Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We have previously shown that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the toxicity of mutant AR. Here we show that in cultured cells 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. To evaluate the potential benefit of exogenous IGF-1 in vivo, we crossed SBMA mice with mice that overexpress a muscle-specific isoform of IGF-1 selectively in skeletal muscle. In the resulting offspring, we found evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescued behavioral and histopathological abnormalities, extended the life span and reduced 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 for the first time that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA.