IGF-1 inversely regulates atrophy-induced genes, such as MAFbx, requiring the activation of both the Akt/FOXO and Akt/mTOR pathways for transcriptional changes.
Skeletal muscle size is regulated by anabolic (hypertrophic) and catabolic (atrophic) processes. We first characterized molecular markers of both hypertrophy and atrophy and identified a small subset of genes that are inversely regulated in these two settings (e.g. up-regulated by an inducer of hypertrophy, insulin-like growth factor-1 (IGF-1), and down-regulated by a mediator of atrophy, dexamethasone). The genes identified as being inversely regulated by atrophy, as opposed to hypertrophy, include the E3 ubiquitin ligase MAFbx (also known as atrogin-1). We next sought to investigate the mechanism by which IGF-1 inversely regulates these markers, and found that the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, which we had previously characterized as being critical for hypertrophy, is also required to be active in order for IGF-1-mediated transcriptional changes to occur. We had recently demonstrated that the IGF1/PI3K/Akt pathway can block dexamethasone-induced up-regulation of the atrophy-induced ubiquitin ligases MuRF1 and MAFbx by blocking nuclear translocation of a FOXO transcription factor. In the current study we demonstrate that an additional step of IGF1 transcriptional regulation occurs downstream of mTOR, which is independent of FOXO. Thus both the Akt/FOXO and the Akt/mTOR pathways are required for the transcriptional changes induced by IGF-1. Skeletal muscle size is regulated by anabolic (hypertrophic) and catabolic (atrophic) processes. We first characterized molecular markers of both hypertrophy and atrophy and identified a small subset of genes that are inversely regulated in these two settings (e.g. up-regulated by an inducer of hypertrophy, insulin-like growth factor-1 (IGF-1), and down-regulated by a mediator of atrophy, dexamethasone). The genes identified as being inversely regulated by atrophy, as opposed to hypertrophy, include the E3 ubiquitin ligase MAFbx (also known as atrogin-1). We next sought to investigate the mechanism by which IGF-1 inversely regulates these markers, and found that the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, which we had previously characterized as being critical for hypertrophy, is also required to be active in order for IGF-1-mediated transcriptional changes to occur. We had recently demonstrated that the IGF1/PI3K/Akt pathway can block dexamethasone-induced up-regulation of the atrophy-induced ubiquitin ligases MuRF1 and MAFbx by blocking nuclear translocation of a FOXO transcription factor. In the current study we demonstrate that an additional step of IGF1 transcriptional regulation occurs downstream of mTOR, which is independent of FOXO. Thus both the Akt/FOXO and the Akt/mTOR pathways are required for the transcriptional changes induced by IGF-1. Skeletal muscle mass and fiber size is regulated in response to changes in workload, activity, conditions such as AIDS, cancer, and aging, and by cachectic glucocorticoids such as dexamethasone (1Glass D.J. Nat. Cell Biol. 2003; 5: 87-90Crossref PubMed Scopus (534) Google Scholar, 2Glass D.J. Trends Mol. Med. 2003; 9: 344-350Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, 3Jagoe R.T. Goldberg A.L. Curr. Opin. Clin. Nutr. Metab. Care. 2001; 4: 183-190Crossref PubMed Scopus (328) Google Scholar). An increase in adult muscle mass and fiber size is called “hypertrophy” and is associated with increased protein synthesis (4Goldspink D.F. Garlick P.J. McNurlan M.A. Biochem. J. 1983; 210: 89-98Crossref PubMed Scopus (101) Google Scholar). A decrease in mass, called “atrophy,” is characterized by enhanced protein degradation (3Jagoe R.T. Goldberg A.L. Curr. Opin. 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Full Text Full Text PDF PubMed Scopus Google Scholar). myotube in with active for on day and with for to in with and with by 2 of with in with and and by for was in of Akt was with and A MAFbx was of MAFbx protein used in the and as previously T.N. Clarke B.A. M. Yancopoulos G.D. Glass D.J. