Unravelling inclusion body myositis using a patient-derived fibroblast model
Por:
Cantó-Santos J, Valls-Roca L, Tobías E, García-García FJ, Guitart-Mampel M, Esteve-Codina A, Martín-Mur B, Casado-Rio M, Artuch-Iriberri R, Solsona-Vilarrasa E, Fernandez-Checa JC, García-Ruiz C, Rentero C, Enrich C, Moreno-Lozano PJ, Milisenda JC, Cardellach F, Grau-Junyent JM and Garrabou G
Publicada:
1 abr 2023
Ahead of Print:
1 mar 2023
Resumen:
BackgroundInclusion 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. MethodsWe 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. ResultsGene 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. ConclusionsThese 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.
Filiaciones:
Cantó-Santos J:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Valls-Roca L:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Tobías E:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
García-García FJ:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Guitart-Mampel M:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Esteve-Codina A:
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain
Martín-Mur B:
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
Casado-Rio M:
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu
Esplugues de Llobregat, Barcelona, Spain
Artuch-Iriberri R:
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu
Esplugues de Llobregat, Barcelona, Spain
Solsona-Vilarrasa E:
Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Liver Unit-HCB-IDIBAPS, Barcelona, Spain
CIBEREHD-Spanish Biomedical Research Centre in Hepatic and Digestive Diseases, Madrid, Spain
Fernandez-Checa JC:
Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Liver Unit-HCB-IDIBAPS, Barcelona, Spain
CIBEREHD-Spanish Biomedical Research Centre in Hepatic and Digestive Diseases, Madrid, Spain
García-Ruiz C:
Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Liver Unit-HCB-IDIBAPS, Barcelona, Spain
CIBEREHD-Spanish Biomedical Research Centre in Hepatic and Digestive Diseases, Madrid, Spain
Rentero C:
Department of Biomedicine, Cell Biology Unit, CELLEX-IDIBAPS, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
Enrich C:
Department of Biomedicine, Cell Biology Unit, CELLEX-IDIBAPS, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
Moreno-Lozano PJ:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Milisenda JC:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Cardellach F:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Grau-Junyent JM:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
Garrabou G:
Muscle 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, Spain
Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain
CIBERER-Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain
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