Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants

Abstract

Muscle wasting is a critical feature of patients afflicted by AIDS or cancer. In a murine model of muscle wasting, tumor necrosis factor α (TNFα) 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 TNFα mice with the antioxidants D-α-tocopherol or BW755c, or the NOS inhibitor nitro-L-arginine.