Single-nucleus RNA sequencing and spatial transcriptomics decode cell type-specific drivers underlying IBM pathogenesis

Inclusion body myositis (IBM) is a progressive inflammatory muscle disease of unknown cause with no effective therapy available. We combined single-nucleus RNA sequencing and spatial transcriptomics to decode cell type-specific drivers underlying IBM pathogenesis compared to immune-mediated necrotizing myopathy (IMNM) and healthy skeletal muscle. In IBM, we observed a selective type 2 myonuclear degeneration paralleled by increased levels of cytotoxic T lymphocytes and cDC1 dendritic cells. We found that IBM myofibers were characterized by upregulation of genomic stress pathway genes featuring GADD45A and the long non-coding RNA NORAD. Also, we noted IBM-specific upregulation of ACHE encoding acetylcholinesterase that can be regulated by NORAD activity and result in functional denervation of myofibers. In summary, our results suggest selective type 2 fiber vulnerability in IBM linked to genomic stress pathways.