Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis.
Journal
Nature aging
ISSN: 2662-8465
Titre abrégé: Nat Aging
Pays: United States
ID NLM: 101773306
Informations de publication
Date de publication:
04 Jun 2024
04 Jun 2024
Historique:
received:
20
09
2023
accepted:
03
05
2024
medline:
5
6
2024
pubmed:
5
6
2024
entrez:
4
6
2024
Statut:
aheadofprint
Résumé
Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.
Identifiants
pubmed: 38834884
doi: 10.1038/s43587-024-00645-9
pii: 10.1038/s43587-024-00645-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
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