Meeting Abstract

P2.180  Saturday, Jan. 5  Transcriptional Regulation of Dual specificity phosphatase 4 (Dusp4) by Muscle specific RING Finger 1 (MuRF1) WADDELL, DS*; HADDOCK, AN; University of North Florida; University of North Florida d.s.waddell@unf.edu

Skeletal muscle atrophy is caused by a range of physiological conditions, including immobilization, spinal cord damage, inflammation and aging. The muscle specific RING finger 1 (MuRF1) protein is an E3 ubiquitin ligase that is induced under nearly all atrophy conditions and is believed to promote protein degradation. The data described in this study however, provide evidence that MuRF1 may also regulate the transcriptional activity of a number of genes that show differential expression following nerve damage-induced atrophy (i.e. denervation). A preliminary investigation using microarray to analyze changes in gene expression in the skeletal muscle of wild-type and MuRF1-null mice following denervation revealed a set of genes with altered expression profiles following nerve damage-induced atrophy in the absence of MuRF1, including the Dual specificity phosphatase 4 (Dusp4) gene. Dusp4 is part of a family of mitogen-activated protein kinase phosphatases (MKP) that have the ability to dephosphorylate and inactivate mitogen-activated protein kinases (MAPK). Furthermore, the Dusp family is able to dephosphorylate both serine/threonine and tyrosine kinases, which could impact a number of important signal transduction cascades. In order to further characterize transcriptional regulation by MuRF1, a fragment of the Dusp4 promoter was cloned into a SEAP reporter plasmid and then transfected into the C2C12 mouse muscle cell line in combination with a MuRF1 expression plasmid. In cells with ectopic expression of MuRF1, there was a significant increase in Dusp4 reporter activity, suggesting that MuRF1 may function as a muscle specific transcriptional regulator. The preliminary findings described in this study offer intriguing evidence of a new function for MuRF1 in controlling skeletal muscle atrophy.