Abstract
Glucocorticoids provide indispensable anti-inflammatory therapies. However, metabolic adverse effects including muscle wasting restrict their use. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) modulates peripheral glucocorticoid responses through pre-receptor metabolism. This study investigates how 11 beta-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 11 beta-HSD1 activity ex vivo. Using the TNF-alpha-transgenic mouse model (TNF-tg) of chronic inflammation, we examined the effects of corticosterone treatment and 11 beta-HSD1 global knock-out (11 beta KO) on skeletal muscle, measuring anti-inflammatory gene expression, muscle weights, fiber size distribution, and catabolic pathways. Muscle 11 beta-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-tg(11 beta KO) mice. TNF-tg mice exhibited reductions in muscle weight and fiber size with glucocorticoid therapy. In contrast, TNF-tg(11 beta KO) mice were protected against glucocorticoid-induced muscle atrophy. Glucocorticoid-mediated activation of catabolic mediators (FoxO1, Trim63) was also diminished in TNF-tg(11 beta KO) compared to TNF-tg mice. In summary, 11 beta-HSD1 knock-out prevents muscle atrophy associated with glucocorticoid therapy in a model of chronic inflammation. Targeting 11 beta-HSD1 may offer a strategy to refine the safety of glucocorticoids.
Original language | English |
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Article number | 7828 |
Number of pages | 14 |
Journal | International Journal of Molecular Sciences |
Volume | 22 |
Issue number | 15 |
DOIs | |
Publication status | Published - 1 Aug 2021 |
Keywords
- sarcopenia
- myopathy
- steroids
- adverse effects
- 11beta hydroxysteroid dehydrogenase type 1
- rheumatoid arthritis
- inflammation
- TUMOR-NECROSIS-FACTOR
- DEHYDROGENASE TYPE-1
- EXPRESSION
- INHIBITION
- METABOLISM
- PROFILES