Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), whilst 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, potently up-regulated 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 pro-inflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF-Tg) driven by overexpression of TNFα 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 ex vivo human and murine muscle biopsies. The contribution of 11β-HSD1 to muscle inflammation and wasting were assessed in vivo using the TNF-Tg mouse on an 11β-HSD1 null background. 11β-HSD1 was significantly upregulated within tibialis anterior and quadriceps muscle from TNF-Tg mice. In human and murine primary myotubes, 11β-HSD1 expression and activity were significantly increased in response to the pro-inflammatory cytokine TNFα (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 pro-inflammatory cytokine output (IL-6, TNFα, and IFNγ), but had little impact on markers of muscle wasting in human myotube cultures. TNF-Tg mice on an 11β-HSD1KO background developed greater muscle wasting than TNF-Tg counterparts (27.4% less; P<0.005), with smaller compacted muscle fibres and increased pro-inflammatory gene expression relative to TNF-Tg with normal 11β-HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11β-HSD1 expression and GC activation within muscle. Whilst concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNFα driven model, local endogenous GC activation appears to be an important anti-inflammatory response that protects against inflammatory muscle wasting in vivo.
07 Nov 2016 - 09 Nov 2016