Global deletion of 11β-HSD1 prevents muscle wasting associated with glucocorticoid therapy in polyarthritis

Justine M. Webster, Michael S. Sagmeister, Chloe G. Fenton, Alex P. Seabright, Yu Chiang Lai, Simon W. Jones, Andrew Filer, Mark S. Cooper, Gareth G. Lavery, Karim Raza, Ramon Langen, Rowan S. Hardy

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Abstract

Glucocorticoids provide indispensable anti-inflammatory therapies. However, metabolic adverse effects including muscle wasting restrict their use. The enzyme 11beta-hydroxysteroid de-hydrogenase type 1 (11β-HSD1) modulates peripheral glucocorticoid responses through pre-recep-tor metabolism. This study investigates how 11β-HSD1 influences skeletal muscle responses to glu-cocorticoid therapy for chronic inflammation. We assessed human skeletal muscle biopsies from patients with rheumatoid arthritis and osteoarthritis for 11β-HSD1 activity ex vivo. Using the TNF-α-transgenic mouse model (TNF-tg) of chronic inflammation, we examined the effects of corti-costerone treatment and 11β-HSD1 global knock-out (11βKO) on skeletal muscle, measuring anti-inflammatory gene expression, muscle weights, fiber size distribution, and catabolic pathways. Muscle 11β-HSD1 activity was elevated in patients with rheumatoid arthritis and correlated with inflammation markers. In murine skeletal muscle, glucocorticoid administration suppressed IL6 expression in TNF-tg mice but not in TNF-tg11βKO mice. TNF-tg mice exhibited reductions in muscle weight and fiber size with glucocorticoid therapy. In contrast, TNF-tg11βKO mice were protected against glucocorticoid-induced muscle atrophy. Glucocorticoid-mediated activation of catabolic mediators (FoxO1, Trim63) was also diminished in TNF-tg11βKO compared to TNF-tg mice. In sum-mary, 11β-HSD1 knock-out prevents muscle atrophy associated with glucocorticoid therapy in a model of chronic inflammation. Targeting 11β-HSD1 may offer a strategy to refine the safety of glucocorticoids.

Original languageEnglish
Article number7828
JournalInternational Journal of Molecular Sciences
Volume22
Issue number15
Early online date22 Jul 2021
DOIs
Publication statusPublished - Aug 2021

Keywords

  • 11beta hydroxysteroid dehydrogenase type 1
  • Adverse effects
  • Inflammation
  • Myopathy
  • Rheumatoid arthritis
  • Sarcopenia
  • Steroids

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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