LAUSR

Abstract Objective: Therapeutic glucocorticoids (GCs) are routinely used in the treatment of chronic inflammatory disease due to their potent anti-inflammatory effects. Despite their efficacy, chronic exposure to GCs elicits undesirable side effects, including muscle atrophy (1). 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs in muscle, is induced by inflammation, and has previously shown to induce muscle wasting (2). We examined the role of 11β-HSD1 in mediating muscle wasting in a mouse model of inflammatory myopathy receiving therapeutic GCs. Methods: Wild type (WT) and global knock out (KO) of 11β-HSD1 animals were crossed onto the TNF-tg murine model of polyarthritis and inflammatory myopathy. Animals received vehicle or the GC corticosterone (100µg/ml) over three weeks in drinking water at therapeutic doses. Quadriceps and tibialis anterior (TA) were examined at 7 weeks and histology assessed. Anabolic, catabolic and inflammatory gene and protein expression were examined by RT-qPCR and western blot. Results: GC activation by 11β-HSD1 was completely attenuated in muscles from TNF-tg11β-HSD1KO animals. Both TNF-tg and TNF-tg11β-HSD1KO animals developed inflammatory myopathy characterised by reduced muscle weights and fibre size. In the TNF-tg mouse, therapeutic GC treatment further exacerbated muscle wasting with reduced muscle weight and fibre size relative to vehicle treated controls. This was characterised by elevated gene expression of atrophy markers (FoxO1, Trim63) and anti-anabolic signalling (REDD1), whilst pro-inflammatory gene expression of IL-6 was markedly suppressed. In contrast TNF-tg11β-HSD1KO animals receiving therapeutic GCs were protected from further muscle wasting, with muscle weights and fibre sizes significantly greater than TNF-tg counterparts. These animals showed a partial protection from the elevated expression of the atrophy markers FoxO1, Trim63 and anti-anabolic marker REDD1. They were also resistant to the suppression of the pro-inflammatory gene of IL-6 and induction of GC response gene GILZ, a mediator of anti-inflammatory effects. These data suggest that whilst therapeutic GCs supress inflammation within muscles of TNF-tg mice, they further exacerbate muscle wasting during chronic inflammation. This was dependant on 11β-HSD1 expression, with TNF-tg/11β-HSD1 KO animals being protected from further muscle wasting in response to therapeutic GCs. Reference: (1) Cushing, H. Obes Res. 1932;2(5):486-508. (2) Morgan et al., Proc Natl Acad Sci U S A. 2014;111(24):E2482-91.