The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene

Abstract

The muscle specific ubiquitin E3 ligase MuRF1 has been implicated as a key regulator of muscle atrophy under a variety of conditions, such as during synthetic glucocorticoid treatment. FOXO class transcription factors have been proposed as important regulators of MuRF1 expression, but its regulation by glucocorticoids is not well understood. The MuRF1 promoter contains a near-perfect palindromic glucocorticoid response element (GRE) 200 base pairs upstream of the transcription start site. The GRE is highly conserved in the mouse, rat, and human genes along with a directly adjacent FOXO binding element (FBE). Transient transfection assays in HepG2 cells and C 2C12 myotubes demonstrate that the MuRF1 promoter is responsive to both the dexamethasone (DEX)-activated glucocorticoid receptor (GR) and FOXO1, whereas coexpression of GR and FOXO1 leads to a dramatic synergistic increase in reporter gene activity. Mutation of either the GRE or the FBE significantly impairs activation of the MuRF1 promoter. Consistent with these findings, DEXinduced upregulation of MuRF1 is significantly attenuated in mice expressing a homodimerization-deficient GR despite no effect on the degree of muscle loss in these mice vs. their wild-type counterparts. Finally, chromatin immunoprecipitation analysis reveals that both GR and FOXO1 bind to the endogenous MuRF1 promoter in C 2C12 myotubes, and IGF-I inhibition of DEX-induced MuRF1 expression correlates with the loss of FOXO1 binding. These findings present new insights into the role of the GR and FOXO family of transcription factors in the transcriptional regulation of the MuRF1 gene, a direct target of the GR in skeletal muscle.forkhead transcription factor class O; muscle RING finger 1; glucocorticoid receptor SKELETAL MUSCLE IS A DYNAMIC TISSUE that has the capacity to continuously regulate its size in response to a variety of external cues, including mechanical load, neural activity, hormones/growth factors, stress, and nutritional status. In addition, skeletal muscle serves as the most significant repository for protein in the body, a source that is tapped to provide a pool of amino acids for tissue repair and gluconeogenesis under conditions of starvation and other metabolic stresses. Muscle loss or "atrophy" occurs as the result of a number of disparate conditions, including aging, immobilization, metabolic diseases, cancer, and neurodegenerative diseases, and as a serious side effect of therapeutic corticosteroid hormone treatment (15,27,32). The recently identified E3 ubiquitin ligase, muscle RING finger 1 (MuRF1

Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

“…Whether the Dmd and RyR2 genes are primary or secondary targets of GR regulation is currently unknown. However, Klf15, Ptgds, and MuRF1 are bona fide glucocorticoid-responsive target genes that are induced by activated GR (11)(12)(13)(14). Accordingly, in the absence of an intact GR signaling pathway in cardiomyocytes, the expression of these genes is significantly repressed.…”

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

“…Recent studies have implicated that NF-κB regulates both MuRF1 and MAFbx/Atrogin-1 [16,33], making it plausible that NF-κB inhibition is preventing the up regulation of these ubiquitin ligases fundamental in skeletal muscle atrophy [13]. However, MuRF1 and MAFbx/Atrogin-1 have been reported to be regulated by the FOXO transcription factors as well as NF-κB [54,58,68]. Additional studies will be needed to determine the role of MuRF1 and MAFbx/Atrogin-1 in cancer cachexia to delineate this relationship between MuRF1 and MAFbx/Atrogin-1 expression regulation and their actual role in the skeletal muscle atrophy process.…”

The administration of high-dose methylprednisolone for 24 h reduced muscle size and increased atrophy-related gene expression in spinal cord-injured rats

“…10 In glucocorticoid-induced atrophy, upregulation of REDD1, an inhibitor of protein synthesis, has been suggested to explain the reduced protein synthetic rates found in this form of muscle atrophy. 11 Whether the brief period of MP administration used at the time of SCI to improve function results in significant or lasting changes in the expression of muscle atrophy genes, (for example, FOXO1, MAFbx, MuRF1 or REDD1) is not known.…”