Muscle Gene Expression Following Denervation and Disuse

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DESCRIPTION (provided by applicant): The primary goal of this research is to clarify the mechanisms responsible for the excessive protein breakdown in muscle following denervation and disuse and to determine whether these mechanisms differ from those of muscle atrophy resulting from systemic diseases. It will be important to elucidate whether there are specific effects due to loss of the trophic stimulus from the nerve, in addition to the effects seen with disuse. To gain a more complete understanding of the changes in gene expression following denervation, gene-chip analysis will be undertaken in order to follow global changes in mRNA leading to enhanced proteolysis and loss of muscle function. These changes will then be compared with those seen with spinal isolation, an experimental model of complete disuse. Furthermore, the expression of specific genes that have already been identified as important to proteolysis (e.g. the newly identified ubiquitin ligase, atrogin-1) will be compared as a function of time after nerve section and disuse. In vitro muscle cell cultures will then be used to examine how activation of signaling pathways that trigger muscle hypertrophy may be involved in suppressing protein degradation. By using growth factors and inhibitors of these pathways and monitoring the expression of the newly identified ubiquitin ligases and other atrophy genes, this research will attempt to identify whether there are common mechanisms regulating hypertrophy and atrophy. These experiments should aid in better understanding of the signals that play a key role in atrophy and how they are regulated following different atrophy states. This research may also help to identify new therapeutic targets and ways to retard muscle wasting in these pathological states.