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

Hassan-Smith, Zaki K. (2014). Glucocorticoids, 11β-hydroxysteroid dehydrogenase type 1 and the aged phenotype. University of Birmingham. Ph.D.

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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.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Clinical and Experimental Medicine
Funders: None/not applicable
Subjects: R Medicine > R Medicine (General)


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