11β-hydroxysteroid dehydrogenase type 1 and age-associated muscle weakness in mice: implications for human ageing

Abstract

BackgroundMuscle 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. MethodsC2C12 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). FindingsGlucocorticoids increased expression of 11β-HSD1 and key atrophy genes, Fbxo32 (p<0·01) and Mstn (p<0·05). Changes in Fbxo32 were attenuated by co-treatment with a selective 11β-HSD1 inhibitor (p<0·05). Tissue weights of quadriceps and tibialis anterior muscles were reduced in wt mice treated with active and inactive glucocorticoids (p<0·05), whereas 11β-HSD1 knockout mice treated with inactive glucocorticoids were protected. wt mice treated with glucocorticoids had reduced grip strength compared with controls (p<0·001), whereas 11β-HSD1 knockout mice were protected. CORT and 11DHC increased expression of Fbxo32, Trim63, Mstn, Foxo1, Gadd45a, eiF4bp, CHARNB, and Ncam1 in wt mice (p<0·01 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<0·05), and old 11β-HSD1 knockout mice had preservation of grip strength. Trim63 (p<0·01), Mstn (p<0·01), Gadd45a (p<0·0001), eiF4bp (p<0·05), CHARNB (p<0·001), and Ncam1 (p<0·05) were upregulated with age in wt mice, but not in 11β-HSD1 knockout mice. In the study of human volunteers, 11β-HSD1 expression was upregulated with age (<50 years 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). InterpretationWe 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. FundingEuropean Research Council.