Microarray Analysis of Gene Expression by Skeletal Muscle of Three Mouse Models of Kennedy Disease/Spinal Bulbar Muscular Atrophy

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.

Distinct Etiological Roles for Myocytes and Motor Neurons in a Mouse Model of Kennedy's Disease/Spinobulbar Muscular Atrophy

“…5C, bottom). These results indicate that polyQ AR action in either muscle or motor neuron is sufficient to alter FG muscle fibers, but this effect is limited by muscle type, as has been reported for contraction dynamics in the HSA-AR model (Oki et al, 2013).…”

“…qPCR for AchRa, AchRb, Ankrd1, Hsp7, Fbxo32 and Vegfa was performed as described in Mo et al, 2010. Briefly, DNase-treated mRNA was reverse transcribed using dT20VN primer (Sigma) with SuperScript II before ampification with SYBR Green JumpStart Taq ReadyMix (Sigma).…”

“…Because diaphorase staining is altered in other mouse models of KD/SBMA Musa et al, 2011;Rinaldi et al, 2012), we examined NADH (corresponding to complex I of the electron transport chain) and SDH (corresponding to complex II of the electron transport chain). Although we did not observe disorganization in diaphorase staining such as that exhibited by HSA-AR mice , we found a global reduction in NADH and SDH staining in both MyoAR and NeuroAR mice (Fig.…”

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

“…Conversely, it is possible that androgens trigger toxic response in satellite cells expressing polyQ-AR contributing to muscle deterioration in SBMA [65]: while androgens and AR have remarkable hypertrophic effects on skeletal muscle, they have detrimental effects in SBMA muscle. PolyQ expansion in AR has been proposed to cause toxicity in muscle through altered gene expression [66]. The SBMA phenotype elicited by overexpression of either wild-type or polyQ-AR in mice is associated with deregulation of gene transcription in muscle.…”

“…Therefore its inhibition, for example using the non-steroid anti-androgen flutamide, may be an ideal target for therapy in SBMA [79] [80]. Although the phenotype does not improve, some benefits are detectable in transgenic mice overexpressing wild type AR, when flutamide is administered at a prenatal stage [62] [81] [66].…”