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar). The of the was of the was and the was by a expression was first In a was the of the was by for and and are and the the and synthesis was by was with of and had a to A known of was used to the of A to that of used in the used in and are on a for for the of with the of of the pathway for IGF-1 mediated changes in PLF, PV, and and of PV, and the the of of are on a for for the of with the of IGF-1 and in previously the in vitro muscle cell as a to the signaling pathways myotube hypertrophy and demonstrated that such hypertrophy is induced by the activation of the PI3K/Akt pathway (12Rommel C. Bodine S.C. Clarke B.A. Rossman R. Nunez L. Stitt T.N. Yancopoulos G.D. Glass D.J. Nat. Cell Biol. 2001; 3: 1009-1013Crossref PubMed Scopus (1208) Google Scholar), a mechanism in hypertrophy in S.C. Stitt T.N. M. R. A. Lawrence J.C. Glass D.J. Yancopoulos G.D. Nat. Cell Biol. 2001; 3: PubMed Scopus Google Scholar). Furthermore, we an in vitro of skeletal muscle atrophy, the cachectic T.N. Clarke B.A. M. Yancopoulos G.D. Glass D.J. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar), which muscle in by the pathway Goldberg A.L. Am. J. Physiol. Google Scholar, Mol. 1995; PubMed Scopus Google and which also protein in vitro T.N. Clarke B.A. M. Yancopoulos G.D. Glass D.J. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. 1995; PubMed Scopus Google Scholar). was to the of genes expression was with sufficient of IGF-1 to induce hypertrophy sufficient of as to induce induce hypertrophy, differentiated for 2 and with IGF-1 for of of IGF-1 demonstrated an increase in myotube of with IGF-1 also induced phosphorylation of Akt as had previously demonstrated in C. Clarke B.A. Zimmermann S. Nunez L. Rossman R. Reid K. Moelling K. Yancopoulos G.D. Glass D.J. Science. 1999; 286: 1738-1741Crossref PubMed Scopus (661) Google Scholar, 12Rommel C. Bodine S.C. Clarke B.A. Rossman R. Nunez L. Stitt T.N. Yancopoulos G.D. Glass D.J. Nat. Cell Biol. 2001; 3: 1009-1013Crossref PubMed Scopus (1208) Google such activation as a that the PI3K/Akt pathway had in the that for induce atrophy, with for The and for changes in myotube of resulted in a with a decrease in myotube of a protein of the E3 ubiquitin ligase MAFbx a previously of skeletal muscle atrophy R.T. A. Goldberg A.L. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, S.C. S. Nunez L. Clarke B.A. K. Stitt T.N. Yancopoulos G.D. Glass D.J. Science. 2001; PubMed Scopus Google Scholar). MAFbx increased both and of used for of Genes in Hypertrophy was to genes regulated atrophy and hypertrophy. In first genes expression in two as being In first a was used genes found to be regulated by IGF-1 and genes regulated by of in genes that inversely regulated by the IGF-1 as opposed to the dexamethasone these inversely regulated genes to be markers, be used in atrophy hypertrophy to the on a molecular of the regulated genes to be inversely regulated in atrophy and hypertrophy, as the we on the genes with that up-regulation of for in both and of the genes that was inversely regulated was a that had previously to be up-regulated in atrophy R.T. A. Goldberg A.L. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, S.C. S. Nunez L. Clarke B.A. K. Stitt T.N. Yancopoulos G.D. Glass D.J. Science. 2001; PubMed Scopus Google Scholar). In addition to both and 2 down-regulated in myotube hypertrophy and up-regulated in myotube was found to be regulated in both processes. was found to be down-regulated in up-regulated in In was up-regulated in hypertrophy and down-regulated in was also found to be inversely was up-regulated in hypertrophy and down-regulated in and of Genes by and the a of a A. N. A. N. J. J. R. M. A. L. J. J. M. I. R. L. A. T. Yancopoulos G. Nat. 2003; PubMed Scopus Google Scholar), was on the as had used in the up-regulation of MAFbx and of MAFbx IGF-1 in with 3, A and a ligase that had previously to be up-regulated in atrophy S.C. S. Nunez L. Clarke B.A. K. Stitt T.N. Yancopoulos G.D. Glass D.J. Science. 