Abstract
ObjectiveInclusion 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.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 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.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.
Highlights
Inclusion body myositis (IBM) is a late-onset, acquired muscle disease with unclear etiology, and the poorly understood molecular pathogenesis is under debate due to several factors
Another pathway outside the top results identified that 29 genes (29/208, p = 7.05E-03) significantly dysregulated in our dataset are involved in calcium signaling. These results prompted us to investigate further for calcium-related issues in cellular signaling, and we found that IPA detects dysregulation of the following processes, mobilization of Ca2+ (80 genes), the release of Ca2+ (33 genes), quantity of C a2+ (51 genes) and flux of C a2+ (51 genes), as significantly disturbed in IBM muscles (Table 4)
Our analysis showed an enrichment of genes involved in the structure and organization of actin filament assembly in IBM muscles and, interestingly, proteins involved in mRNA processing and metabolism
Summary
Inclusion body myositis (IBM) is a late-onset, acquired muscle disease with unclear etiology, and the poorly understood molecular pathogenesis is under debate due to several factors. A partial clinical and histopathological overlap with other rimmed-vacuolar (RV) myopathies [3] including accumulations of similar proteins in the RVs [4] support a degenerative pathophysiology. Accumulation/aggregation of these misfolded proteins suggests that IBM could. Journal of Neurology (2022) 269:4161–4173 be a protein aggregate disease with the immune-mediated cytotoxic inflammation as a resulting secondary feature [5]. There is a significant variance in nature and the number of accumulated proteins observed in the IBM muscle biopsies [6]. Similar aggregates observed in HIVassociated IBM [7] suggest that protein aggregation can still be a downstream effect of immune dysfunction. The occurrence of rare familial cases [8] and a strong association with immune MHC locus 8.1 ancestral haplotype [9, 10] support a possible genetic predisposition for IBM
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