Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast Model
Background: Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non-established bi...
| Autores: | , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/208271 |
| Acceso en línea: | https://hdl.handle.net/2445/208271 |
| Access Level: | acceso abierto |
| Palabra clave: | Autofàgia Músculs Fibroblasts Miositis Inflamació Mitocondris Autophagy Muscles Myositis Inflammation Mitochondria |
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Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast ModelCantó Santos, JudithValls Roca, LauraTobías, EsterGarcía-García, Francesc JosepGuitart Mampel, MarionaEsteve Codina, AnnaMartín Mur, BeatrizCasado, MercedesArtuch Iriberri, RafaelSolsona Vilarrasa, EstelFernández Checa Torres, José CarlosGarcía Ruiz, CarmenRentero Alfonso, CarlesEnrich Bastús, CarlesMoreno Lozano, Pedro JuanMilisenda, JoséCardellach, FrancescGrau Junyent, Josep M. (Josep Maria)Garrabou Tornos, GlòriaAutofàgiaMúsculsFibroblastsMiositisInflamacióMitocondrisAutophagyMusclesFibroblastsMyositisInflammationMitochondriaBackground: Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non-established biomarkers or effective treatments are available, partly due to the lack of validated disease models. Methods: We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n = 14) and healthy controls (n = 12), paired by age and sex. The results comprise an mRNA-seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls. Results: Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P-value adj < 0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three-fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time-course autophagosome formation (LC3BII 39% reduced, P-value < 0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P-value < 0.05) and function (30.2%-decrease in respiration, 45.6%-decline in enzymatic activity (P-value < 0.001), 14.3%-higher oxidative stress, 135.2%-increased antioxidant defence (P-value < 0.05), 11.6%-reduced mitochondrial membrane potential (P-value < 0.05) and 42.8%-reduced mitochondrial elongation (P-value < 0.05)). In accordance, at the metabolite level, organic acid showed a 1.8-fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis. Conclusions: These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients’ derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.John Wiley & Sons2024202420232024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion14 p.application/pdfhttps://hdl.handle.net/2445/208271Articles publicats en revistes (Medicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/doi: 10.1002/jcsm.13178Journal of Cachexia Sarcopenia and Muscle, 2023, vol. 14, num.2, p. 964-977https://doi.org/doi: 10.1002/jcsm.13178cc-by (c) Judith Cantó-Santos et al., 2023http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2082712026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast Model |
| title |
Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast Model |
| spellingShingle |
Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast Model Cantó Santos, Judith Autofàgia Músculs Fibroblasts Miositis Inflamació Mitocondris Autophagy Muscles Fibroblasts Myositis Inflammation Mitochondria |
| title_short |
Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast Model |
| title_full |
Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast Model |
| title_fullStr |
Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast Model |
| title_full_unstemmed |
Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast Model |
| title_sort |
Unraveling Inclusion Body Myositis Using a Patient-derived Fibroblast Model |
| dc.creator.none.fl_str_mv |
Cantó Santos, Judith Valls Roca, Laura Tobías, Ester García-García, Francesc Josep Guitart Mampel, Mariona Esteve Codina, Anna Martín Mur, Beatriz Casado, Mercedes Artuch Iriberri, Rafael Solsona Vilarrasa, Estel Fernández Checa Torres, José Carlos García Ruiz, Carmen Rentero Alfonso, Carles Enrich Bastús, Carles Moreno Lozano, Pedro Juan Milisenda, José Cardellach, Francesc Grau Junyent, Josep M. (Josep Maria) Garrabou Tornos, Glòria |
| author |
Cantó Santos, Judith |
| author_facet |
Cantó Santos, Judith Valls Roca, Laura Tobías, Ester García-García, Francesc Josep Guitart Mampel, Mariona Esteve Codina, Anna Martín Mur, Beatriz Casado, Mercedes Artuch Iriberri, Rafael Solsona Vilarrasa, Estel Fernández Checa Torres, José Carlos García Ruiz, Carmen Rentero Alfonso, Carles Enrich Bastús, Carles Moreno Lozano, Pedro Juan Milisenda, José Cardellach, Francesc Grau Junyent, Josep M. (Josep Maria) Garrabou Tornos, Glòria |
| author_role |
author |
| author2 |
Valls Roca, Laura Tobías, Ester García-García, Francesc Josep Guitart Mampel, Mariona Esteve Codina, Anna Martín Mur, Beatriz Casado, Mercedes Artuch Iriberri, Rafael Solsona Vilarrasa, Estel Fernández Checa Torres, José Carlos García Ruiz, Carmen Rentero Alfonso, Carles Enrich Bastús, Carles Moreno Lozano, Pedro Juan Milisenda, José Cardellach, Francesc Grau Junyent, Josep M. (Josep Maria) Garrabou Tornos, Glòria |
| author2_role |
author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Autofàgia Músculs Fibroblasts Miositis Inflamació Mitocondris Autophagy Muscles Fibroblasts Myositis Inflammation Mitochondria |
| topic |
Autofàgia Músculs Fibroblasts Miositis Inflamació Mitocondris Autophagy Muscles Fibroblasts Myositis Inflammation Mitochondria |
| description |
Background: Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non-established biomarkers or effective treatments are available, partly due to the lack of validated disease models. Methods: We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n = 14) and healthy controls (n = 12), paired by age and sex. The results comprise an mRNA-seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls. Results: Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P-value adj < 0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three-fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time-course autophagosome formation (LC3BII 39% reduced, P-value < 0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P-value < 0.05) and function (30.2%-decrease in respiration, 45.6%-decline in enzymatic activity (P-value < 0.001), 14.3%-higher oxidative stress, 135.2%-increased antioxidant defence (P-value < 0.05), 11.6%-reduced mitochondrial membrane potential (P-value < 0.05) and 42.8%-reduced mitochondrial elongation (P-value < 0.05)). In accordance, at the metabolite level, organic acid showed a 1.8-fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis. Conclusions: These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients’ derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2024 2024 2024 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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https://hdl.handle.net/2445/208271 |
| url |
https://hdl.handle.net/2445/208271 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/doi: 10.1002/jcsm.13178 Journal of Cachexia Sarcopenia and Muscle, 2023, vol. 14, num.2, p. 964-977 https://doi.org/doi: 10.1002/jcsm.13178 |
| dc.rights.none.fl_str_mv |
cc-by (c) Judith Cantó-Santos et al., 2023 http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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cc-by (c) Judith Cantó-Santos et al., 2023 http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
| dc.format.none.fl_str_mv |
14 p. application/pdf |
| dc.publisher.none.fl_str_mv |
John Wiley & Sons |
| publisher.none.fl_str_mv |
John Wiley & Sons |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Medicina) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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