Meeting Abstract
Skeletal muscle atrophy results from a wide range of conditions, including immobilization, spinal cord damage, inflammation and aging. An investigation designed to identify and characterize changes in gene expression in skeletal muscle following denervation revealed a set of genes that show differential expression patterns in response to neurogenic atrophy, including Nip30 and Rspry1. In order to further characterize the transcriptional regulation of Nip30 and Rspry1, a fragment of the promoter region of each gene was cloned, fused to a reporter gene, and transfected into muscle cells in combination with expression plasmids for Muscle RING Finger 1 (MuRF1) and myogenic regulatory factors (MRFs). The MuRF1 protein is an E3 ubiquitin ligase that is induced under most atrophic conditions and is believed to promote protein degradation; however, data presented in this study suggests that MuRF1 may also regulate the transcriptional activity of genes that are differentially expressed following neurogenic atrophy. Myogenic regulatory factors (MRFs) are a class of E-box binding proteins that regulate muscle-specific gene expression. The results of this study demonstrate that MuRF1 and MRFs cooperatively repress Rspry1 and Nip30 reporter activity. Furthermore, mutation of a conserved E-box element in the shared regulatory region of Nip30 and Rspry11 eliminated the MuRF1 and MRF cooperative repression of these genes. Identifying novel atrophy-induced genes, elucidating the transcriptional regulatory role of MuRF1 and MRFs, and characterizing how these genes impact the atrophy cascade may help further our understanding of the molecular mechanisms of muscle wasting.
