title: 11β-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.
abstract: 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.
authors: Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.|Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.|Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, Edgbaston, Birmingham, UK.
authors: Rowan S
authors: RS
authors: Hardy
authors: Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, Edgbaston, Birmingham, UK.
authors: Craig L
authors: CL
authors: Doig
authors: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.|Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, Edgbaston, Birmingham, UK.
authors: Zahrah
authors: Z
authors: Hussain
authors: Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
authors: Mary
authors: M
authors: O'Leary
authors: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.|Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, Edgbaston, Birmingham, UK.
authors: Stuart A
authors: SA
authors: Morgan
authors: Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
authors: Mark J
authors: MJ
authors: Pearson
authors: Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
authors: Amy
authors: A
authors: Naylor
authors: Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
authors: Simon W
authors: SW
authors: Jones
authors: Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
authors: Andrew
authors: A
authors: Filer
authors: Faculty of Medicine and Health, School of Medicine, University of Leeds, Leeds, UK.
authors: Paul M
authors: PM
authors: Stewart
authors: Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
authors: Christopher D
authors: CD
authors: Buckley
authors: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.|Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, Edgbaston, Birmingham, UK.
authors: Gareth G
authors: GG
authors: Lavery
authors: ANZAC Research Institute, University of Sydney, Sydney, Australia.
authors: Mark S
authors: MS
authors: Cooper
authors: Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.|Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
authors: Karim
authors: K
authors: Raza
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000368:Aged; D000818:Animals; D001706:Biopsy; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D008822:Mice, Transgenic; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009220:Myositis / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D055948:Sarcopenia / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D014409:Tumor Necrosis Factor-alpha; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone
keywords: 11β-HSD1; animal models; chronic inflammation; glucocorticoids; muscle wasting