Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy

Neuron. 2009 Aug 13;63(3):316-28. doi: 10.1016/j.neuron.2009.07.019.

Abstract

Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Cell Line, Transformed
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Humans
  • Insulin-Like Growth Factor I / genetics*
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor I / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Muscular Atrophy / physiopathology*
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / mortality
  • Muscular Atrophy, Spinal / pathology*
  • Muscular Atrophy, Spinal / therapy
  • Mutation / genetics
  • Oncogene Protein v-akt / metabolism
  • Peptides / genetics
  • Peptides / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Serine / metabolism
  • Time Factors
  • Transfection / methods
  • Trinucleotide Repeat Expansion / drug effects
  • Trinucleotide Repeat Expansion / physiology
  • Ubiquitin / metabolism

Substances

  • Enzyme Inhibitors
  • Muscle Proteins
  • Peptides
  • Receptors, Androgen
  • Ubiquitin
  • polyglutamine
  • Serine
  • Insulin-Like Growth Factor I
  • Pik3cd protein, mouse
  • Oncogene Protein v-akt