title: Foxo/atrogin induction in human and experimental myositis.
abstract: Skeletal muscle atrophy can occur rapidly in various fasting, cancerous, systemic inflammatory, deranged metabolic or neurogenic states. The ubiquitin ligase Atrogin-1 (MAFbx) is induced in animal models of these conditions, causing excessive myoprotein degradation. It is unknown if Atrogin upregulation also occurs in acquired human myositis. Intracellular β-amyloid (Aβi), phosphorylated neurofilaments, scattered infiltrates and atrophy involving selective muscle groups characterize human sporadic Inclusion Body Myositis (sIBM). In Polymyositis (PM), inflammation is more pronounced and atrophy is symmetric and proximal. IBM and PM share various inflammatory markers. We found that forkhead family transcription factor Foxo3A is directed to the nucleus and Atrogin-1 transcript is increased in both conditions. Expression of Aβ in transgenic mice and differentiated C2C12 myotubes was sufficient to upregulate Atrogin-1 mRNA and cause atrophy. Aβi reduces levels of p-Akt and downstream p-Foxo3A, resulting in Foxo3A translocation and Atrogin-1 induction. In a mouse model of autoimmune myositis, cellular inflammation alone was associated with similar Foxo3A and Atrogin changes. Thus, either Aβi accumulation or cellular immune stimulation may independently drive muscle atrophy in sIBM and PM, respectively, through pathways converging on Foxo and Atrogin-1. In sIBM it is additionally possible that both mechanisms synergize.
authors.affiliation: Department of Neurology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.
authors.forename: Han-Kyu
authors.initials: HK
authors.lastname: Lee
authors.forename: Edward
authors.initials: E
authors.lastname: Rocnik
authors.forename: Qinghao
authors.initials: Q
authors.lastname: Fu
authors.forename: Bumsup
authors.initials: B
authors.lastname: Kwon
authors.forename: Ling
authors.initials: L
authors.lastname: Zeng
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Henry
authors.initials: H
authors.lastname: Querfurth
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D009220:Myositis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009124:Muscle Proteins; C440907:FBXO32 protein, human; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases