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.
Highlights
Glucocorticoids are indispensable in modern medicine as highly effective anti-inflamm atory medications
Measuring ex vivo cortisone to cortisol conversion rate, we confirmed that 11β-HSD1 enzymatic activity was higher in muscle biopsies taken from patients with rheumatoid arthritis (RA) compared to patients with OA
11β-HSD1 contributes to muscle wasting in our model of glucocorticoid therapy for chronic inflammation, we examined several regulators of muscle protein metabolism
Summary
Glucocorticoids are indispensable in modern medicine as highly effective anti-inflamm atory medications They are widely used with applications ranging from autoimmune diseases to cancer, organ transplantation, or COVID-19 pneumonia. Our data show that global 11β-HSD1 knock out (11βKO) has a protective effect against skeletal muscle wasting when mice with chronic TNF-α overexpression receive oral corticosterone. This offers new insights into the driving factors for muscle wasting in glucocorticoid-treated inflammatory disease, with implications for strategies to mitigate the adverse effects of glucocorticoid treatments in the future
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