Identification of an 11 Beta-Hydroxysteroid Dehydrogenase Type 1 Regulated Gene Expression Profile Common to Glucocorticoid and Age Associated Myopathies

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 1-25-Glucocorticoid Actions & HPA Axis
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-15
Zaki K Hassan-Smith*, Stuart Andrew Morgan, Mark Sherlock, Nicola Crabtree, Iwona Bujalska, Mark Cooper, Jeremy W Tomlinson, Gareth Geoffrey Lavery and Paul Michael Stewart
University of Birmingham, United Kingdom
Myopathy, characterized by muscle atrophy and reduced strength, is a key discriminatory feature of Cushing’s Syndrome. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) functions as a reductase converting inactive cortisone to active cortisol in humans, and inactive 11-dehydrocorticosterone (11DHC) to active corticosterone (CORT) in mice, thus amplifying local glucocorticoid (GC) action. We hypothesize that in muscle 11β-HSD1 mediated GC generation contributes to age associated sarcopenia. To investigate this we assessed 6-week old male wildtype (WT) mice treated with CORT (100μg/mL), 11DHC (100μg/mL) or vehicle via drinking water for 5 weeks, and young (26 wks) and aged (112 wks) WT and 11β-HSD1KO mice. Grip strength and tissue weights were assessed as markers of muscle function with muscle mRNA expression profiles completed using fluidigm arrays. In WT quadriceps, both CORT and 11DHC increased expression of key muscle atrophy genes including FOXO1, FOXO3a, MuRF1, atrogin-1, myostatin, GSK3β, and GADD45a. This was paralleled by decreased quadriceps weight and grip strength compared to vehicle treated mice. WT mice at 112 wks of age shared a common atrophy gene expression profile with CORT treated mice, and demonstrated an age-dependent decrease in grip strength. However, aged 11β-HSD1KO mice were protected from the atrophy associated gene expression profile and retained a muscle mass and grip strength phenotype similar to that of a young WT. In human clinical studies we assessed muscle function using Leonardo jump plate mechanography, and carried out fluidigm gene expression profiling on percutaneous vastus lateralis muscle biopsies in 70 patients ranging from 20-80 years of age. This revealed again an increase in FOXO1, FOXO3a and GADD45a expression with age. Furthermore, there was an inverse relationship between maximum peak power and maximal velocity during upward movement and expression of muscle atrophy genes including FOXO1, FOXO3a, myostatin and GADD45a. In summary, we have identified a muscle gene expression profile common to both GC and age associated myopathy, which is not seen in aged 11β-HSD1KO mice. Furthermore, human studies have identified the importance of these genes in the muscle aging phenotype. These data suggest that muscle 11β-HSD1 could offer a novel therapeutic target in the treatment of both GC-associated myopathy and sarcopenia.

Nothing to Disclose: ZKH, SAM, MS, NC, IB, MC, JWT, GGL, PMS

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Sources of Research Support: European Research Council Grant.