Endocrine Abstracts

Introduction: There is growing evidence that 11β-HSD1 expression/activity increases with age in key target tissues including adipose tissue, bone, and skin, implicating local amplification of glucocorticoids in the pathophysiology of related disease. We have previously shown that 11β-HSD1KO mice are protected from both the adverse metabolic effects of excess glucocorticoids and age-associated muscle weakness. We investigated changes in global activity and skeletal muscle gene expression of 11β-HSD1 with human ageing.

Methods: 135 healthy volunteers (women n=77, men n=58, aged 20–80 years) were recruited. DEXA body composition analysis, strength testing, serum and 24-h urine collection (analysed by GC/MS) and vastus lateralis muscle biopsies (92 genes analysed by microfluidic array) were performed.

Results: Skeletal muscle 11β-HSD1 expression increased with age in women. Furthermore, women aged >70 years had increased urine (THF+5αTHF)/THE ratios vs women in their 1920s. 11β-HSD1 expression was positively correlated with serum gonadotrophins, body fat and total cholesterol and was negatively correlated with bone mineral content, grip strength and serum IGF1, in women. Total F metabolites were positively correlated with fat mass, in both sexes. In skeletal muscle, we observed age-related changes in genes encoding proteins with functions in pre-receptor GC metabolism (11β-HSD1, H6PDH) cell stress response (GADD45a, HIF-1α, CDKN1A, HSP90B1, SIRT3) and proteolysis (PSMA2, PSMD4).

Conclusion: Skeletal muscle 11β-HSD1 expression increases with age in women, and this change may be driven by the menopause. The therapeutic potential of selective inhibitors of 11β-HSD1 in ameliorating the adverse metabolic and body composition profile associated with ageing and the menopause remains to be determined.