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bioRxiv · 10.1101/2021.06.30.450477

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

Johari, M.·Vihola, A.·Palmio, J.·Jokela, M.·Jonson, P. H.·Sarparanta, J.·Huovinen, S.·Savarese, M.·Hackman, P.·Udd, B.
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Abstract

ObjectiveInclusion body myositis (IBM) has an unclear molecular etiology due to the co-existence of characteristic cytotoxic T-cell activity and 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. MethodsWe 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). ResultsWe observe dysregulation of genes involved in calcium homeostasis, particularly affecting the T-cell activity and regulation, causing disturbed Ca2+ induced apoptotic pathway of T cells in IBM muscles. Additionally, LCK/p56, which is an essential gene in regulating the fate of T-cell apoptosis, shows altered expression and splicing usage in IBM muscles InterpretationOur 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.

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Johari, M., Vihola, A., Palmio, J., Jokela, M., Jonson, P. H., Sarparanta, J., Huovinen, S., Savarese, M., Hackman, P., Udd, B.. 2021-07-01. Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis. https://doi.org/10.1101/2021.06.30.450477

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