Regulation of components of the ubiquitin system by insulin-like growth factor I and growth hormone in skeletal muscle of rats made catabolic with dexamethasone.
To investigate whether the anabolic effects of insulin-like growth factor I (IGF-I) and GH are mediated through regulation of the ubiquitin (Ub) pathway, we examined the effect of IGF-I (0.35 microg/100 g) and/or GH (0.3 mg/100 g BW) on the expression of Ub and Ub-conjugating (E2) enzyme messenger RNAs (mRNAs) in skeletal muscle of rats made catabolic by treatment with dexamethasone (Dex; 0.5 mg/100 g BW) for 3 days. Dex caused a significant loss of body and gastrocnemius weight (14% and 25%, respectively) concurrent with an increase in the 2.8- and 1.2-kb transcripts of Ub (14.3- and 12-fold increases, respectively), the 1.8- and 1.2-kb transcripts of 14-kDa Ub-conjugating enzyme (E2-14 kDa; 5.6- and 7.7-fold increases, respectively), the 4.4- and 2.4-kb transcripts of Ub-E2G (6.5- and 8.2-fold increases, respectively), and the 2E isoform of the 17-kDa E2 mRNA (3.5-fold increase). Injections of IGF-I in Dex-treated animals ameliorated the body weight loss, and the gastrocnemius tended to be heavier. This improvement was also accompanied by a significant suppression of transcripts for Ub (58% and 66% decreases), E2-14 kDa (58% and 68% decreases), and Ub-E2G (78% decrease), whereas the 2E isoform of the 17-kDa E2 was only modestly affected (20% decrease). GH restored serum IGF-I levels to normal in Dex-treated rats, but had no effect on the body weight loss or on any of the studied components of the Ub pathway. Administration of IGF-I to the Dex/GH-treated animals decreased the activated mRNAs of the Ub pathway in a manner and degree similar to those observed in the Dex/ IGF-I group. In summary, these results provide evidence that IGF-I regulates the expression of mRNAs encoding components of the Ub pathway during catabolism and suggest a possible mechanism for the antiproteolytic actions of IGF-I. On the other hand, GH, which is believed not to affect proteolysis but only protein synthesis, had no effect on any of the mRNAs studied.
Chrysis
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Department of Pediatrics, University of North Carolina, Chapel Hill 27599-7220, USA.
Underwood
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D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D013006:Growth Hormone / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008025:Ligases / Q000235:genetics*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044763:Ubiquitin-Conjugating Enzymes; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
D005938:Glucocorticoids; D012333:RNA, Messenger; D014452:Ubiquitins; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D013006:Growth Hormone; D044763:Ubiquitin-Conjugating Enzymes; D008025:Ligases