title: Activation of the Unfolded Protein Response in Sporadic Inclusion-Body Myositis but Not in Hereditary GNE Inclusion-Body Myopathy.
abstract: Muscle fibers in patients with sporadic inclusion-body myositis (s-IBM),the most common age-associated myopathy, are characterized by autophagic vacuoles and accumulation of ubiquitinated and congophilic multiprotein aggregates that contain amyloid-β and phosphorylated tau. Muscle fibers of autosomal-recessive hereditary inclusion-body myopathy caused by the GNE mutation (GNE-h-IBM) display similar pathologic features, except with less pronounced congophilia. Accumulation of unfolded/misfolded proteins inside the endoplasmic reticulum (ER) lumen leads to ER stress, which elicits the unfolded protein response (UPR) as a protective mechanism. Here we demonstrate for the first time that UPR is activated in s-IBM muscle biopsies, since there was 1) increased activating transcription factor 4 (ATF4) protein and increased mRNA of its target C/EBP homologous protein; 2) cleavage of the ATF6 and increased mRNA of its target glucose-regulated protein 78; and 3) an increase of the spliced form of X-box binding protein 1 and increased mRNA of ER degradation-enhancing α-mannosidase-like protein, target of heterodimer of cleaved ATF6 and spliced X-box binding protein 1. In contrast, we did not find similar evidence of the UPR induction in GNE-h-IBM patient muscle, suggesting that different intracellular mechanisms might lead to similar pathologic phenotypes. Interestingly, cultured GNE-h-IBM muscle fibers had a robust UPR response to experimental ER stress stimuli, suggesting that the GNE mutation per se is not responsible for the lack of UPR in GNE-h-IBM biopsied muscle.
authors.affiliation: From the USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California (AN, CDA, WKE, MC, VA); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (SA, KM).
authors.forename: Anna
authors.initials: A
authors.lastname: Nogalska
authors.forename: Carla
authors.initials: C
authors.lastname: D'Agostino
authors.forename: W King
authors.initials: WK
authors.lastname: Engel
authors.forename: Mafalda
authors.initials: M
authors.lastname: Cacciottolo
authors.forename: Shinichi
authors.initials: S
authors.lastname: Asada
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Valerie
authors.initials: V
authors.lastname: Askanas
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000368:Aged; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D049310:Distal Myopathies / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D018979:Myositis, Inclusion Body / Q000473:pathology* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*
chemical_list: C497109:ATF4 protein, human; C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D015820:Cadherins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D051701:Activating Transcription Factor 4