Dual Specificity Phosphatase and Pro Isomerase Domain Containing 1 (Dupd1) is Upregulated During Neurogenic Skeletal Muscle Atrophy and is Differentially Expressed in MuRF1‐null Mice

Abstract

Skeletal muscle atrophy is caused by a decrease in muscle size and strength and results from a range of physiological conditions, including denervation, immobilization, corticosteroid exposure and aging. Dual Specificity Phosphatase and Pro Isomerase Domain Containing 1 (Dupd1) has been identified as a novel atrophy‐induced gene in skeletal muscle and has been found to be differentially regulated in wild‐type mice compared to Muscle RING Finger 1 (MuRF1) knockout mice in response to denervation. Muscle RING Finger 1 (MuRF1), an E3 ubiquitin ligase, has previously been shown to be upregulated under almost all conditions of skeletal muscle wasting. Preliminary data described in this study provides evidence that MuRF1 may play a more complex role in the muscle atrophy cascade than previously believed and appears to be necessary for full activation of a subset of neurogenic atrophy‐induced genes, including Dupd1. A recent study that utilized microarray analysis of skeletal muscle isolated from wild‐type and MuRF1‐null mice revealed that Dupd1 expression is significantly induced at 3 days and 14 days post‐denervation in wild‐type mice, while Dupd1 expression is dramatically blunted in the MuRF1‐null mice at both 3 days and 14 days post‐denervation. qPCR analysis revealed that Dupd1 is significantly upregulated during differentiation of cultured muscle cells. To determine how Dupd1 might be transcriptionally regulated in skeletal muscle, fragments of the promoter region of Dupd1 were cloned, fused to a reporter gene and found to be highly inducible in response to ectopic expression of MyoD and myogenin. Furthermore, site‐directed mutagenesis of conserved E‐box elements in the proximal promoter of Dupd1 rendered the Dupd1 reporter genes incapable of being induced by overexpression of myogenic regulatory factors. The Dupd1 gene codes for a dual specificity phosphatase (DUSP) that can recognize and dephosphorylate tyrosine, serine and threonine amino acids of substrate proteins. Finally, we have found that Dupd1, an atypical DUSP, can modulate the ERK branch of the MAP Kinase signaling in muscle cells and inhibits muscle cell differentiation when ectopically expressed in proliferating muscle cells. Elucidating the role of Dupd1 in muscle will help contribute new insight into the molecular mechanisms for skeletal muscle atrophy.Support or Funding InformationThe work was support by University of North Florida Transformational Learning Opportunity grants and a University of North Florida Foundation Board Grant to D.W.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.