Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy

• Published in: Neuron (Cambridge, Mass.) Mass.), 2009-08, Vol.63 (3), p.316-328
• Main Authors: Palazzolo, Isabella, Stack, Conor, Kong, Lingling, Musaro, Antonio, Adachi, Hiroaki, Katsuno, Masahisa, Sobue, Gen, Taylor, J. Paul, Sumner, Charlotte J., Fischbeck, Kenneth H., Pennuto, Maria
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Behavior, Animal - physiology; Cell culture; Cell Line, Transformed; Chlorocebus aethiops; Class I Phosphatidylinositol 3-Kinases; Disease; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Humans; HUMDISEASE; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; Kinases; Ligands; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular weight; MOLNEURO; 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; Muscular system; Musculoskeletal system; Mutation - genetics; Neurons; Oncogene Protein v-akt - metabolism; Pathology; Peptides - genetics; Peptides - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - genetics; PROTEINS; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Rodents; Serine - metabolism; Statistical analysis; Time Factors; Transfection - methods; Trinucleotide Repeat Expansion - drug effects; Trinucleotide Repeat Expansion - physiology; Ubiquitin - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2009.07.019

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.