Endocrine Abstracts (2012) 28 OC4.2

Age-dependent increase in the expression/activity of 11[beta]-HSD1 in key metabolic tissues may underpin the ageing phenotype notably sarcopenia

Stuart Morgan, Mark Sherlock, Gareth Lavery, Zaki Hassan-Smith, Lianne Abrahams & Paul Stewart

School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom.

The pathophysiological effects of glucocorticoid (GC) excess (Cushing’s syndrome) are similar to the aging phenotype. As such, we hypothesise that age-related changed in body composition (central obesity, reduced bone density, reduced muscle mass and skin thinning), and resultant chronic disease (type 2 diabetes, osteoporosis, sarcopenia and heart disease) may be caused by increased GC exposure with age. However, circulating GC’s show little change with advancing age. Within key metabolic tissues, murine 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts 11-dehydrocorticosterone to the active GC, corticosterone and thus amplifies local GC action. We have previously shown 11β-HSD1 expression and activity to increase with age in primary osteoblasts and skin, which may underpin age-related osteoporosis and skin thinning respectively. In C57b/6 mice (8 weeks vs. 112 weeks) we found 11β-HSD1 activity to increase with age in several key metabolic tissues including: liver (2-fold, P<0.05), epididymal adipose (2.7-fold, P<0.05), quadriceps muscles (2.1-fold, P<0.01) and soleus muscles (1.7-fold, P<0.05). This was paralleled by increased mRNA expression of 11β-HSD1 in epididymal adipose tissue (2.3-fold, P<0.05), quadriceps muscles (6.3-fold, P<0.05), tibialis anterior muscles (8-fold, P<0.001) and soleus muscles (16-fold, P<0.001). Using C2C12 myotubes, corticosterone (100 μM, 24 h) increased the mRNA expression of key atrophy markers: MAFbx-1 (5.6-fold, P<0.001) and MuRF-1 (2-fold, P<0.001). Critically, these genes were also upregulated in quadriceps muscles (MAFbx: 3.5-fold, P<0.001; MuRF-1: 2.3-fold, P<0.001) and tibialis anterior muscles (MAFbx: 4-fold, P<0.001; MuRF-1: 1.9-fold, P<0.05) of the above mice with age. This was paralleled by an age-dependent decreased in fore (0.38-fold, P<0.001) and hind (0.51-fold, P<0.01) grip strength. In summary, the expression/activity of 11β-HSD1 increases with age in several key metabolic tissues, and this may accelerate sarcopenia and contribute to reduced healthy lifespan.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.

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