Objective: Therapeutic glucocorticoids (GCs) are commonly used in the treatment of chronic inflammatory disease. Unfortunately, their long-term administration is associated with deleterious systemic side effects including muscle atrophy. 11 beta-hydroxysteroid dehydrogenase type 1 (11βHSD1) activates glucocorticoids within muscle, is increased with inflammation, and has previously been shown to mediate GC induced muscle wasting. We examined the role of 11 beta-hydroxysteroid dehydrogenase type 1 in mediating muscle wasting in a mouse model of inflammatory myopathy receiving therapeutic GCs.
Methods: Wild type (WT) and mice with a global deletion of 11β-HSD1 were crossed onto the TNF-tg murine model of chronic inflammation that develops inflammatory myopathy. Animals received either vehicle or the GC corticosterone (100 ug/ml) in drinking water, over 3 weeks at therapeutic doses. Tibialis anterior (TA) and quadriceps muscle weights were examined at 7 weeks. Anabolic, catabolic and inflammatory gene expression was examined by RT-PCR.
Results: Significant GC activation by 11β-HSD1 was identified in WT and TNF-tg animals at 7 weeks (0.06+0.001 and 0.072+0.002 pmol/mg/hr), whilst activity was completely abolished in 11β-HSD1 KO and TNF-tg/11βHSD1-KO animals. TNF-tg and TNF-tg/11βHSD1-KO developed significant muscle atrophy characterised by reduced TA and Quadriceps weights and increased expression of pro-inflammatory cytokines (IL-6 and TNFα). In addition, muscle catabolism related gene expression (MYOST, FOXO-1, TRIM63) was increased in TNF-tg muscle. In response to cort, muscle atrophy exacerbated in TNF-TG but not TNF/11βKO mice, despite an equal or larger increase in CORT-induced catabolic gene expression in TNF/11βKO compared to TNF-Tg mice. Moreover, CORT suppressed inflammatory gene expression in TNF but not TNF/11βKO muscle.
Conclusions: These data suggest that GCs and inflammation additively induce muscle wasting during chronic inflammation and that 11β-HSD1 is involved in mediating local anti-inflammatory and catabolic effects of corticosterone.
19 Nov 2018 - 21 Nov 2018