Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha.
Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha.
复制标题
DOI：
--
复制
发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Y. Li;R. Schwartz;I. Waddell;B. Holloway;M. Reid
中科院分区：
文献类型：
--
作者：
Y. Li;R. Schwartz;I. Waddell;B. Holloway;M. Reid
骨骼肌萎缩和无力被认为是由肿瘤坏死因子α（TNF-α）在各种慢性疾病刺激。然而，关于TNF-α对分化的骨骼肌细胞的直接作用或所涉及的信号传导机制知之甚少。我们已经测试了TNF-α对小鼠来源的C2 C12肌肉细胞系和大鼠骨骼肌原代培养物的影响。TNF-α处理分化的肌管刺激总蛋白含量的时间和浓度依赖性降低和成人肌球蛋白重链（MHCf）含量的损失;这些变化在低TNF-α浓度（1-3 ng/ml）下明显，不改变肌肉DNA含量，也不与MHCf合成减少相关。TNF-α激活核因子κ B（NF-κ B）与其靶向DNA序列的结合，并刺激NF-κ B抑制蛋白I-κ B α的降解。TNF-α刺激总泛素结合，而26 S蛋白酶体抑制剂（MG 132 10-40 μ M）阻断TNF-α对NF-κ B的活化。过氧化氢酶1 kU/ml抑制TNF-α激活NF-κ B;外源性过氧化氢200 μ M激活NF-κ B并刺激I-κ B α降解。这些数据表明，TNF-α直接诱导骨骼肌蛋白质损失，NF-κ B在分化的骨骼肌细胞中被TNF-α快速激活，并且骨骼肌中的TNF-α/NF-κ B信号传导受内源性活性氧调节。
Skeletal muscle atrophy and weakness are thought to be stimulated by tumor necrosis factor alpha (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 kappaB (NF-kappaB) to its targeted DNA sequence and stimulated degradation of I-kappaBalpha, an NF-kappaB inhibitory protein. TNF-alpha stimulated total ubiquitin conjugation whereas a 26S proteasome inhibitor (MG132 10-40 microM) blocked TNF-alpha activation of NF-kappaB. Catalase 1 kU/ml inhibited NF-kappaB activation by TNF-alpha; exogenous hydrogen peroxide 200 microM activated NF-kappaB and stimulated I-kappaBalpha degradation. These data demonstrate that TNF-alpha directly induces skeletal muscle protein loss, that NF-kappaB is rapidly activated by TNF-alpha in differentiated skeletal muscle cells, and that TNF-alpha/NF-kappaB signaling in skeletal muscle is regulated by endogenous reactive oxygen species.