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1 Department of Physiology & Biophysics, University of California, Irvine, Irvine, CA, USA
* To whom correspondence should be addressed. E-mail: gradams{at}uci.edu.
Insulin-like growth factor-I (IGF-I) has been shown to stimulate a hypertrophy response in skeletal muscles in vivo. In vitro studies have delineated two primary intracellular pathways that appear to mediate the effects of IGF-I in skeletal muscle: the Ras-ERK pathway and the PI3 kinase pathway. In vitro, the Ras pathway appears to regulate the mitogenic effects of IGF-I signaling while the PI3 kinase pathway is associated with cellular differentiation. Based on the results from in vitro studies we hypothesized that the co-infusion of both IGF-I and an inhibitor of the Ras pathway would result in some increase in muscle protein but an inhibition of cell proliferation. Our results show that 14 days of co-infusion of MEK inhibitor PD-098059 (PD) limited the phosphorylation of ERK and prevented IGF-I induced increases in protein (18%, P<0.05 vs. 7%, n.s.) or myofibrillar protein (23%, P<0.01 vs. 5%, n.s.). However, there were similar increases in indicators of cell proliferation (e.g., total DNA, 50 & 52%, P<0.001) in both the IGF and IGF+PD infused muscles. The most notable impact on IGF-I signaling was a significant blunting of IGF-I induced increase in S6K1 phosphorylation by PD-98059 co-infusion (~5 fold, P<0.001 vs. 3 Fold P<0.01). These results suggest that there are interactions between the various pathways down stream of the IGF-I receptor that may behave differently in vivo than in myogenic cell lines in vitro.
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