Enhanced proteasome activity in perifascicular myofibres is a hallmark of dermatomyositis and its inhibition is efficient in preclinical models
Authors' conclusion
Enhanced proteasome activity in perifascicular myofibres is a hallmark of DM; its inhibition, deemed effective in preclinical models, may represent a new therapeutic strategy for this disease.
Study context
- Population
- Patients with untreated and early dermatomyositis (DM) (symptoms <6 months), other inflammatory myopathies, or without neuromuscular disease; human myotubes and experimental myositis mice
- Participants
- 7 / 6 / 5
- Comparison
- Peri- and endofascicular myofibres in DM vs other inflammatory myopathies vs no neuromuscular disease; ixazomib in preclinical models
- DMn = 7
- Other inflammatory myopathiesn = 6
- Without neuromuscular diseasen = 5reference
- Outcome
- Molecular pathways characterising DM perifascicular myofibres
Methodological detailsRNA-sequencing of microdissected myofibres, computational drug repurposing, cellular and animal preclinical models
- RNA-sequencing of microdissected myofibres
- Computational drug repurposing
- Cellular and animal preclinical models
Main finding
As reported in the abstract
- Upregulation of the proteasome pathway, prevailing in perifascicular myofibres, is a hallmark of DM
- Validation cohort: β5i (PSMB8) predominantly expressed in cytoplasm of perifascicular muscle fibres in DM, which also predominantly expressed MxA and HLA-I
- Human myotubes: Interferon (IFN)-β enhances β5i expression and chymotrypsin-like activity
- Drug repurposing analysis identified ixazomib (proteasome inhibitor) as the drug with highest therapeutic potential
- Human myotubes: ixazomib prevented IFN-β-induced DM-like lesions (atrophy, MHC-I expression, mitochondrial dysfunctions) without impacting ISG expression
- Experimental myositis (EM) mice on ixazomib: recovered muscle strength, normalised serum creatine kinase; ISG expression unchanged, sarcolemmal MHC-I abolished, myofibre size variability normalised, inflammatory infiltrate decreased
Original publication
Enhanced proteasome activity in perifascicular myofibres is a hallmark of dermatomyositis and its inhibition is efficient in preclinical models. Ann Rheum Dis. Published 7 October 2025. doi:10.
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