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 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 of BW755c, or the NOS inhibitor nitro-L-arginine.
Buck
M
M
Department of Medicine, Veterans Affairs Medical Center, San Diego, CA, USA.
Chojkier
M
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001483:Base Sequence; D016466:CHO Cells; D002100:Cachexia / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D002454:Cell Differentiation; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology*; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D018384:Oxidative Stress; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D015431:Weight Loss / Q000187:drug effects
D000975:Antioxidants; D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D004247:DNA; D003402:Creatine Kinase; D009218:Myosins