Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy

Cell. 2004 Apr 30;117(3):399-412. doi: 10.1016/s0092-8674(04)00400-3.

Abstract

Skeletal muscle atrophy is a debilitating response to fasting, disuse, cancer, and other systemic diseases. In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy. Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. When Foxo activation is blocked by a dominant-negative construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented. Thus, forkhead factor(s) play a critical role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Cells, Cultured
  • Cloning, Molecular
  • Fasting / metabolism
  • Gene Expression Regulation
  • Genetic Vectors
  • Glucocorticoids / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Ligases / genetics
  • Ligases / metabolism*
  • Mice
  • Models, Biological
  • Muscle Cells / enzymology
  • Muscle Proteins
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Muscular Atrophy / etiology
  • Muscular Atrophy / genetics*
  • Muscular Atrophy / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA Interference
  • SKP Cullin F-Box Protein Ligases
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Glucocorticoids
  • Muscle Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Insulin-Like Growth Factor I
  • Fbxo32 protein, rat
  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin-Protein Ligases
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ligases