Unravelling inclusion body myositis using a patient‐derived fibroblast model
Abstract 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‐establ...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-04-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.13178 |
| _version_ | 1827267644864069632 |
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| author | Judith Cantó‐Santos Laura Valls‐Roca Ester Tobías Francesc Josep García‐García Mariona Guitart‐Mampel Anna Esteve‐Codina Beatriz Martín‐Mur Mercedes Casado Rafael Artuch Estel Solsona‐Vilarrasa José Carlos Fernandez‐Checa Carmen García‐Ruiz Carles Rentero Carlos Enrich Pedro J. Moreno‐Lozano José César Milisenda Francesc Cardellach Josep M. Grau‐Junyent Glòria Garrabou |
| author_facet | Judith Cantó‐Santos Laura Valls‐Roca Ester Tobías Francesc Josep García‐García Mariona Guitart‐Mampel Anna Esteve‐Codina Beatriz Martín‐Mur Mercedes Casado Rafael Artuch Estel Solsona‐Vilarrasa José Carlos Fernandez‐Checa Carmen García‐Ruiz Carles Rentero Carlos Enrich Pedro J. Moreno‐Lozano José César Milisenda Francesc Cardellach Josep M. Grau‐Junyent Glòria Garrabou |
| author_sort | Judith Cantó‐Santos |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-09T20:01:33Z |
| format | Article |
| id | doaj.art-0f82886d569447a682acbe705f05bfcc |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2025-03-22T04:37:02Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-0f82886d569447a682acbe705f05bfcc2024-04-28T00:01:48ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092023-04-0114296497710.1002/jcsm.13178Unravelling inclusion body myositis using a patient‐derived fibroblast modelJudith Cantó‐Santos0Laura Valls‐Roca1Ester Tobías2Francesc Josep García‐García3Mariona Guitart‐Mampel4Anna Esteve‐Codina5Beatriz Martín‐Mur6Mercedes Casado7Rafael Artuch8Estel Solsona‐Vilarrasa9José Carlos Fernandez‐Checa10Carmen García‐Ruiz11Carles Rentero12Carlos Enrich13Pedro J. Moreno‐Lozano14José César Milisenda15Francesc Cardellach16Josep M. Grau‐Junyent17Glòria Garrabou18Muscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainMuscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainMuscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainMuscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainMuscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainCNAG‐CRG, Centre for Genomic Regulation Barcelona Institute of Science and Technology Barcelona SpainCNAG‐CRG, Centre for Genomic Regulation Barcelona Institute of Science and Technology Barcelona SpainCIBERER—Spanish Biomedical Research Centre in Rare Diseases Madrid SpainCIBERER—Spanish Biomedical Research Centre in Rare Diseases Madrid SpainDepartment of Cell Death and Proliferation Institute of Biomedical Research of Barcelona (IIBB‐CSIC), Liver Unit‐HCB‐IDIBAPS Barcelona SpainDepartment of Cell Death and Proliferation Institute of Biomedical Research of Barcelona (IIBB‐CSIC), Liver Unit‐HCB‐IDIBAPS Barcelona SpainDepartment of Cell Death and Proliferation Institute of Biomedical Research of Barcelona (IIBB‐CSIC), Liver Unit‐HCB‐IDIBAPS Barcelona SpainDepartment of Biomedicine, Cell Biology Unit, CELLEX‐IDIBAPS, Faculty of Medicine and Health Sciences University of Barcelona Barcelona SpainDepartment of Biomedicine, Cell Biology Unit, CELLEX‐IDIBAPS, Faculty of Medicine and Health Sciences University of Barcelona Barcelona SpainMuscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainMuscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainMuscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainMuscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainMuscle Research and Mitochondrial Function Lab, Centre de Recerca Biomèdica CELLEX ‐ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona Barcelona SpainAbstract 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.https://doi.org/10.1002/jcsm.13178Inclusion body myositisMyopathyFibroblastsAutophagyInflammationMitochondria |
| spellingShingle | Judith Cantó‐Santos Laura Valls‐Roca Ester Tobías Francesc Josep García‐García Mariona Guitart‐Mampel Anna Esteve‐Codina Beatriz Martín‐Mur Mercedes Casado Rafael Artuch Estel Solsona‐Vilarrasa José Carlos Fernandez‐Checa Carmen García‐Ruiz Carles Rentero Carlos Enrich Pedro J. Moreno‐Lozano José César Milisenda Francesc Cardellach Josep M. Grau‐Junyent Glòria Garrabou Unravelling inclusion body myositis using a patient‐derived fibroblast model Journal of Cachexia, Sarcopenia and Muscle Inclusion body myositis Myopathy Fibroblasts Autophagy Inflammation Mitochondria |
| title | Unravelling inclusion body myositis using a patient‐derived fibroblast model |
| title_full | Unravelling inclusion body myositis using a patient‐derived fibroblast model |
| title_fullStr | Unravelling inclusion body myositis using a patient‐derived fibroblast model |
| title_full_unstemmed | Unravelling inclusion body myositis using a patient‐derived fibroblast model |
| title_short | Unravelling inclusion body myositis using a patient‐derived fibroblast model |
| title_sort | unravelling inclusion body myositis using a patient derived fibroblast model |
| topic | Inclusion body myositis Myopathy Fibroblasts Autophagy Inflammation Mitochondria |
| url | https://doi.org/10.1002/jcsm.13178 |
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