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| Pàgina inicial > Articles > Articles publicats > Human induced pluripotent stem cell-derived myotubes to model inclusion body myositis |
(Hospital Clínic i Provincial de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Universitat Pompeu Fabra) (Centro Nacional de Análisis Genómico) (Hospital Clínic i Provincial de Barcelona) (Universitat Autònoma de Barcelona. Departament de Medicina) (Universitat de Barcelona) (Centro de Investigación Biomédica en Red de Enfermedades Raras) (Centro de Investigación Biomédica en Red de Enfermedades Raras)
| Data: | 2025 |
| Resum: | Inclusion body myositis (IBM) is an inflammatory myopathy that displays proximal and distal muscle weakness. At the histopathological level, the muscles of IBM patients show inflammatory infiltrates, rimmed vacuoles and mitochondrial changes. The etiology of IBM remains unknown, and there is a lack of validated disease models, biomarkers and effective treatments. To contribute to unveil disease underpins we developed a cell model based on myotubes derived from induced pluripotent stem cells (iPSC-myotubes) from IBM patients and compared the molecular phenotype vs. age and sex-paired controls (n = 3 IBM and 4 CTL). We evaluated protein histological findings and the gene expression profile by mRNA-seq, alongside functional analysis of inflammation, degeneration and mitochondrial function. Briefly, IBM iPSC-myotubes replicated relevant muscle histopathology features of IBM, including aberrant expression of HLA, TDP-43 and COX markers. mRNA seq analysis identified 1007 differentially expressed genes (DEGs) (p-value adj < 0. 01; 789 upregulated and 218 downregulated), associated with myopathy, muscle structure and developmental changes. Among these, 1 DEG was related to inflammation, 28 to autophagy and 28 to mitochondria. At the functional level, inflammation was similar between the IBM and CTL groups under basal conditions (mean cytokine expression in IBM 4. 6 ± 1. 4 vs. 6. 7 ± 3. 4 in CTL), but increased in IBM iPSC-myotubes after lipopolysaccharide treatment (72. 5 ± 21. 8 in IBM vs. 13. 0 ± 6. 7 in CTL). Additionally, autophagy was disturbed, with 40. 14% reduction in autophagy mediators. Mitochondrial dysfunction was strongly manifested, showing a conserved respiratory profile and antioxidant capacity, but a 56. 33% lower cytochrome c oxidase/citrate synthase ratio and a 66. 59% increase in lactate secretion. Overall, these findings support patient-derived iPSC-myotubes as a relevant model for IBM, reflecting the main muscle hallmarks, including inflammation, autophagy dysfunction and mitochondrial alterations at transcriptomic, protein and functional levels. |
| Ajuts: | Instituto de Salud Carlos III PI21/00935 Instituto de Salud Carlos III PI24/00428 Instituto de Salud Carlos III CD21/00019 Agencia Estatal de Investigación PID2022-137672NB-I00 Ministerio de Ciencia e Innovación PDC2022-133826-100 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00453 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01423 |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Inclusion body myositis (IBM) ; Ipsc ; Myotubes ; Inflammation ; Autophagy ; Mitochondria |
| Publicat a: | Acta neuropathologica communications, Vol. 13 Núm. 1 (February 2025) , ISSN 2051-5960 |
