Abstract
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 phosphoinositide-3 kinase pathway. In vitro, the Ras pathway appears to regulate the mitogenic effects of IGF-I signaling, whereas the phosphoinositide-3 kinase pathway is associated with cellular differentiation. On the basis of the results from in vitro studies, we hypothesized that the coinfusion 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 coinfusion of MAPK/ERK kinase inhibitor PD-098059 (PD) limited the phosphorylation of ERK and prevented IGF-I induced increases in protein (18%, P < 0.05 vs. 7%, not significant) or myofibrillar protein (23%, P < 0.01 vs. 5%, not significant). However, there were similar increases in indicators of cell proliferation (e.g., total DNA, 50 and 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 coinfusion ( approximately 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.
Highlights
Our results show that 14 days of coinfusion of MAPK/ERK kinase inhibitor PD-098059 (PD) limited the phosphorylation of ERK and prevented Insulin-like growth factor-I (IGF-I) induced increases in protein (18%, P Ͻ 0.05 vs. 7%, not significant) or myofibrillar protein (23%, P Ͻ 0.01 vs. 5%, not significant)
In vitro characterization of the intracellular signaling pathways that respond to the ligation of IGFR1 in skeletal muscle has lead to a model focused primarily on two pathways, one that is characterized by increased activity of Ras-ERK cascade and a second that involves phosphoinositide-3 kinase (PI3K) signaling [13, 45]
Experiments that include in vivo transfection, transgenic mice, or direct infusion have all demonstrated that increased IGF-I will induce muscle hypertrophy [4, 7, 12]
Summary
SKELETAL MUSCLE RESPONDS TO chronic increases in mechanical loading with a compensatory hypertrophy. Analysis of the IGF type 1 receptor (IGFR1) indicates that the ability to promote cell differentiation can be dissociated from the mitogenic effects of IGFR1 ligation, suggesting that distinct intracellular signaling pathways may mediate these processes [29]. Coolican et al found that the Ras-ERK pathway was important for stimulating cell proliferation, whereas the PI3K pathway was linked to cell differentiation. The results of this study indicate that intact signaling through MEK to the ERKs is necessary for the development of IGF-I-induced skeletal muscle hypertrophy in vivo
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