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
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Cell Line, Transformed
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Chlorocebus aethiops
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Class I Phosphatidylinositol 3-Kinases
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics*
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Humans
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Insulin-Like Growth Factor I / genetics*
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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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Mice, Inbred C57BL
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Mice, Transgenic
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism*
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Muscular Atrophy / physiopathology*
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Muscular Atrophy, Spinal / genetics*
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Muscular Atrophy, Spinal / mortality
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Muscular Atrophy, Spinal / pathology*
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Muscular Atrophy, Spinal / therapy
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Mutation / genetics
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Oncogene Protein v-akt / metabolism
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Peptides / genetics
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Peptides / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Phosphorylation / genetics
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Serine / metabolism
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Time Factors
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Transfection / methods
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Trinucleotide Repeat Expansion / drug effects
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Trinucleotide Repeat Expansion / physiology
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Ubiquitin / metabolism
Substances
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Enzyme Inhibitors
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Muscle Proteins
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Peptides
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Receptors, Androgen
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Ubiquitin
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polyglutamine
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Serine
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Insulin-Like Growth Factor I
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Class I Phosphatidylinositol 3-Kinases
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Pik3cd protein, mouse
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Oncogene Protein v-akt