title: NF-κB but not FoxO sites in the MuRF1 promoter are required for transcriptional activation in disuse muscle atrophy.
abstract: The muscle-specific ring finger protein 1 (MuRF1) gene is required for most types of skeletal muscle atrophy yet we have little understanding of its transcriptional regulation. The purpose of this study is to identify whether NF-κB and/or FoxO response elements in the MuRF1 promoter are required for MuRF1 gene activation during skeletal muscle atrophy due to the removal of hindlimb weight bearing ("unloading"). Both NF-κB -dependent and FoxO-dependent luciferase reporter activities were significantly increased at 5 days of unloading. Using a 4.4-kb MuRF1 promoter reporter construct, a fourfold increase in reporter (i.e., luciferase) activity was found in rat soleus muscles after 5 days of hindlimb unloading. This activation was abolished by mutagenesis of either of the two distal putative NF-κB sites or all three putative NF-κB sites but not by mutagenesis of all four putative FoxO sites. This work provides the first direct evidence that NF-κB sites, but not FoxO sites, are required for MuRF1 promoter activation in muscle disuse atrophy in vivo.
authors.affiliation: Department of Health Sciences, Boston University, Boston, Massachusetts.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Wu
authors.forename: Evangeline W
authors.initials: EW
authors.lastname: Cornwell
authors.forename: Robert W
authors.initials: RW
authors.lastname: Jackman
authors.forename: Susan C
authors.initials: SC
authors.lastname: Kandarian
mesh_terms: D000818:Animals; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019417:Hindlimb Suspension; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D015533:Transcriptional Activation / Q000502:physiology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; D009124:Muscle Proteins; D016328:NF-kappa B; D000070584:Tripartite Motif Proteins; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases
keywords: FoxO; MuRF1; NF-κB; muscle wasting; unloading