Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway.
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.
Latres
Esther
E
Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591-6707, USA.
Amini
Ami R
AR
Amini
Ashley A
AA
Griffiths
Jennifer
J
Martin
Francis J
FJ
Wei
Yi
Y
Lin
Hsin Chieh
HC
Yancopoulos
George D
GD
Glass
David J
DJ
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001284:Atrophy; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000378:metabolism; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D003907:Dexamethasone; D005938:Glucocorticoids; D007334:Insulin-Like Growth Factor I; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D044843:SKP Cullin F-Box Protein Ligases; D058570:TOR Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C440907:FBXO32 protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse