We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Global Deletion of 11β-HSD1 Prevents Muscle Wasting Associated with Glucocorticoid Therapy in Polyarthritis.
- Authors
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; Langen, Ramon; Hardy, Rowan S.
- 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.
- Subjects
MUSCULAR atrophy; GLUCOCORTICOIDS; LABORATORY mice; WEIGHT loss; RHEUMATOID arthritis
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 15, p7828
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms22157828