Journal Article

DKFZ-2025-01776

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mutual reinforcement of lymphotoxin-driven myositis and impaired autophagy in murine muscle.

Bremer, J. ; Nagel, J. ; Zschüntzsch, J. ; Zajt, K. K. ; Palaz, T. ; Blank, T. ; Ikis, A. ; Fischer, L. A. ; Sensmeyer, A. S. M. ; Wiechers, L. ; Reichelt, J. J. ; Hofmann, K.DKFZ* ; Wolf, M. J. ; Leuchtenberger, C.DKFZ* ; Tripathi, P. ; Einer, C. ; Zischka, H. ; Rothermel, U.DKFZ* ; Eck, A.-L.DKFZ* ; Reimann, R. ; Kana, V. ; Rushing, E. ; Aguzzi, A. ; Prinz, M. ; Liebetanz, D. ; Odoardi, F. ; Kuo, C.-C. ; Weis, J. ; Kraft, F. ; Schmidt, J. ; Heikenwälder, M. (Last author)DKFZ*

2025
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awaf260

Abstract: 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 at establishing a novel preclinical mouse model. First, we used quantitative PCR to determine expression of pro-inflammatory chemo- and cytokines including lymphotoxin (LT)-signaling pathway components in human skeletal muscle tissue diagnosed with myositis. Based on these results we generated a mouse model that we analyzed at the histological, ultrastructural, transcriptional, biochemical, and behavioral level. Lastly, we subjected this model to anti-inflammatory treatments. After confirming and extending previous data on activation of lymphotoxin (LT)-signaling in human myositis, we generated distinct transgenic mouse lines co-expressing LTα and -β in skeletal muscle fibers. Transgenic mice displayed chronic myositis accompanied by dysregulated proteostasis, including an altered autophagolysosomal pathway that initially shows 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. 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.

Keyword(s): NF-κB signaling ; autophagy ; inclusion body myositis ; lymphotoxin ; lymphotoxin signaling ; myositis

Note: #LA:D440# / epub

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Contributing Institute(s):

1. Chronische Entzündung und Krebs (D440)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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