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

@article{citeulike:5435249, 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.}, author = {Palazzolo, Isabella and Stack, Conor and Kong, Lingling and Musaro, Antonio and Adachi, Hiroaki and Katsuno, Masahisa and Sobue, Gen and Taylor, J. Paul and Sumner, Charlotte J. and Fischbeck, Kenneth H. and Pennuto, Maria}, citeulike-article-id = {5435249}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.neuron.2009.07.019}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S0896627309005480}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19679072}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19679072}, day = {13}, doi = {10.1016/j.neuron.2009.07.019}, issn = {1097-4199}, journal = {Neuron}, keywords = {igf, mouse, muscle, sbma}, month = {August}, number = {3}, pages = {316--328}, posted-at = {2009-10-31 20:09:22}, priority = {2}, title = {Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy.}, url = {http://dx.doi.org/10.1016/j.neuron.2009.07.019}, volume = {63}, year = {2009} }

TY - JOUR ID - citeulike:5435249 L3 - citeulike-article-id:5435249 N2 - 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. IS - 3 JF - Neuron SN - 1097-4199 EP - 328 TI - Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. VL - 63 SP - 316 KW - igf KW - mouse KW - muscle KW - sbma AU - Palazzolo, Isabella AU - Stack, Conor AU - Kong, Lingling AU - Musaro, Antonio AU - Adachi, Hiroaki AU - Katsuno, Masahisa AU - Sobue, Gen AU - Taylor, Paul AU - Sumner, Charlotte AU - Fischbeck, Kenneth AU - Pennuto, Maria PY - 2009/08/13/ UR - http://dx.doi.org/10.1016/j.neuron.2009.07.019 ER -