2001; PubMed Scopus Google Scholar), was up-regulated in study was inversely down-regulated by IGF-1 to a 3, A and that both and down-regulated in the as with Furthermore, these genes also to be up-regulated in response to 3, A and and for both In to and of which up-regulated in atrophy down-regulated hypertrophy, and found to be up-regulated with IGF-1, in with and down-regulated with 3, A and A response was with DEX, that inversely regulated genes by are also regulated The previously demonstrated that the pathway skeletal muscle hypertrophy in by protein synthesis pathways (12Rommel C. Bodine S.C. Clarke B.A. Rossman R. Nunez L. Stitt T.N. Yancopoulos G.D. Glass D.J. Nat. Cell Biol. 2001; 3: 1009-1013Crossref PubMed Scopus (1208) Google Scholar, S.C. Stitt T.N. M. R. A. Lawrence J.C. Glass D.J. Yancopoulos G.D. Nat. Cell Biol. 2001; 3: PubMed Scopus Google Scholar). We sought to pathway also a in transcription and the inversely regulated genes we had identified as markers of skeletal muscle atrophy and hypertrophy. as a we the and of the PI3K and the on the that be used for that differentiated for 2 with and In the of IGF-1 of PI3K in myotube size IGF-1 a increase in myotube which was to by of the hypertrophy induced by IGF-1 The of the and used in the was demonstrated by to these signaling IGF-1 was for on as opposed to the used to induce changes IGF-1-mediated activation of RAP, which downstream of block phosphorylation of Akt phosphorylation of p70S6K, which activation for its phosphorylation downstream of IGF-1 in skeletal (12Rommel C. Bodine S.C. Clarke B.A. Rossman R. Nunez L. Stitt T.N. Yancopoulos G.D. Glass D.J. Nat. Cell Biol. 2001; 3: 1009-1013Crossref PubMed Scopus (1208) Google of the Genes by a we the expression of genes with IGF-1, LY, RAP, IGF-1 LY, and IGF-1 In an was used the the was genes that regulated IGF-1 regulated genes of the changes induced by IGF-1, that the PI3K pathway of the transcriptional induced by IGF-1 the IGF-1 regulated genes that by with LY, also with IGF-1 RAP, that the Akt/mTOR pathway downstream of PI3K was required to transcription activation by IGF-1. in of the genes that inversely regulated by IGF-1 as opposed to required an pathway, with the regulation of IGF-1. that the pathway is for changes of PLF, PV, and hypertrophy. In study we used an that The regulation of as as the regulation of the genes identified by by We and M. C. A. C. A. K. S. Goldberg A.L. Full Text Full Text PDF PubMed Scopus Google Scholar, T.N. Clarke B.A. M. Yancopoulos G.D. Glass D.J. Mol. Full Text Full Text PDF PubMed Scopus Google that the the of transcription In FOXO proteins in the by Akt and to the of and a of which had its Akt phosphorylation to the is nuclear of PI3K by with nuclear translocation of of by rapamycin had in nuclear translocation that the transcriptional of are induced by and an transcriptional mediator downstream of mTOR, which is required for IGF-1-mediated Skeletal muscle atrophy is accompanied by the of a transcriptional characterized in by the up-regulation of two genes that E3 ubiquitin MuRF1 and MAFbx D.J. Trends Mol. Med. 2003; 9: 344-350Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). In study we of an in vitro of skeletal myotube atrophy to study genes that are inversely regulated by atrophy and hypertrophy. in vitro atrophy of with the cachectic which we demonstrate is sufficient to induce of the atrophy a decrease in myotube and an of MuRF1 and In a study T.N. Clarke B.A. M. Yancopoulos G.D. Glass D.J. