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Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis

Objective Inclusion body myositis (IBM) has an unclear molecular etiology exhibiting both characteristic inflammatory T-cell activity and rimmed-vacuolar degeneration of muscle fibers. Using in-depth gene expression and splicing studies, we aimed at understanding the different components of the mole...

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Bibliographic Details
Published in:Journal of neurology 2022-08, Vol.269 (8), p.4161-4173
Main Authors: Johari, Mridul, Vihola, Anna, Palmio, Johanna, Jokela, Manu, Jonson, Per Harald, Sarparanta, Jaakko, Huovinen, Sanna, Savarese, Marco, Hackman, Peter, Udd, Bjarne
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Language:English
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Summary:Objective Inclusion body myositis (IBM) has an unclear molecular etiology exhibiting both characteristic inflammatory T-cell activity and rimmed-vacuolar degeneration of muscle fibers. Using in-depth gene expression and splicing studies, we aimed at understanding the different components of the molecular pathomechanisms in IBM. Methods We performed RNA-seq on RNA extracted from skeletal muscle biopsies of clinically and histopathologically defined IBM ( n  = 24), tibial muscular dystrophy ( n  = 6), and histopathologically normal group ( n  = 9). In a comprehensive transcriptomics analysis, we analyzed the differential gene expression, differential splicing and exon usage, downstream pathway analysis, and the interplay between coding and non-coding RNAs (micro RNAs and long non-coding RNAs). Results We observe dysregulation of genes involved in calcium homeostasis, particularly affecting the T-cell activity and regulation, causing disturbed Ca 2+ -induced apoptotic pathways of T cells in IBM muscles. Additionally, LCK/p56, which is an essential gene in regulating the fate of T-cell apoptosis, shows increased expression and altered splicing usage in IBM muscles. Interpretation Our analysis provides a novel understanding of the molecular mechanisms in IBM by showing a detailed dysregulation of genes involved in calcium homeostasis and its effect on T-cell functioning in IBM muscles. Loss of T-cell regulation is hypothesized to be involved in the consistent observation of no response to immune therapies in IBM patients. Our results show that loss of apoptotic control of cytotoxic T cells could indeed be one component of their abnormal cytolytic activity in IBM muscles.
ISSN:0340-5354
1432-1459
DOI:10.1007/s00415-022-11029-7