The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors

Mol Cell. 2004 May 7;14(3):395-403. doi: 10.1016/s1097-2765(04)00211-4.

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

  • Animals
  • Cell Line
  • Denervation / adverse effects
  • Dexamethasone / pharmacology
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Glucocorticoids / pharmacology
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor I / pharmacology
  • Mice
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / growth & development
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Atrophy / chemically induced
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / pathology
  • Mutation / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Glucocorticoids
  • Muscle Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Transcription Factors
  • Tripartite Motif Proteins
  • Insulin-Like Growth Factor I
  • Dexamethasone
  • FBXO32 protein, human
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases
  • TRIM63 protein, human
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt