Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants
Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants
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DOI：
10.1002/j.1460-2075.1996.tb00524.x
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发表时间：
1996-04-15
期刊：
影响因子：
11.4
通讯作者：
Chojkier, M
中科院分区：
文献类型：
--
作者：
Buck, M;Chojkier, M
肌肉萎缩是艾滋病或癌症患者的一个重要特征。在小鼠肌肉萎缩模型中，肿瘤坏死因子α (TNF α)诱导骨骼肌氧化应激和一氧化氮合酶（NOS），导致肌球蛋白肌酸酐磷酸激酶（MCK）表达和结合活性降低。MCK-E盒子结合活性受损是由异常的肌原素-Jun-D复合物引起的，并通过添加Jun-D、二硫苏糖醇或核氧化还原蛋白Ref-1而恢复正常。用磷酯、超氧化物生成系统、NO供体或Jun-D反义寡核苷酸处理骨骼肌细胞，可降低Jun-D活性和MCK-E盒子的转录，而抗氧化剂、还原物清除剂、NOS抑制剂和/或Jun-D的过表达可阻止这种活性和转录。用抗氧化剂d - α -生育酚或BW755c或NOS抑制剂硝基- l -精氨酸处理TNF - α小鼠，可防止其体重下降、肌肉萎缩和恶病质骨骼肌分子异常。
Muscle wasting is a critical feature of patients afflicted by AIDS or cancer. In a murine model of muscle wasting, tumor necrosis factor alpha (TNF alpha) induces oxidative stress and nitric oxide synthase (NOS) in skeletal muscle, leading to decreased myosin creatinine phosphokinase (MCK) expression and binding activities. The impaired MCK-E box binding activities resulted from abnormal myogenin-Jun-D complexes, and were normalized by the addition of Jun-D, dithiothreitol or Ref-1, a nuclear redox protein. Treatment of skeletal muscle cells with a phorbol ester, a superoxide-generating system, an NO donor or a Jun-D antisense oligonucleotide decreased Jun-D activity and transcription from the MCK-E box, which were prevented by antioxidants, a scavenger of reducing equivalents, a NOS inhibitor and/or overexpression of Jun-D. The decreased body weight, muscle wasting and skeletal muscle molecular abnormalities of cachexia were prevented by treatment of TNF alpha mice with the antioxidants D-alpha-tocopherol or BW755c, or the NOS inhibitor nitro-L-arginine.