Global Deletion of 11β-HSD1 Prevents Muscle Wasting Associated with Glucocorticoid Therapy in Polyarthritis.
Webster, Justine M Sagmeister, Michael S Fenton, Chloe G Seabright, Alex P Lai, Yu-Chiang Jones, Simon W Filer, Andrew Cooper, Mark S Lavery, Gareth G Raza, Karim
Webster, Justine M
Sagmeister, Michael S
Fenton, Chloe G
Seabright, Alex P
Lai, Yu-Chiang
Jones, Simon W
Filer, Andrew
Cooper, Mark S
Lavery, Gareth G
Raza, Karim
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Affiliation
University of Birmingham; Maastricht University; The University of Sydney; Sandwell and West Birmingham NHS Trust
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Publication date
2021-07-22
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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.
Citation
Webster JM, Sagmeister MS, Fenton CG, Seabright AP, Lai YC, Jones SW, Filer A, Cooper MS, Lavery GG, Raza K, Langen R, Hardy RS. Global Deletion of 11β-HSD1 Prevents Muscle Wasting Associated with Glucocorticoid Therapy in Polyarthritis. Int J Mol Sci. 2021 Jul 22;22(15):7828.
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Article