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Effect of type I interferon on engineered pediatric skeletal muscle: a promising model for juvenile dermatomyositis.

Publication ,  Journal Article
Covert, LT; Patel, H; Osman, A; Duncan, L; Dvergsten, J; Truskey, GA
Published in: Rheumatology (Oxford)
January 4, 2024

OBJECTIVE: To investigate pathogenic mechanisms underlying JDM, we defined the effect of type I IFN, IFN-α and IFN-β, on pediatric skeletal muscle function and expression of myositis-related proteins using an in vitro engineered human skeletal muscle model (myobundle). METHODS: Primary myoblasts were isolated from three healthy pediatric donors and used to create myobundles that mimic functioning skeletal muscle in structural architecture and physiologic function. Myobundles were exposed to 0, 5, 10 or 20 ng/ml IFN-α or IFN-β for 7 days and then functionally tested under electrical stimulation and analyzed immunohistochemically for structural and myositis-related proteins. Additionally, IFN-β-exposed myobundles were treated with Janus kinase inhibitors (JAKis) tofacitinib and baricitinib. These myobundles were also analyzed for contractile force and immunohistochemistry. RESULTS: IFN-β, but not IFN-α, was associated with decreased contractile tetanus force and slowed twitch kinetics. These effects were reversed by tofacitinib and baricitinib. Type I IFN paradoxically reduced myobundle fatigue, which did not reverse after JAKi. Additionally, type I IFN correlated with MHC I upregulation, which normalized after JAKi treatment, but expression of myositis-specific autoantigens Mi-2, melanocyte differentiation-associated protein 5 and the endoplasmic reticulum stress marker GRP78 were variable and donor specific after type I IFN exposure. CONCLUSION: IFN-α and IFN-β have distinct effects on pediatric skeletal muscle and these effects can partially be reversed by JAKi treatment. This is the first study illustrating effective use of a three-dimensional human skeletal muscle model to investigate JDM pathogenesis and test novel therapeutics.

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Published In

Rheumatology (Oxford)

DOI

EISSN

1462-0332

Publication Date

January 4, 2024

Volume

63

Issue

1

Start / End Page

209 / 217

Location

England

Related Subject Headings

  • Myositis
  • Muscular Diseases
  • Muscle, Skeletal
  • Interferon Type I
  • Humans
  • Dermatomyositis
  • Child
  • Arthritis & Rheumatology
  • 3204 Immunology
  • 3202 Clinical sciences
 

Citation

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Covert, L. T., Patel, H., Osman, A., Duncan, L., Dvergsten, J., & Truskey, G. A. (2024). Effect of type I interferon on engineered pediatric skeletal muscle: a promising model for juvenile dermatomyositis. Rheumatology (Oxford), 63(1), 209–217. https://doi.org/10.1093/rheumatology/kead186
Covert, Lauren T., Hailee Patel, Alaa Osman, Lavonia Duncan, Jeffrey Dvergsten, and George A. Truskey. “Effect of type I interferon on engineered pediatric skeletal muscle: a promising model for juvenile dermatomyositis.Rheumatology (Oxford) 63, no. 1 (January 4, 2024): 209–17. https://doi.org/10.1093/rheumatology/kead186.
Covert LT, Patel H, Osman A, Duncan L, Dvergsten J, Truskey GA. Effect of type I interferon on engineered pediatric skeletal muscle: a promising model for juvenile dermatomyositis. Rheumatology (Oxford). 2024 Jan 4;63(1):209–17.
Covert, Lauren T., et al. “Effect of type I interferon on engineered pediatric skeletal muscle: a promising model for juvenile dermatomyositis.Rheumatology (Oxford), vol. 63, no. 1, Jan. 2024, pp. 209–17. Pubmed, doi:10.1093/rheumatology/kead186.
Covert LT, Patel H, Osman A, Duncan L, Dvergsten J, Truskey GA. Effect of type I interferon on engineered pediatric skeletal muscle: a promising model for juvenile dermatomyositis. Rheumatology (Oxford). 2024 Jan 4;63(1):209–217.
Journal cover image

Published In

Rheumatology (Oxford)

DOI

EISSN

1462-0332

Publication Date

January 4, 2024

Volume

63

Issue

1

Start / End Page

209 / 217

Location

England

Related Subject Headings

  • Myositis
  • Muscular Diseases
  • Muscle, Skeletal
  • Interferon Type I
  • Humans
  • Dermatomyositis
  • Child
  • Arthritis & Rheumatology
  • 3204 Immunology
  • 3202 Clinical sciences