title: Forkhead box O3 plays a role in skeletal muscle atrophy through expression of E3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing's syndrome.
abstract: Cushing's syndrome is caused by overproduction of the adrenocorticotropic hormone (ACTH), which stimulates the adrenal grand to make cortisol. Skeletal muscle wasting occurs in pathophysiological response to Cushing's syndrome. The forkhead box (FOX) protein family has been implicated as a key regulator of muscle loss under conditions such as diabetes and sepsis. However, the mechanistic role of the FOXO family in ACTH-induced muscle atrophy is not understood. We hypothesized that FOXO3a plays a role in muscle atrophy through expression of the E3 ubiquitin ligases, muscle RING finger protein-1 (MuRF-1), and atrogin-1 in Cushing's syndrome. For establishment of a Cushing's syndrome animal model, Sprague-Dawley rats were implanted with osmotic minipumps containing ACTH (40 ng·kg-1·day-1). ACTH infusion significantly reduced muscle weight. In ACTH-infused rats, MuRF-1, atrogin-1, and FOXO3a were upregulated and the FOXO3a promoter was targeted by the glucocorticoid receptor (GR). Transcriptional activity and expression of FOXO3a were significantly decreased by the GR antagonist RU486. Treatment with RU486 reduced MuRF-1 and atrogin-1 expression in accordance with reduced enrichment of FOXO3a and Pol II on the promoters. Knockdown of FOXO3a prevented dexamethasone-induced MuRF-1 and atrogin-1 expression. These results indicate that FOXO3a plays a role in muscle atrophy through expression of MuRF-1 and atrogin-1 in Cushing's syndrome.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Republic of Korea.|BK21 Plus Kyungpook National University Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Hae-Ahm
authors.initials: HA
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Republic of Korea.|BK21 Plus Kyungpook National University Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Mina
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Republic of Korea.|BK21 Plus Kyungpook National University Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Eunjo
authors.initials: E
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea; and.
authors.forename: Uy Dong
authors.initials: UD
authors.lastname: Sohn
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Republic of Korea; inkim@knu.ac.kr.|BK21 Plus Kyungpook National University Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Inkyeom
authors.initials: I
authors.lastname: Kim
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003480:Cushing Syndrome / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D044843:SKP Cullin F-Box Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D005938:Glucocorticoids; D006727:Hormone Antagonists; D009124:Muscle Proteins; D011965:Receptors, Glucocorticoid; D000070584:Tripartite Motif Proteins; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases
keywords: Cushing’s syndrome; forkhead box O3; glucocorticoid receptor; skeletal muscle atrophy