Objective: Therapeutic glucocorticoids (GCs) are used to treat chronic inflammatory disease, due to their anti-inflammatory effects. Despite their efficacy, chronic exposure to GCs elicits undesirable side effects, including muscle atrophy. 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs within muscle, is induced by inflammation, and has previously shown to drive GC-induced muscle wasting. We examined the role of 11β-HSD1 in mediating muscle wasting in chronic inflammatory disease when treated with therapeutic GCs.
Methods: Muscle biopsies were taken from patients with osteoarthritis (OA) or rheumatoid arthritis (RA). Cortisol production in the muscle was measured using thin-layer chromatography (TLC), and catabolic and inflammatory gene expression assessed. Global 11β-HSD1 knock out (KO) animals were crossed onto the TNF-tg murine model of polyarthritis and received vehicle or corticosterone (100 µg/ml) over 3 weeks in drinking water. Muscles were histologically assessed, and anabolic, catabolic and inflammatory gene and protein expression were examined by RT-qPCR and western blot. WT and 11β-HSD1/KO murine muscle cultures were exposed to TNFα, dehydrocorticosterone or both. Catabolic and inflammatory gene expression was measured.
Results: Cortisol activation in muscle was increased in RA patients than OA patients, and correlated with serum CRP levels. Local inflammation (IL-6 mRNA) was increased in RA compared to OA, correlated with 11β-HSD1, and was accompanied by elevated Mstn and FoxO1 expression. The myopathy previously described in TNF-tg and TNF-tg11β-HSD1KO mice, was aggravated by therapeutic GCs in TNF-Tg mice based on reduced muscle weights and fibre size, while their TNF-tg11β-HSD1KO were protected from muscle wasting. This was accompanied by an attenuated GC-induced elevation of FoxO1, Trim63 and Fbxo32 mRNA abundance, and alterations in FoxO1 and ribosomal S6 phosphorylation. These data were in part recapitulated in primary muscle cultures. Together, these data suggest that 11β-HSD1 inhibition may protect against therapeutic GC-induced muscle wasting in chronic inflammatory disease.
11 Nov 2019 - 13 Nov 2019