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

Justine Webster, Michael Sagmeister, Chloe Fenton, Alex Seabright, Yu-Chiang Lai, Simon Jones, Andrew Filer, Mark S. Cooper, Gareth Lavery, Karim Raza, Ramon Langen, Rowan 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 dehydrogenase type 1 (11β-HSD1) modulates peripheral glucocorticoid responses through pre-receptor metabolism. This study investigates how 11β-HSD1 influences skeletal muscle responses to glucocorticoid 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 corticosterone 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 summary, 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
Number of pages14
JournalInternational Journal of Molecular Sciences
Volume22
Issue number15
DOIs
Publication statusPublished - 22 Jul 2021

Keywords

  • sarcopenia
  • myopathy
  • steroids
  • adverse effects
  • 11beta hydroxysteroid dehydrogenase type 1
  • rheumatoid arthritis
  • inflammation

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