MUSCLE WASTING AND DEDIFFERENTIATION INDUCED BY OXIDATIVE STRESS IN AMURINE 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 alp ha (TNF alpha) induces oxidative stress and nitric oxide synthase (NOS ) in skeletal muscle, leading to decreased myosin creatinine phosphoki nase (MCK) expression and binding activities. The impaired MCK-E box b inding 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 phorb ol ester, a superoxide-generating system, an NO donor or a Jun-D antis ense oligonucleotide decreased Jun-D activity and transcription from t he MCK-E box, which were prevented by antioxidants, a scavenger of red ucing equivalents, a NOS inhibitor and/or overexpression of Jun-D. The decreased body weight, muscle wasting and skeletal muscle molecular a bnormalities of cachexia were prevented by treatment of TNF alpha mice with the antioxidants D-alpha-tocopherol or BW755c, or the NOS inhibi tor nitro-L-arginine.