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1 Cedars-Sinai Medical Center
2 Cedars Sinai Medical Center
* To whom correspondence should be addressed. E-mail: michael.lewis{at}cshs.org.
Increased expression of forkhead box O (Foxo) transcription factors were reported in cultured myotubes and mouse limb muscle with corticosteroid (CS) treatment. We previously reported that administration of CS to rats resulted in muscle fiber atrophy only by day 7. The aim of this study therefore, was to evaluate the time-course changes in the expression of Foxo transcription factors and muscle specific ubiquitin E3 ligases in rat limb muscle following CS administration. Triamcinolone (TR; 1 mg/kg/d, im) was administered for 1, 3, or 7 days. Control (CTL) rats were given saline. Muscle mRNA was analyzed by real-time RT-PCR. Compared to CTL, body weights of TR treated animals decreased by 3, 12 and 21% at days 1, 3 and 7, respectively. Muscle IGF-1 mRNA levels decreased by 33, 65 and 58% at days 1, 3 and 7 in TR treated rats compared to CTL. Levels of phosphorylated Akt were 28, 50 and 36% lower in TR animals at these time points. Foxo1 mRNA increased progressively by 1.2, 1.4 and 2.5-fold at days 1, 3 and 7 in TR animals. Similar changes were noted in the expression of Foxo3a mRNA (1.3, 1.4 and 2.6-fold increments). By contrast, Foxo4 mRNA was not significantly changed in TR animals. With TR, muscle atrophy F box/Atrogin-1 increased by 1.8, 4.1 and 7.5-fold at days 1, 3 and 7 compared to CTL rats. By contrast, muscle RING finger 1 increased only from day 7 (2.7-fold). Gradual reduction in IGF-I expression with TR over the time series, paralleled that of Akt. These findings are consistent with a progressive stimulus to muscle protein degradation and the need to process/remove disassembled muscle proteins via the ubiquitin-proteasome system. Elucidating the dynamic catabolic responses to CS challenge is important in understanding the mechanisms underlying muscle atrophy, and therapeutic measures to offset this.
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