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Activation of chaperone\u2010assisted autophagy was described as being part of the molecular etiology of IMNM. Endoplasmic reticulum (ER)\/sarcoplasmic reticulum (SR)\u2010stress accompanied by activation of the unfolded protein response (UPR) often precedes activation of the protein clearance machinery and represents a cellular defense mechanism toward restoration of proteostasis. Here, we show that ER\/SR\u2010stress may be part of the molecular etiology of IMNM. To address this assumption, ER\/SR\u2010stress related key players covering the three known branches (PERK\u2010mediated, IRE1\u2010mediated, and ATF6\u2010mediated) were investigated on both, the transcript and the protein levels utilizing 39 muscle biopsy specimens derived from IMNM\u2010patients. Our results demonstrate an activation of all three UPR\u2010branches in IMNM, which most likely precedes the activation of the protein clearance machinery. In detail, we identified increased phosphorylation of PERK and eIF2a along with increased expression and protein abundance of ATF4, all well\u2010documented characteristics for the activation of the UPR. Further, we identified increased general <jats:italic>XBP1<\/jats:italic>\u2010level, and elevated XBP1 protein levels. Additionally, our transcript studies revealed an increased <jats:italic>ATF6<\/jats:italic>\u2010expression, which was confirmed by immunostaining studies indicating a myonuclear translocation of the cleaved ATF6\u2010form toward the forced transcription of UPR\u2010related chaperones. In accordance with that, our data demonstrate an increase of downstream factors including ER\/SR co\u2010chaperones and chaperones (e.g., SIL1) indicating an UPR\u2010activation on a broader level with no significant differences between seropositive and seronegative patients. Taken together, one might assume that UPR\u2010activation within muscle fibers might not only serve to restore protein homeostasis, but also enhance sarcolemmal presentation of proteins crucial for attracting immune cells. Since modulation of ER\u2010stress and UPR via application of chemical chaperones became a promising therapeutic treatment approach, our findings might represent the starting point for new interventional concepts.<\/jats:p>","DOI":"10.1111\/bpa.13084","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T08:36:33Z","timestamp":1655282193000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Endoplasmic reticulum\u2010stress and unfolded protein response\u2010activation in immune\u2010mediated necrotizing myopathy"],"prefix":"10.1111","volume":"32","author":[{"given":"Corinna","family":"Preusse","sequence":"first","affiliation":[{"name":"Department of Neuropathology Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin  Berlin Germany"},{"name":"Department of Neurology with Institute for Translational Neurology University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore","family":"Marteau","sequence":"additional","affiliation":[{"name":"Pediatric Neurology University Children's Hospital, Faculty of Medicine, University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norina","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Neuropathology Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Hentschel","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Institut f\u00fcr Analytische Wissenschaften \u2010 ISAS \u2010 e.V  Dortmund 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Hospital, Faculty of Medicine, University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Meyer","sequence":"additional","affiliation":[{"name":"Pediatric Neurology University Children's Hospital, Faculty of Medicine, University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Ruck","sequence":"additional","affiliation":[{"name":"Department of Neurology Medical Faculty, Heinrich\u2010Heine\u2010University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora F.","family":"Dengler","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Prudlo","sequence":"additional","affiliation":[{"name":"Department of Neurology Rostock University Medical Center  Rostock Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) Rostock\/Greifswald  Rostock Germany"},{"name":"Department of Neurology University of Rostock  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ales","family":"Dudesek","sequence":"additional","affiliation":[{"name":"Department of Neurology Rostock University Medical Center  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman","family":"G\u00f6rl","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Klinikum S\u00fcdstadt Rostock  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Allenbach","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Clinical Immunology Sorbonne Universit\u00e9, APHP, Piti\u00e9\u2010Salp\u00eatri\u00e8re University Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Benveniste","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Clinical Immunology Sorbonne Universit\u00e9, APHP, Piti\u00e9\u2010Salp\u00eatri\u00e8re University Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010Hilmar","family":"Goebel","sequence":"additional","affiliation":[{"name":"Department of Neuropathology Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin  Berlin Germany"},{"name":"Department of Neuropathology University Hospital Mainz  Mainz 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