Human induced pluripotent stem cell-derived myotubes to model inclusion body myositis

作者：Judith Cantó‐Santos, Laura Valls‐Roca, Ester Tobías, Francesc Josep García‐García, Mariona Guitart‐Mampel, Félix Andújar-Sánchez, Adrià Vilaseca-Capel, Anna Esteve‐Codina, Beatriz Martín‐Mur, Joan Padrosa, Emma Peruga, Irene Madrigal, Paula Segalés, Carmen García‐Ruiz, José C. Fernández‐Checa, Pedro Moreno, Albert Selva-O’Callaghan, Ana Sevilla, José C. Milisenda, Glòria Garrabou · 发表于：Acta Neuropathologica Communications · 年份：2025 · DOI：10.1186/s40478-025-01933-0 · 被引用次数：7 · 研究领域：Muscle Physiology and Disorders、Biomedical Ethics and Regulation、Neurogenetic and Muscular Disorders Research

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....