Zaki K Hassan-Smith1, Stuart A Morgan1, Mark Sherlock1, Beverly Hughes1, Angela E Taylor1, Gareth G Lavery1, Jeremy W Tomlinson1, Paul M Stewart1. 1. Centre for Endocrinology, Diabetes, and Metabolism (Z.K.H.-S., S.A.M., B.H., A.E.T., G.G.L.), School of Clinical and Experimental Medicine, Institute for Biomedical Research, University of Birmingham, Edgbaston B15 2TT, United Kingdom; Department of Endocrinology (M.S.), Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland; Trinity College (M.S.), Dublin 2, Ireland; Oxford Centre for Diabetes, Endocrinology, and Metabolism (J.W.T.), University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LE, United Kingdom; and Faculty of Medicine and Health (P.M.S.), University of Leeds, Leeds LS2 9NL, United Kingdom.
Abstract
CONTEXT: Cushing's syndrome is characterized by marked changes in body composition (sarcopenia, obesity, and osteoporosis) that have similarities with those seen in aging. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts glucocorticoids to their active form (cortisone to cortisol in humans), resulting in local tissue amplification of effect. OBJECTIVE: To evaluate 11β-HSD1 expression and activity with age, specifically in muscle. To determine putative causes for increased activity with age and its consequences upon phenotypic markers of adverse aging. DESIGN: Cross-sectional observational study. SETTING: National Institute for Health Research-Wellcome Trust Clinical Research Facility, Birmingham, United Kingdom. PATIENTS OR OTHER PARTICIPANTS: Healthy human volunteers age 20 to 81 years (n = 134; 77 women, 57 men). INTERVENTIONS: Day attendance at research facility for baseline observations, body composition analysis by dual-energy x-ray absorptiometry, jump-plate mechanography, grip strength analysis, baseline biochemical profiling, urine collection, and vastus lateralis muscle biopsy. MAIN OUTCOME MEASURE(S): Skeletal muscle gene expression, urine steroid profile, bivariate correlations between expression/activity and phenotypic/biochemical variables. RESULTS: Skeletal muscle 11β-HSD1 expression was increased 2.72-fold in women over 60 years of age compared to those aged 20-40 years; no differences were observed in men. There was a significant positive correlation between skeletal muscle 11β-HSD1 expression and age in women across the group (rho = 0.40; P = .009). No differences in expression of 11β-HSD type 2, glucocorticoid receptor, or hexose-6-phosphate dehydrogenase between age groups were observed in either sex. Urinary steroid markers of 11β-HSD1, 11β-HSD type 2, or 5α-reductase were similar between age groups. Skeletal muscle 11β-HSD1 expression was associated with reduced grip strength in both sexes and correlated positively with percentage of body fat, homeostasis model of assessment for insulin resistance, total cholesterol, LH, and FSH and negatively with bone mineral content and IGF-1 in women. CONCLUSIONS: Skeletal muscle 11β-HSD1 is up-regulated with age in women and is associated with reduced grip strength, insulin resistance, and an adverse body composition profile. Selective inhibition of 11β-HSD1 may offer a novel strategy to prevent and/or reverse age-related sarcopenia.
CONTEXT: Cushing's syndrome is characterized by marked changes in body composition (sarcopenia, obesity, and osteoporosis) that have similarities with those seen in aging. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts glucocorticoids to their active form (cortisone to cortisol in humans), resulting in local tissue amplification of effect. OBJECTIVE: To evaluate 11β-HSD1 expression and activity with age, specifically in muscle. To determine putative causes for increased activity with age and its consequences upon phenotypic markers of adverse aging. DESIGN: Cross-sectional observational study. SETTING: National Institute for Health Research-Wellcome Trust Clinical Research Facility, Birmingham, United Kingdom. PATIENTS OR OTHER PARTICIPANTS: Healthy human volunteers age 20 to 81 years (n = 134; 77 women, 57 men). INTERVENTIONS: Day attendance at research facility for baseline observations, body composition analysis by dual-energy x-ray absorptiometry, jump-plate mechanography, grip strength analysis, baseline biochemical profiling, urine collection, and vastus lateralis muscle biopsy. MAIN OUTCOME MEASURE(S): Skeletal muscle gene expression, urine steroid profile, bivariate correlations between expression/activity and phenotypic/biochemical variables. RESULTS: Skeletal muscle 11β-HSD1 expression was increased 2.72-fold in women over 60 years of age compared to those aged 20-40 years; no differences were observed in men. There was a significant positive correlation between skeletal muscle 11β-HSD1 expression and age in women across the group (rho = 0.40; P = .009). No differences in expression of 11β-HSD type 2, glucocorticoid receptor, or hexose-6-phosphate dehydrogenase between age groups were observed in either sex. Urinary steroid markers of 11β-HSD1, 11β-HSD type 2, or 5α-reductase were similar between age groups. Skeletal muscle 11β-HSD1 expression was associated with reduced grip strength in both sexes and correlated positively with percentage of body fat, homeostasis model of assessment for insulin resistance, total cholesterol, LH, and FSH and negatively with bone mineral content and IGF-1 in women. CONCLUSIONS: Skeletal muscle 11β-HSD1 is up-regulated with age in women and is associated with reduced grip strength, insulin resistance, and an adverse body composition profile. Selective inhibition of 11β-HSD1 may offer a novel strategy to prevent and/or reverse age-related sarcopenia.
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