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


METHODS
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.
Inder
Warrick J
WJ
Department of Endocrinology, St Vincent's Hospital, Parade, Fitzroy, VIC 3065, Australia. winder@medstv.unimelb.edu.au
Jang
Christina
C
Obeyesekere
Varuni R
VR
Alford
Frank P
FP
D003907:Dexamethasone / Q000009:adverse effects / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000096:biosynthesis*; D013739:Testosterone / Q000097:blood
D012333:RNA, Messenger; D011944:Receptors, Androgen; D013739:Testosterone; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D017526:Receptor, IGF Type 1