Spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, is an X-linked neurodegenerative disease caused by expansion of a CAG repeat encoding polyglutamine in the first exon of the androgen receptor (AR) gene (La Spada et al., 1991
). The repeat is polymorphic in length, and individuals with an expansion over 36 residues develop disease. Expansion of polyglutamine is the cause of at least eight other neurodegenerative disorders, including Huntington’s disease, dentatorubral and pallidoluysian atrophy, and six types of spinocerebellar ataxia (Orr and Zoghbi, 2007
). A hallmark of the polyglutamine diseases is the accumulation of mutant protein into aggregates and inclusions, which can be detected using biochemical and histopathological techniques, respectively (Li et al., 2007
; Ross and Poirier, 2004
; Taylor et al., 2003
). Although common features are shared by the polyglutamine diseases, different populations of neurons are vulnerable to each of the mutant proteins, resulting in clinically distinct disease manifestations.
Expansion of polyglutamine in AR causes loss of lower motor neurons in the brainstem and spinal cord, together with weakness, fasciculations and muscle atrophy (Katsuno et al., 2006
). SBMA is a gender-specific disease, with only males fully affected. Females, even if homozygous for the mutation, have few if any symptoms (Schmidt et al., 2002
). In both transgenic and knock in mouse models of SBMA, male but not female mice expressing mutant AR develop full disease manifestations (Katsuno et al., 2002
; Yu et al., 2006
). Importantly, reduction of testosterone levels in male mice ameliorates disease manifestations, suggesting a potential therapy for SBMA (Katsuno et al., 2003
). Indeed, a phase 2 clinical trial shows benefits of androgen deprivation by leuprorelin acetate (Banno et al., 2009
). However, the use of anti-androgens as therapy may have undesired side-effects.
Emerging evidence suggests a role for muscle in SBMA pathogenesis. Histological and molecular signs of muscle pathology are detectable before the appearance of pathological abnormalities in the spinal cord in a knock in mouse model of SBMA (Yu et al., 2006
), suggesting that mutant AR may exert a direct toxic effect on skeletal muscle. In support of this notion is the observation that overexpression of normal AR in the skeletal muscle induces a phenotype similar to SBMA (Monks et al., 2007
). Analysis of muscle biopsy samples derived from SBMA patients suggests a mixed pathology with both myopathic and neurogenic features (Soraru et al., 2008
). Although the extent to which weakness in SBMA is a consequence of motor neuron degeneration with denervation and secondary muscle atrophy, or primary muscle degeneration with secondary effects on the motor neurons is unknown, these observations suggest that skeletal muscle may be an important target for disease treatment (Jordan and Lieberman, 2008
). Among the protective factors that help maintain muscle integrity, insulin-like growth factor 1 (IGF-1) has been shown to have an anabolic effect on skeletal muscle (reviewed by Sandri, 2008
). Transgenic mice that overexpress a muscle isoform of IGF-1 (mIGF-1) selectively in skeletal muscle develop extensive muscle hypertrophy (Musaro et al., 2001
). IGF-1 induces muscle regeneration by stimulating the proliferation of satellite cells in normal (Musaro et al., 2001
) and pathological conditions, such as amyotrophic lateral sclerosis (Dobrowolny et al., 2005
). At the molecular level, IGF-1 promotes muscle hypertrophy through activation of the phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway (Rommel et al., 2001
). Beyond the general potential benefit for IGF-1 in myopathic conditions, there is a specific rationale for IGF-1 in the treatment of SBMA based on its ability to inactivate the AR through an Akt-dependent mechanism (Palazzolo et al., 2007
). We have previously shown that phosphorylation of AR by Akt blocks ligand binding, thus reducing ligand-induced nuclear translocation and transactivation of AR in cell culture. Moreover, we have shown that IGF-1 reduces mutant AR toxicity in cultured cells through phosphorylation of AR at the Akt consensus sites. These observations suggest IGF-1 and Akt-mediated inactivation of AR as potential therapy for SBMA.
Here, we report that augmentation of IGF-1 levels decreases mutant AR aggregation and increases AR clearance through the ubiquitin-proteasome system, and that this effect is dependent on AR phosphorylation by Akt. In a mouse model of SBMA, muscle-specific overexpression of IGF-1 activates Akt and increases AR phosphorylation at Akt consensus sites. This correlates with decreased AR aggregation in both the muscle and spinal cord. Furthermore, overexpression of IGF-1 rescues behavioral and histopathological abnormalities, delays disease onset, and prolongs the life span of SBMA mice. Importantly, IGF-1 attenuates both the morphological and molecular signs of myopathic and neurogenic muscle pathology and increases motor neuron survival. Our results highlight a disease-specific mechanism of action of IGF-1 in SBMA muscle, which likely involves phosphorylation and inactivation of AR by Akt and presents an opportunity to mitigate the disease manifestations in vivo. Moreover, our study indicates that muscle is a reasonable target tissue and highlights IGF-1 as a promising therapy for SBMA.