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@ARTICLE{Bremer:304113,
      author       = {J. Bremer and J. Nagel and J. Zschüntzsch and K. K. Zajt
                      and T. Palaz and T. Blank and A. Ikis and L. A. Fischer and
                      A. S. M. Sensmeyer and L. Wiechers and J. J. Reichelt and K.
                      Hofmann$^*$ and M. J. Wolf and C. Leuchtenberger$^*$ and P.
                      Tripathi and C. Einer and H. Zischka and U. Rothermel$^*$
                      and A.-L. Eck$^*$ and R. Reimann and V. Kana and E. Rushing
                      and A. Aguzzi and M. Prinz and D. Liebetanz and F. Odoardi
                      and C.-C. Kuo and J. Weis and F. Kraft and J. Schmidt and M.
                      Heikenwälder$^*$},
      title        = {{M}utual reinforcement of lymphotoxin-driven myositis and
                      impaired autophagy in murine muscle.},
      journal      = {Brain},
      volume       = {nn},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2025-01776},
      pages        = {nn},
      year         = {2025},
      note         = {#LA:D440# / epub},
      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.},
      keywords     = {NF-κB signaling (Other) / autophagy (Other) / inclusion
                      body myositis (Other) / lymphotoxin (Other) / lymphotoxin
                      signaling (Other) / myositis (Other)},
      cin          = {D440},
      ddc          = {610},
      cid          = {I:(DE-He78)D440-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40853947},
      doi          = {10.1093/brain/awaf260},
      url          = {https://inrepo02.dkfz.de/record/304113},
}