differentiated myotubes stimulated time- and concentration-dependent reductions in total protein content and loss of adult myosin heavy chain (MHCf) content; these changes were evident at low TNF-alpha concentrations (1-3 ng/ml) that did not alter muscle DNA content and were not associated with a decrease in MHCf synthesis. TNF-alpha activated binding of nuclear factor KB (NF-kappa B) to its targeted DNA sequence and stimulated degradation of I-kappa B alpha, an NF-kappa B inhibitory protein. TNF-alpha stimulated total ubiquitin conjugation whereas a 26S proteasome inhibitor (MG132 10-40 mu M) blocked TNF-alpha activation of NF-kappa B, Catalase 1 kU/ml inhibited NF-kappa B activation by TNF-alpha; exogenous hydrogen peroxide 200 mu M activated NF-kappa B and stimulated I-kappa B alpha degradation. These data demonstrate that TNF-alpha directly induces skeletal muscle protein loss, that NF-kappa B is rapidly activated by TNF-alpha in differentiated skeletal muscle cells, and that TNF-alpha/NF-kappa B signaling in skeletal muscle is regulated by endogenous reactive oxygen species.-Li, Y.-P., Schwartz, R. J., Waddell, I. D., Holloway, B. R., Reid, M. B. Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappa B activation in response to tumor necrosis factor alpha.