Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy.
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.
Palazzolo
Isabella
I
Neurogenetics Branch, NINDS, NIH, Bethesda, MD 20892, USA.
Stack
Conor
C
Kong
Lingling
L
Musaro
Antonio
A
Adachi
Hiroaki
H
Katsuno
Masahisa
M
Sobue
Gen
G
Taylor
J Paul
JP
Sumner
Charlotte J
CJ
Fischbeck
Kenneth H
KH
Pennuto
Maria
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009133:Muscular Atrophy / Q000503:physiopathology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism
D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D009124:Muscle Proteins; D051058:Oncogene Protein v-akt; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D011944:Receptors, Androgen; D012694:Serine; D025801:Ubiquitin; C097188:polyglutamine; C421683:Pik3cd protein, mouse
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