Abstract
Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic) and catabolic (or atrophic) processes. Previously, no link between the molecular mediators of atrophy and hypertrophy had been reported. We demonstrate a hierarchy between the signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt-mediated inhibition of MuRF1 and MAFbx upregulation. Our study thus defines a previously uncharacterized function for Akt, which has important therapeutic relevance: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.
MeSH terms
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Animals
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Cell Line
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Denervation / adverse effects
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Dexamethasone / pharmacology
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Glucocorticoids / pharmacology
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Insulin-Like Growth Factor I / metabolism*
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Insulin-Like Growth Factor I / pharmacology
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Mice
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / metabolism
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Muscle, Skeletal / growth & development
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Muscle, Skeletal / metabolism*
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Muscle, Skeletal / pathology
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Muscular Atrophy / chemically induced
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Muscular Atrophy / metabolism*
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Muscular Atrophy / pathology
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Mutation / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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SKP Cullin F-Box Protein Ligases / genetics
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SKP Cullin F-Box Protein Ligases / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics*
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / genetics
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Tripartite Motif Proteins
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Up-Regulation / drug effects
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Up-Regulation / genetics
Substances
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Glucocorticoids
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Muscle Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Transcription Factors
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Tripartite Motif Proteins
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Insulin-Like Growth Factor I
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Dexamethasone
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FBXO32 protein, human
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Fbxo32 protein, mouse
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SKP Cullin F-Box Protein Ligases
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TRIM63 protein, human
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Trim63 protein, mouse
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Ubiquitin-Protein Ligases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt