title: IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1.
abstract: Muscle atrophy results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin ligases (E3s): atrogin-1 and muscle ring finger 1 (MuRF1). Glucocorticoids are essential for many types of muscle atrophy, and their effects are opposite to those of insulin-like growth factor I (IGF-I) and insulin, which promote growth. In myotubes, dexamethasone (Dex) inhibited growth and enhanced breakdown of long-lived cell proteins, especially myofibrillar proteins (as measured by 3-methylhistidine release), while also increasing atrogin-1 and MuRF1 mRNA. Conversely, IGF-I suppressed protein degradation and prevented the Dex-induced increase in proteolysis. IGF-I rapidly reduced atrogin-1 expression within 1 h by blocking mRNA synthesis without affecting mRNA degradation, whereas IGF-I decreased MuRF1 mRNA slowly. IGF-I and insulin also blocked Dex induction of these E3s and several other atrophy-related genes ("atrogenes"). Changes in overall proteolysis with Dex and IGF-I correlated tightly with changes in atrogin-1 mRNA content, but not with changes in MuRF1 mRNA. IGF-I activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and inhibition of this pathway [but not the calcineurin-nuclear factor of activated T cell (NFAT) or the MEK-ERK pathway] increased proteolysis and atrogin-1 mRNA expression. Thus an important component of growth stimulation by IGF-I, through the PI3K-Akt pathway, is its ability to rapidly suppress transcription of the atrophy-related E3 atrogin-1 and other atrogenes and degradation of myofibrillar proteins.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sacheck
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtsuka
authors.forename: S Christine
authors.initials: SC
authors.lastname: McLary
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
mesh_terms: D015152:Blotting, Northern; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008762:Methylhistidines / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development*; D009133:Muscular Atrophy / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D013268:Stimulation, Chemical; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000096:biosynthesis; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D008762:Methylhistidines; D009124:Muscle Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases; C028118:3-methylhistidine