{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T12:40:02Z","timestamp":1764160802730,"version":"3.46.0"},"reference-count":135,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Helmholtz Future topic Inflammation","award":["ZT-0027"],"award-info":[{"award-number":["ZT-0027"]}]},{"DOI":"10.13039\/501100003130","name":"Research Foundation Flanders","doi-asserted-by":"publisher","award":["30826052"],"award-info":[{"award-number":["30826052"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015700","name":"EOS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Inclusion body myositis (IBM) is a progressive muscle disorder characterized by inflammation and degeneration with altered proteostasis. To better understand the interrelationship between these two features, we aimed to establish a novel preclinical mouse model.<\/jats:p>\n                  <jats:p>First, we used quantitative PCR, in situ hybridization and immunohistochemistry to determine the expression of pro-inflammatory chemokines and cytokines including lymphotoxin (LT)-signalling pathway components in human skeletal muscle tissue diagnosed with myositis. Based on these results, we generated a mouse model that we analysed at the histological, ultrastructural, transcriptional, biochemical and behavioural level. Lastly, we subjected this model to anti-inflammatory treatments.<\/jats:p>\n                  <jats:p>After confirming and extending previous data on activation of LT-signalling in human myositis, we generated distinct transgenic mouse lines co-expressing LT\u03b1 and -\u03b2 in skeletal muscle fibres. Transgenic mice displayed chronic myositis accompanied by dysregulated proteostasis, including an altered autophagolysosomal pathway that initially showed signs of activation and later exhaustion and decreased flux. To enhance the latter, we genetically impaired autophagy in skeletal muscle cells. Autophagy impairment alone induced a pro-inflammatory transcriptional state, but no obvious cellular inflammation. However, the combination of LT-driven myositis with autophagy impairment induced the full spectrum of characteristic molecular and pathological features of IBM in skeletal muscle, including protein inclusions with typical ultrastructural morphology and mild mitochondrial pathology. Our attempts to treat the pathology by subjecting these mice to corticosteroids or anti-Thy1.2 antibodies mirrored recent treatment failures in humans, i.e. none of these treatments resulted in significant clinical improvement of motor performance or the transcriptional profile of muscle pathology.<\/jats:p>\n                  <jats:p>In summary, these data provide evidence that inflammation and autophagy disruption play a synergistic role in the development of IBM-like muscular pathology. Furthermore, once established, IBM-like pathology in these mice, as in human IBM patients, cannot be reverted or prevented from progression by conventional means of immunosuppression. We expect that this novel mouse model will help to identify future treatment modalities for IBM.<\/jats:p>","DOI":"10.1093\/brain\/awaf260","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T17:25:40Z","timestamp":1756142740000},"source":"Crossref","is-referenced-by-count":0,"title":["Mutual reinforcement of lymphotoxin-driven myositis and impaired autophagy in murine muscle"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0268-9425","authenticated-orcid":false,"given":"Juliane","family":"Bremer","sequence":"first","affiliation":[{"name":"Institute of Neuropathology, University Hospital RWTH Aachen , Aachen 52074 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Nagel","sequence":"additional","affiliation":[{"name":"Institute of Toxicology and Environmental Hygiene, Technical University of Munich, School of Medicine and Health , Munich 80802 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7062-5319","authenticated-orcid":false,"given":"Jana","family":"Zsch\u00fcntzsch","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center G\u00f6ttingen , G\u00f6ttingen 37075 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6280-3464","authenticated-orcid":false,"given":"Kamil K","family":"Zajt","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital RWTH Aachen , Aachen 52074 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tayfun","family":"Palaz","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital RWTH Aachen , Aachen 52074 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Blank","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Neuropathology, University of Freiburg , Freiburg 79106 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aylin","family":"Ikis","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital RWTH Aachen , Aachen 52074 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura A","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center G\u00f6ttingen , G\u00f6ttingen 37075 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna S M","family":"Sensmeyer","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center G\u00f6ttingen , G\u00f6ttingen 37075 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lara","family":"Wiechers","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center G\u00f6ttingen , G\u00f6ttingen 37075 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef J","family":"Reichelt","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center G\u00f6ttingen , G\u00f6ttingen 37075 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai P","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of Chronic Inflammation and Cancer, DKFZ Heidelberg , Heidelberg 69120 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika J","family":"Wolf","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital Z\u00fcrich , Z\u00fcrich 8091 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Medicine and Health , Munich 80802 ,","place":["Germany"]},{"name":"Institute of Molecular Toxicology and Pharmacology, Helmholtz Munich , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike","family":"Rothermel","sequence":"additional","affiliation":[{"name":"Department of Chronic Inflammation and Cancer, DKFZ Heidelberg , Heidelberg 69120 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna-L","family":"Eck","sequence":"additional","affiliation":[{"name":"Department of Chronic Inflammation and Cancer, DKFZ Heidelberg , Heidelberg 69120 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6396-4195","authenticated-orcid":false,"given":"Regina R","family":"Reimann","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital Z\u00fcrich , Z\u00fcrich 8091 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Eberhard-Karls University , T\u00fcbingen 72016 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"2025112607370539300_awaf260-B1","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1097\/WCO.0000000000000855","article-title":"Where are we moving in the classification of idiopathic inflammatory myopathies?","volume":"33","author":"Tanboon","year":"2020","journal-title":"Curr Opin Neurol"},{"key":"2025112607370539300_awaf260-B2","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3233\/JND-160198","article-title":"A systematic review and meta-analysis of prevalence studies of sporadic inclusion body myositis","volume":"4","author":"Callan","year":"2017","journal-title":"J Neuromuscul Dis"},{"key":"2025112607370539300_awaf260-B3","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.nmd.2013.08.007","article-title":"188th ENMC international workshop: 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