Regulation of signaling pathways downstream of IGF-I/insulin by androgen in skeletal muscle of glucocorticoid-treated rats.
BACKGROUND
The mechanisms by which androgens ameliorate glucocorticoid-induced muscle wasting are still under investigation. In the present study, we tested the hypothesis that androgen's effects in reversing muscle wasting are related to activating the signaling pathways downstream of insulin-like growth factor-1 (IGF-I)/insulin.


METHODS
Forty female Sprague-Dawley rats were randomly divided into four groups: control group, dexamethasone (DEX) group, testosterone (TES) group, and TES + DEX group. Each group was injected with saline or DEX (0.1 mg/100 g/d) for 10 days and sesame oil or TES (0.5 mg/100 g/d) for 13 days. Several downstream targets of IGF-I/insulin in skeletal muscle including protein kinase B (Akt), p70 ribosomal protein S6 kinase (p70S6K), and glycogen synthase kinase-3beta (GSK-3beta) that are associated with protein synthesis were examined. Two proteolysis-related ubiquitin E3-ligases, muscle atrophy F-box, and muscle RING finger-1 that are also regulated by IGF-I/insulin were also assessed.


RESULTS
TES attenuated gastrocnemius muscle atrophy induced by DEX. TES prevented the DEX-induced decrease of IGF-I expression in gastrocnemius muscle, but not in serum. TES ameliorated DEX-induced dephosphorylation of Akt and p70S6K and promoted the phosphorylation of GSK-3beta in gastrocnemius muscle. The total amount of Akt, p70S6K, or GSK-3beta proteins was not changed among these groups. TES did not show any effects on the DEX-induced upregulation of muscle atrophy F-box, and muscle RING finger-1 mRNA in gastrocnemius muscle.


CONCLUSIONS
This findings suggest that the effects of TES in reversing DEX-induced muscle atrophy are related to signaling pathways downstream of IGF-I/insulin that are associated with protein synthesis.
Department of Burns and Plastic Surgery, Burns Institute, First Affiliated Hospital of General Hospital of PLA, Beijing, China.
Hui-Nan
HN
Yin
Jia-Ke
JK
Chai
Yong-Ming
YM
Yu
Chuan-An
CA
Shen
Yan-Qiu
YQ
Wu
Yong-Ming
YM
Yao
Hui
H
Liu
Li-Ming
LM
Liang
Ronald G
RG
Tompkins
Zhi-Yong
ZY
Sheng
D000728:Androgens / Q000502:physiology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013739:Testosterone / Q000097:blood / Q000502:physiology*
D000728:Androgens; D005938:Glucocorticoids; D009124:Muscle Proteins; D013739:Testosterone; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa