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Submitted on July 8, 2004
Accepted on March 21, 2005
INHIBITORS
Shriners Hospital for Children, Cincinnati, Ohio; Department of Surgery, University of Cincinnati, Cincinnati, Ohio; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
* To whom correspondence should be addressed. E-mail: cfang{at}shrinenet.org.
We reported previously that IGF-I inhibits burn-induced muscle proteolysis. Recent studies suggest that activation of the PI3K/Akt signaling pathway with downstream phosphorylation of Foxo transcription factors is an important mechanism of IGF-I-induced anabolic effects in skeletal muscle. The potential role of other mechanisms in the anabolic effects of IGF-I is less well understood. Here we tested the role of mTOR and GSK-3
phosphorylation as well as MAPK- and calcineurin-dependent signaling pathways in the anti-catabolic effects of IGF-I by incubating extensor digitorum longus muscles from burned rats in the presence of IGF-I and specific signaling pathway inhibitors. Surprisingly, the PI3K inhibitors LY294002 and wortmannin reduced basal protein breakdown. No further inhibition by IGF-I was noticed in the presence of LY294002 or wortmannin. Inhibition of proteolysis by IGF-I was associated with phosphorylation (inactivation) of GSK-3. In addition, the GSK-3 inhibitors LiCl and TDZD-8 reduced protein breakdown in a similar fashion as IGF-I. LiCl, but not TDZD-8, increased the levels of phosphorylated Foxo 1 in incubated muscles from burned rats. Inhibitors of mTOR, MAPK, and calcineurin did not prevent the IGF-I-induced inhibition of muscle proteolysis. Our results suggest that IGF-I inhibits protein breakdown at least in part through a PI3K/Akt/GSK3-dependent mechanism. Additional experiments showed that similar mechanisms were responsible for the effect of IGF-I in muscle from non-burned rats. Taken together with recent reports in the literature, the present results suggest that IGF-I inhibits protein breakdown in skeletal muscle by multiple mechanisms, including PI3K/Akt-mediated inactivation of GSK-3 and Foxo transcription factors.
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