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- W2002076476 abstract "Abstract Background Muscle weakness is a key discriminatory feature of Cushing's syndrome, which is characterised by glucocorticoid excess. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive glucocorticoids to their active form (cortisone to cortisol in man, 11-dehydrocorticosterone [11DHC] to corticosterone [CORT] in mice). We hypothesised that chronic exposure of tissues to active glucocorticoids contributes to the sarcopenia of ageing, and that absence or inhibition of 11β-HSD1 modulates this effect. Methods C2C12 murine myotubes were used to identify glucocorticoid-regulated genes involved in muscle atrophy and to assess the effect of selective 11β-HSD1 inhibition. Regulation of glucocorticoid excess and ageing was assessed in mice on a high-fat diet: for glucocorticoid excess, 6-week-old male wildtype (wt) mice treated with CORT (100 μg/mL), 11DHC (100 μg/mL), or vehicle via drinking water for 5 weeks; for ageing, young (26 weeks) and aged (112 weeks) wt and 11β-HSD1 knockout mice. Grip strength and weights of muscle tissue were assessed as markers of muscle function with muscle mRNA expression profiles completed by microfluidic arrays. Biopsy samples of vastus lateralis muscle were taken in a study of healthy human volunteers (55 women, 24 men). Findings Glucocorticoids increased expression of 11β-HSD1 and key atrophy genes, Fbxo32 (p Mstn (p Fbxo32 were attenuated by co-treatment with a selective 11β-HSD1 inhibitor (p Fbxo32, Trim63, Mstn, Foxo1, Gadd45a, eiF4bp, CHARNB , and Ncam1 in wt mice (p vs wt control), and these changes were attenuated in 11β-HSD1 knockout mice. Old wt mice had reduced grip strength compared with young wt mice (p Trim63 (p Mstn (p Gadd45a (p eiF4bp (p CHARNB (p Ncam1 (p vs >50 years, p=0·0007 in women), along with GADD45a (p=0·005 women, p=0·04 men) and PSMA2 (p=0·004 women), and PSMD4 (p=0·006 women, p=0·04 men). Interpretation We have identified changes in skeletal muscle gene expression common to both glucocorticoid excess and ageing, that parallel changes in muscle function. Absence of 11β-HSD1 attenuates these changes and results in protection against muscle weakness. Human studies showed that 11β-HSD1 expression is increased with age in women, along with genes involved in proteolysis. Selective inhibition of 11β-HSD1 might offer a novel therapeutic target for the treatment of both glucocorticoid-induced myopathy and age-related sarcopenia. Funding European Research Council." @default.
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- W2002076476 date "2014-02-01" @default.
- W2002076476 modified "2023-09-27" @default.
- W2002076476 title "11β-hydroxysteroid dehydrogenase type 1 and age-associated muscle weakness in mice: implications for human ageing" @default.
- W2002076476 doi "https://doi.org/10.1016/s0140-6736(14)60316-0" @default.
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