Transcription factors in muscle atrophy caused by blocked neuromuscular transmission and muscle unloading in rats

The muscle wasting associated with long-term intensive care unit (ICU) treatment has a negative effect on muscle function resulting in prolonged periods of rehabilitation and a decreased quality of life. To identify mechanisms behind this form of muscle wasting, we have used a rat model designed to mimic the conditions in an ICU. Rats were pharmacologically paralyzed with a postsynaptic blocker of neuromuscular transmission, and mechanically ventilated for one to two weeks, thereby unloading the limb muscles. Transcription factors were analyzed for cellular localization and nuclear concentration in the fast-twitch muscle extensor digitorum longus (EDL) and in the slow-twitch soleus. Significant muscle wasting and upregulation of mRNA for the ubiquitin ligases MAFbx and MuRF1 followed the treatment. The I kappa B family-member Bcl-3 displayed a concomitant decrease in concentration, suggesting altered kappa B controlled gene expression, although NF kappa B p65 was not significantly affected. The nuclear levels of the glucocorticold receptor (GR) and the thyroid receptor alpha l (TR alpha l) were altered and also suggested as potential mediators of the MAFbx- and MuRF1-induction in the absence of induced Foxol. We believe that this model, and the strategy of quanfifying nuclear proteins, will provide a valuable fool for further, more detailed, analyses of the muscle wasting occurring in patients kept on a mechanical ventilator.