Glucocorticoids, 11β-hydroxysteroid dehydrogenase type 1 and the aged phenotype

[摘要] Cushing’s syndrome is characterised by changes in body composition and cardiovascular disease risk profiles that have similarities to the aged phenotype. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive glucocorticoids(GCs) to their active form (cortisone to cortisol in humans). There is growing evidence that 11β-HSD1 expression/activity increases with age in key target tissues including adipose tissue, bone, and skin. This thesis encompasses a series of novel studies investigating the role of GCs and their pre-receptor metabolism in determining the ageing phenotype, with a central focus on skeletal muscle. We show that although cure of Cushing’s disease results in rapid improvements in clinical parameters, excess mortality may persist. We show in-vitro evidence of regulation of proteolytic genes by 11β-HSD1 and that 11β-HSD1KO mice are protected from muscle weakness due to GCs and ageing. We recruited healthy subjects (n=135, 20-80 years) for in-depth phenotyping, along with muscle biopsies (analysed by gene expression array) and urine steroid metabolite analysis. Skeletal muscle 11β-HSD1 expression increased 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.

[发布机构] University:University of Birmingham;Department:School of Clinical and Experimental Medicine

[关键词] R Medicine;R Medicine (General)