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar), was demonstrated that dexamethasone also a decrease in protein in the with the increased protein The of atrophy is hypertrophy, which is induced by an increase in protein synthesis and is characterized by an increase in muscle fiber In to atrophy, markers of the hypertrophy IGF-1-mediated myotube hypertrophy used as a to study the pathways that the increase in protein synthesis and muscle hypertrophy. both atrophy and hypertrophy conditions the current study a of regulated that are by an atrophy that are inversely regulated hypertrophy. inversely regulated subset of genes an of markers genes regulated by atrophy hypertrophy the to be regulated by the conditions the of of genes a of the growth of the The inversely regulated genes characterized in study include the previously identified atrophy which is up-regulated MAFbx is also down-regulated hypertrophy. The regulation of MAFbx by IGF-1 was also in a which on and ubiquitin regulation by IGF-1 J.M. A. S.C. Goldberg A.L. Am. J. Physiol. PubMed Scopus Google Scholar). In addition to a of genes that found to be inversely regulated the a of proteins that previously identified as atrophy markers J.M. A. S.C. Goldberg A.L. Am. J. Physiol. PubMed Scopus Google Scholar, R.T. A. M. J. S.R. W.E. Goldberg A.L. J. PubMed Scopus Google Scholar). the that be of a regulated signaling pathway that the in skeletal of proteins that and are involved in atrophy are the ubiquitin we that are in of the such that enhanced the of In a was that of the PI3K signaling pathway was sufficient to induce MAFbx up-regulation J.M. A. S.C. Goldberg A.L. Am. J. Physiol. PubMed Scopus Google Scholar). In a to conditions M. C. A. C. A. K. S. Goldberg A.L. Full Text Full Text PDF PubMed Scopus Google Scholar). In changes in the of both and as opposed to When an up-regulation of MuRF1 and MAFbx was by PI3K for up-regulation of the atrophy markers MuRF1 and MAFbx the required the of is that of the pathway and the PI3K pathway is sufficient to is regulated by the of K. K. C. J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In addition to the genes that are inversely regulated in atrophy and hypertrophy, study a signaling pathway downstream of IGF-1, which the regulation of atrophy-induced genes by IGF-1. IGF-1 the activation of the PI3K/Akt pathway, as an increase in protein translation activation of and of (also known as N. M. A. S.C. Hemmings B.A. G. Science. 1998; PubMed Scopus Google Scholar, S.R. Ming N. G. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar, M.A. N. N. Genes Dev. 1998; PubMed Scopus Google Scholar, R. S. C. Sweeney G. A. Am. J. Physiol. 1998; Google Scholar, R.T. R. N. 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Full Text Full Text PDF PubMed Scopus Google Scholar). study is the in that on in the of a atrophy In that the study an additional of the signaling the of PI3K block the of to inversely atrophy-induced also that the of mTOR, which is downstream of is sufficient to of of the genes regulated by IGF-1 in the of pathways by IGF-1, was to that of the pathway was sufficient to block the of the genes regulated by IGF-1. a in which transcription is and by the signaling pathways downstream of IGF-1 and in which of is sufficient to block changes in that skeletal muscle that to be protein synthesis can Akt the pathway is a of be for the to protein the of the muscle is to hypertrophy signaling is the muscle that FOXO also be the and growth signaling is with The that FOXO translocation was by with rapamycin the downstream of is a transcriptional in study we demonstrate for the first that the Akt/mTOR pathway is required for of the IGF-1 mediated transcriptional changes in skeletal muscle is to that the be in the of a atrophy such as a the that IGF-1 can and inversely key atrophy-induced genes the PI3K/Akt pathway to pathway as a target for activation by We L. S. P. and the for We Stitt and for We also for We are to S. and for
Latres et al. (Fri,) conducted a other in Skeletal muscle atrophy and hypertrophy. Insulin-like growth factor-1 (IGF-1) vs. Dexamethasone was evaluated on Transcriptional regulation of atrophy-induced genes (e.g., MAFbx). IGF-1 inversely regulates atrophy-induced genes, such as MAFbx, requiring the activation of both the Akt/FOXO and Akt/mTOR pathways for transcriptional changes.