Dexamethasone administration inhibits skeletal muscle expression of the androgen receptor and IGF-1 - implications for steroid-induced myopathy

• Published in: Clinical endocrinology (Oxford) Vol. 73; no. 1; pp. 126 - 132
• Main Authors: Inder, Warrick J., Jang, Christina, Obeyesekere, Varuni R., Alford, Frank P.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2010; Blackwell; Wiley Subscription Services, Inc
• Subjects: Biological and medical sciences; Dexamethasone - adverse effects; Dexamethasone - pharmacology; Diabetes Mellitus, Type 2 - metabolism; Down-Regulation; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Humans; Insulin-Like Growth Factor I - biosynthesis; Male; Medical sciences; Middle Aged; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscular Diseases - chemically induced; Muscular Diseases - metabolism; Receptor, IGF Type 1 - biosynthesis; Receptors, Androgen - biosynthesis; RNA, Messenger - metabolism; Testosterone - blood; Vertebrates: endocrinology; Steroid; Corticosteroid; Dexamethasone; Steroid hormone; Antiinflammatory agent; Gene expression; Insulin like growth factor 1; Striated muscle; Androgen receptor; Inhibitor; Endocrinology; Myopathy; Hormonal receptor
• ISSN: 0300-0664; 1365-2265; 1365-2265
• DOI: 10.1111/j.1365-2265.2009.03683.x

Summary Context  Glucocorticoids are a well‐recognized cause of muscle weakness. The early effects of glucocorticoids on skeletal muscle (SkM) androgen and IGF‐1 pathways have not been previously investigated in human subjects. Objective  To determine if administration of the potent glucocorticoid dexamethasone down‐regulates SkM androgen receptor and the IGF‐1 signalling pathway. Methods and subjects  Twenty‐four subjects (12 men and 12 women), including 12 with type 2 diabetes and 12 nondiabetics were enrolled. Venous blood sampling and biopsy of vastus lateralis were performed before and after administration of oral dexamethasone 4 mg/day for 4 days. Main outcome measures  Changes in plasma testosterone and IGF‐1, SkM androgen receptor mRNA, SkM IGF‐1mRNA and SkM IGF‐1 receptor mRNA by quantitative RT‐PCR after dexamethasone. Results  Relative expression of SkM androgen receptor was similar in male (1·63 ± 0·37) vs. female (1·57 ± 0·30) subjects, despite the significant difference in plasma testosterone levels. Plasma IGF‐1 and SkM expression of IGF‐1 and IGF‐1 receptor were also similar between males and females. Following dexamethasone, there was a significant down‐regulation of SkM androgen receptor (1·60 ± 0·23 vs. 1·11 ± 0·16, P < 0·05) and IGF‐1 (1·72 ± 0·29 vs. 1·06 ± 0·14, P < 0·05) mRNA, but no change in expression of the IGF‐1 receptor. Plasma testosterone fell significantly in both sexes (male: 15·0 ± 1·3 vs. 11·3 ± 1·2 nmol/l, P < 0·01, female: 1·8 ± 0·5 vs. 0·5 ± 0·1 nmol/l, P < 0·05). Conclusions  Exogenous steroid excess results in relative androgen deficiency at two levels, reduced circulating testosterone and SkM androgen receptor mRNA, along with reduced SkM IGF‐1 mRNA. These defects may contribute to the development of steroid‐induced myopathy.