Schmidt, Karsten

[["dc.bibliographiccitation.journal","Frontiers in Physiology"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Herbelet, Sandrine"],["dc.contributor.author","De Vlieghere, Elly"],["dc.contributor.author","Gonçalves, Amanda"],["dc.contributor.author","De Paepe, Boel"],["dc.contributor.author","Schmidt, Karsten"],["dc.contributor.author","Nys, Eline"],["dc.contributor.author","Weynants, Laurens"],["dc.contributor.author","Weis, Joachim"],["dc.contributor.author","Van Peer, Gert"],["dc.contributor.author","Vandesompele, Jo"],["dc.contributor.author","Schmidt, Jens"],["dc.contributor.author","De Wever, Olivier"],["dc.contributor.author","De Bleecker, Jan L."],["dc.date.accessioned","2020-12-10T18:44:37Z"],["dc.date.available","2020-12-10T18:44:37Z"],["dc.date.issued","2018"],["dc.description.abstract","Aims: Regeneration in skeletal muscle relies on regulated myoblast migration and differentiation, in which the transcription factor nuclear factor of activated T-cells 5 (NFAT5) participates. Impaired muscle regeneration and chronic inflammation are prevalent in myositis. Little is known about the impact of inflammation on NFAT5 localization and expression in this group of diseases. The goal of this study was to investigate NFAT5 physiology in unaffected myoblasts exposed to cytokine or hyperosmolar stress and in myositis. Methods: NFAT5 intracellular localization and expression were studied in vitro using a cell culture model of myositis. Myoblasts were exposed to DMEM solutions enriched with pro-inflammatory cytokines IFN-γ with IL-1β or hyperosmolar DMEM obtained by NaCl supplementation. NFAT5 localization was visualized using immunohistochemistry (IHC) and Western blotting (WB) in fractionated cell lysates. NFAT5 expression was assessed by WB and RT-qPCR. In vivo localization and expression of NFAT5 were studied in muscle biopsies of patients diagnosed with polymyositis (n = 6), dermatomyositis (n = 10), inclusion body myositis (n = 11) and were compared to NFAT5 localization and expression in non-myopathic controls (n = 13). Muscle biopsies were studied by means of quantitative IHC and WB of total protein extracts. Results: In unaffected myoblasts, hyperosmolar stress ensues in NFAT5 nuclear translocation and increased NFAT5 mRNA and protein expression. In contrast, pro-inflammatory cytokines did not lead to NFAT5 nuclear translocation nor increased expression. Cytokines IL-1β with IFN-γ induced colocalization of NFAT5 with histone deacetylase 6 (HDAC6), involved in cell motility. In muscle biopsies from dermatomyositis and polymyositis patients, NFAT5 colocalized with HDAC6, while in IBM, this was often absent. Conclusions: Our data suggest impaired NFAT5 localization and expression in unaffected myoblasts in response to inflammation. This disturbed myogenic NFAT5 physiology could possibly explain deleterious effects on muscle regeneration in myositis."],["dc.identifier.doi","10.3389/fphys.2018.00126"],["dc.identifier.eissn","1664-042X"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/78529"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1664-042X"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Localization and Expression of Nuclear Factor of Activated T-Cells 5 in Myoblasts Exposed to Pro-inflammatory Cytokines or Hyperosmolar Stress and in Biopsies from Myositis Patients"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","48"],["dc.bibliographiccitation.journal","BMC Neurology"],["dc.bibliographiccitation.volume","16"],["dc.contributor.author","Schmidt, Karsten"],["dc.contributor.author","Kleinschnitz, Konstanze"],["dc.contributor.author","Rakocevic, Goran"],["dc.contributor.author","Dalakas, Marinas C."],["dc.contributor.author","Schmidt, Jens"],["dc.date.accessioned","2018-11-07T10:15:30Z"],["dc.date.available","2018-11-07T10:15:30Z"],["dc.date.issued","2016"],["dc.description.abstract","Background: Mechanisms of inflammation and protein accumulation are crucial in inclusion body myositis (IBM). Recent evidence demonstrated that intravenous immunoglobulin failed to suppress cell-stress mediators in IBM. Here we studied the molecular changes in skeletal muscle biopsies from patients with IBM before and after treatment with alemtuzumab. Methods: Relevant inflammatory and degeneration-associated markers