SFEBES2014 Poster Presentations Steroids (39 abstracts)
Glucocorticoid activation in muscle by 11β-hydroxysteroid dehydrogenase type 1: contributions to inflammatory muscle wasting
Rowan Hardy 1, , Gareth Lavery 1 , Mark Pierson 4 , Craig Doug 1 , Andrew Filer 4 , Christopher Buckley 4 , Janet Lord 4 , Paul Stewart 3 , Mark Cooper 2 & Karim Raza 4
1Clinical and Experimental Medicine 2nd floor IBR, The University of Birmingham, Birmingham, West Midlands, UK; 2The University of Sydney, Concord Clinical School, Sydney, New South Wales, Australia; 3Faculty of Medicine and Health, School of Medicine Leeds, The University of Leeds LS2 9NL, UK; 4School of Immunity and Infection, 2nd floor IBR, The University of Birmingham, Birmingham, West Midlands, UK.
Muscle wasting remains a significant complication in patients with inflammatory disease where it contributes to disability, risk of falls and early mortality. Interestingly, muscle wasting in patients with glucocorticoid excess mirrors that observed in patients with inflammatory disease. We have previously reported that the glucocorticoid activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is potently up-regulated within mesenchymal derived cell populations in response to pro-inflammatory stimuli.
Consequently, we hypothesise that muscle wasting in patients with inflammatory disease is driven by elevated glucocorticoid activation in mesenchymal derived myocytes. In this study we have collected biopsies of quadriceps from 14 patients with osteoarthritis. 11β-HSD1 expression and activity in muscle was examined by real-time RT PCR, immunohistochemistry and tritiated steroid conversion assays. In vitro regulation of 11β-HSD1 by the pro-inflammatory cytokines TNFα and IL1β (10 ng/ml) was assessed in primary myocyte culture.
Positive 11β-HSD1 mRNA expression was identified in muscle (Avg ΔCt=16.6±0.75), with enzyme expression observed ubiquitously throughout the tissue. This was supported by significant oxoreductase activity (14±5 fmol/mg tissue per hr). In primary cultures of myocytes, 11β-HSD1 was potently up-regulated at 24 h by the cytokines TNFα and IL1β (7.8±0.9 and 18.2±2.1-fold respectively; P<0.05). This effect was abrogated by the NFκB inhibitor parthenolide (1 μM). 11β-HSD1 mRNA expression in muscle was shown to positively correlate with markers of inflammation (IL6, R2=0.62; P<0.05) and atrophy (FOXO-1, R2=0.36; P<0.05).
These findings demonstrate that 11β-HSD1 is actively expressed within human muscle and primary myocytes, where it is positively regulated by pro-inflammatory cytokines and correlates with markers of muscle inflammation and atrophy. Consequently, these data support a role for glucocorticoid activation by 11β-HSD1 in driving inflammatory muscle wasting.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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