Journal
ANNALS OF NEUROLOGY
Volume 91, Issue 3, Pages 317-328Publisher
WILEY
DOI: 10.1002/ana.26304
Keywords
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Categories
Funding
- Myositis Association [90097118]
- Japan Society for the Promotion of Science (JSPS) [16H06279]
- JSPS [KAKENHI 19K07956, KAKENHI 22129001, KAKENHI 22129002, KAKENHI JP20H00526, KAKENHI JP26461265]
- Ministry of Health, Welfare, and Labor [H23-Jitsuyoka [Nanbyo]-Ippan-004, H26-Jitsuyoka [Nanbyo]-Ippan-080]
- Japan Agency for Medical Research and Development (AMED) [15ek0108065h0002, 16kk0205001h0001, 17kk0205001h0002, 17ek0109279h0001]
- AMED [JP20ek0109456h0001]
- Ministry of Education, Culture, Sports, Science, and Technology [MEXT KAKENHI JP221S0002]
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This study explored the molecular features of inclusion body myositis (IBM) and found that the differentially expressed genes and pathways in IBM and polymyositis were mostly comparable. However, the pathways related to cell adhesion molecules were upregulated in IBM. The study also discovered the overexpression of the epidermal cell junction protein cadherin 1 in the muscles of IBM, which could provide valuable insights into the pathological mechanisms of IBM.
Objective This study aimed to elucidate the molecular features of inclusion body myositis (IBM). Methods We performed RNA sequencing analysis of muscle biopsy samples from 67 participants, consisting of 58 myositis patients with the pathological finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class I (43 IBM, 6 polymyositis, and 9 unclassifiable myositis), and 9 controls. Results Cluster analysis, principal component analysis, and pathway analysis showed that differentially expressed genes and pathways identified in IBM and polymyositis were mostly comparable. However, pathways related to cell adhesion molecules were upregulated in IBM as compared with polymyositis and controls (p < 0.01). Notably, CDH1, which encodes the epidermal cell junction protein cadherin 1, was overexpressed in the muscles of IBM, which was validated by another RNA sequencing dataset from previous publications. Western blotting confirmed the presence of mature cadherin 1 protein in the muscles of IBM. Immunohistochemical staining confirmed the positivity for anti-cadherin 1 antibody in the muscles of IBM, whereas there was no muscle fiber positive for anti-cadherin 1 antibody in immune-mediated necrotizing myopathy, antisynthetase syndrome, and controls. The fibers stained with anti-cadherin 1 antibody did not have rimmed vacuoles or abnormal protein accumulation. Experimental skeletal muscle regeneration and differentiation systems showed that CDH1 is expressed during skeletal muscle regeneration and differentiation. Interpretation CDH1 was detected as a differentially expressed gene, and immunohistochemistry showed that cadherin 1 exists in the muscles of IBM, whereas it was rarely seen in those of other idiopathic inflammatory myopathies. Cadherin 1 upregulation in muscle could provide a valuable clue to the pathological mechanisms of IBM. ANN NEUROL 2022
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