were assessed by quantitative-PCR and immunohistochemistry in repeated muscle biopsy specimens from patients with IBM, which had been treated in a previously published uncontrolled proof-of-concept trial with alemtuzumab. Results: There were no significant changes of the mRNA expression levels of the pro-inflammatory chemokines CXCL-9, CCL-4, and the cytokines IFN-gamma, TGF-beta, TNF-alpha, and IL-1 beta. Similarly, the degeneration-associated molecules ubiquitin, APP and aB-crystallin did not substantially change. Although no overall beneficial treatment effect was noted except for a 6-month stabilization, some patients experienced a transient improvement in muscle strength. In such responders, a trend towards reduced expression of inflammatory markers was noted. In contrast, the expression remained unchanged in the others who did not experience any change. The expression levels of IL-1 beta and MHC-I correlated with the positive clinical effect. By immunohistochemistry, some inflammatory mediators like CD8, CXCL-9, and MHC-I were downmodulated. However, no consistent changes were noted for ubiquitin, nitrotyrosin and beta-amyloid. Conclusions: Alemtuzumab showed a trend towards downregulation of the expression of some inflammatory molecules in skeletal muscle of IBM patients but has no effect on several crucial markers of cell stress and degeneration. The data are helpful to explain the molecular treatment effects of future lymphocyte-targeted immunotherapies in IBM."],["dc.identifier.doi","10.1186/s12883-016-0568-5"],["dc.identifier.isi","000374855600001"],["dc.identifier.pmid","27083892"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13488"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40822"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1471-2377"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Molecular treatment effects of alemtuzumab in skeletal muscles of patients with IBM"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","5470831"],["dc.bibliographiccitation.journal","Mediators of Inflammation"],["dc.contributor.author","Schmidt, Karsten"],["dc.contributor.author","Wienken, Magdalena"],["dc.contributor.author","Keller, Christian W."],["dc.contributor.author","Balcarek, Peter"],["dc.contributor.author","Münz, Christian"],["dc.contributor.author","Schmidt, Jens"],["dc.date.accessioned","2018-11-07T10:29:09Z"],["dc.date.available","2018-11-07T10:29:09Z"],["dc.date.issued","2017"],["dc.description.abstract","The pathology of inclusion body myositis (IBM) involves an inflammatory response and beta-amyloid deposits in muscle fibres. It is believed that MAP kinases such as the ERK signalling pathway mediate the inflammatory signalling in cells. Further, there is evidence that autophagic activity plays a crucial role in the pathogenesis of IBM. Using a well established in vitro model of IBM, the autophagic pathway, MAP kinases, and accumulation of beta-amyloid were examined. We demonstrate that stimulation of muscle cells with IL-1 beta and IFN-gamma led to an increased phosphorylation of ERK. The ERK inhibitor PD98059 diminished the expression of proinflammatory markers as well as the accumulation of beta-amyloid. In addition, IL-1 beta and IFN-gamma led to an increase of autophagic activity, upregulation of APP, and subsequent accumulation of beta-sheet aggregates. Taken together, the data demonstrate that the ERK pathway contributes to formation of beta-amyloid and regulation of autophagic activity in muscle cells exposed to proinflammatory cell stress. This suggests that ERK serves as an important mediator between inflammatory mechanisms and protein deposition in skeletal muscle and is a crucial element of the pathology of IBM."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2016"],["dc.identifier.doi","10.1155/2017/5470831"],["dc.identifier.isi","000394098400001"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14140"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43582"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Hindawi Ltd"],["dc.relation.issn","1466-1861"],["dc.relation.issn","0962-9351"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","IL-1 beta-Induced Accumulation of Amyloid: Macroautophagy in Skeletal Muscle Depends on ERK"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]