Abstract
BackgroundEmerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disease. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q), a polyQ AR transgenic model (AR97Q), and a transgenic mouse that overexpresses wild type AR solely in skeletal muscle (HSA-AR). HSA-AR mice were included because they substantially reproduce the KD/SBMA phenotype despite the absence of polyQ AR.Methodology/Principal FindingsWe performed microarray analysis of lower hindlimb muscles taken from these three models relative to wild type controls using high density oligonucleotide arrays. All microarray comparisons were made with at least 3 animals in each condition, and only those genes having at least 2-fold difference and whose coefficient of variance was less than 100% were considered to be differentially expressed. When considered globally, there was a similar overlap in gene changes between the 3 models: 19% between HSA-AR and AR97Q, 21% between AR97Q and AR113Q, and 17% between HSA-AR and AR113Q, with 8% shared by all models. Several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, muscle atrophy and myogenesis. We additionally measured changes similar to those observed in skeletal muscle of a mouse model of Huntington's Disease, and to those common to muscle atrophy from diverse causes.Conclusions/SignificanceBy comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA.
Highlights
Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA), is a progressive neuromuscular disease [1,2], which is caused by an expanded trinucleotide repeat length encoding the polyglutamine tract of the androgen receptor (AR) gene [3]
This analysis indicated a similar degree of overlap between the 3 models, and suggested that a core pattern of altered gene expression is associated with the symptoms of KD/SBMA common to the three models
When considered in the context of the putative protective or toxic functions of these genes, the general pattern of regulation observed in our samples for damage-inducible transcript 4-like (Ddit4l), Enabled homolog (Enah) and Itgb1bp3 are consistent with adaptive tissue response to toxicity and that observed for Phosphorylase kinase alpha 1 (Phka1) and Pla2g7 is consistent with a causal role in myopathy
Summary
Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA), is a progressive neuromuscular disease [1,2], which is caused by an expanded trinucleotide repeat length encoding the polyglutamine (polyQ) tract of the androgen receptor (AR) gene [3]. Recent insight from mouse models of KD/SBMA have suggested that primary myogenic pathology, and pathological alterations in gene expression within skeletal muscle, might contribute to this disease (reviewed in [5]). This evidence consists mainly of 2 major findings: that myopathy precedes neuropathy in mice with genetic polyQ expansion mutations in the AR [6], and that overexpression of AR in muscle fibers is sufficient to reproduce several hallmark features of KD/SBMA [7]. Emerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). HSA-AR mice were included because they substantially reproduce the KD/ SBMA phenotype despite the absence of polyQ AR
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