Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) is a bidirectional GC‐activating enzyme that is potently upregulated by inflammation within mesenchymal‐derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11β‐HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF‐Tg) driven by overexpression of tumour necrosis factor (TNF)‐α within tissues, including muscle. The inflammatory regulation and functional consequences of 11β‐HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11β‐HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF‐Tg mouse on an 11β‐HSD1 null background. 11β‐HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF‐Tg mice. In human and murine primary myotubes, 11β‐HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF‐α (mRNA, 7.6‐fold, p < 0.005; activity, 4.1‐fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11β‐HSD1 suppressed proinflammatory cytokine output (interkeukin‐6, TNF‐α, and interferon‐γ), but had little impact on markers of muscle wasting in human myotube cultures. TNF‐Tg mice on an 11β‐11β‐HSD1 knockout background developed greater muscle wasting than their TNF‐Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF‐Tg mice with normal 11β‐HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11β‐HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF‐α‐driven model, local endogenous GC activation appears to be an important anti‐inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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BackgroundLocal generation of endogenous glucocorticoids (GCs) by the enzyme 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1) with inflammation has been shown to be an important anti-inflammatory pathway in both acute and chronic inflammatory disease. Whilst beneficial within inflamed tissues such as the rheumatoid synovium (through suppression of pro-inflammatory pathways), the inflammatory regulation and impact of 11beta-HSD1 on neighbouring tissues such as muscle remain poorly defined.ObjectivesTo characterise the inflammatory regulation of 11beta-HSD1 in muscle during systemic inflammation and examine its functional consequences on muscle inflammation and wasting in vitro and in vivo using primary human tissue and a transgenic murine model of polyarthritis.MethodsInflammatory regulation of 11beta-HSD1 was examined in primary myotube culture and ex vivo muscle biopsies isolated from human donors and from transgenic TNF overexpressing (TNF-tg) mice, as a model of systemic polyarthritis. Inflammatory cytokine output, myotube viability and markers of inflammatory muscle wasting were measured following exposure to endogenous GCs activated by 11beta-HSD1. The contribution of 11beta-HSD1 to muscle status in vivo was examined in the TNF-tg mouse on an 11beta-HSD1 global null background.ResultsIn both human and murine primary muscle culture, 11beta-HSD1 mRNA and activity were significantly increased in response to the pro-inflammatory cytokine TNFa (mRNA; 7.6 fold, p<0.005, activity 4.1 fold, p<0.005). 11beta-HSD1 mRNA and activity were evident in ex vivo biopsies of murine and human muscle from tibialis anterior and quadriceps. This expression was augmented in response to TNFa and in muscles harvested from TNF-tg mice relative to wild type controls. Endogenous GCs activated by 11beta-HSD1 suppressed pro-inflammatory cytokine output of IL-6, TNFa, and IFNg, but had little impact on markers of muscle wasting and cell viability in myotube culture. To delineate the contribution of 11beta-HSD1 to suppression of inflammation and muscle wasting in vivo, we generated a TNF-tg mouse on an 11beta-HSD1KO background. These animals had more marked muscle wasting with reduced muscle weight relative to body weight (TNF-tg; 13.45%; TNF/11bKO, 36.2%; p<0.005), smaller compacted muscle fibres and increased pro-inflammatory gene expression.ConclusionsThis study demonstrates that in muscle, as observed in tissues such as the rheumatoid synovium, 11beta-HSD1 and endogenous glucocorticoid activation are markedly increased in response to inflammation. Whilst concerns have been raised that excess levels of GCs may contribute to factors such as muscle wasting, in this model, local endogenous glucocorticoid activation appears to be overwhelmingly anti-inflammatory in nature and protective in regards to inflammatory muscle wasting in vivo.Disclosure of InterestNone declared