Abstract
Spinal bulbar muscular atrophy (SBMA) is a slowly progressive, androgen-dependent neuromuscular disease in men that is characterized by both muscle and synaptic dysfunction. Because gene expression in muscle is heterogeneous, with synaptic myonuclei expressing genes that regulate synaptic function and extrasynaptic myonuclei expressing genes to regulate contractile function, we used quantitative PCR to compare gene expression in these two domains of muscle from three different mouse models of SBMA: the “97Q” model that ubiquitously expresses mutant human androgen receptor (AR), the 113Q knock-in (KI) model that expresses humanized mouse AR with an expanded glutamine tract, and the “myogenic” model that overexpresses wild-type rat AR only in skeletal muscle. We were particularly interested in neurotrophic factors because of their role in maintaining neuromuscular function via effects on both muscle and synaptic function, and their implicated role in SBMA. We confirmed previous reports of the enriched expression of select genes (e.g., the acetylcholine receptor) in the synaptic region of muscle, and are the first to report the synaptic enrichment of others (e.g., glial cell line-derived neurotrophic factor). Interestingly, all three models displayed comparably dysregulated expression of most genes examined in both the synaptic and extrasynaptic domains of muscle, with only modest differences between regions and models. These findings of comprehensive gene dysregulation in muscle support the emerging view that skeletal muscle may be a prime therapeutic target for restoring function of both muscles and motoneurons in SBMA.
Highlights
Spinal bulbar muscular atrophy (SBMA) is a neuromuscular disease that causes muscle weakness and atrophy leading to a slow, progressive loss of motor function [1]
We evaluated for the first time whether disease triggered by toxic androgen receptor (AR) affects gene expression differently in the synaptic versus the extrasynaptic regions of skeletal muscle
Intrigued by recent findings that AR in muscle has the capacity to drive significant dysfunction in both muscle and motoneurons in mouse models of SBMA [10,11,12,13,14], we asked whether gene expression in diseased muscle was impaired in a region-specific manner
Summary
Spinal bulbar muscular atrophy (SBMA) is a neuromuscular disease that causes muscle weakness and atrophy leading to a slow, progressive loss of motor function [1]. SBMA is linked to a polyglutamine expansion mutation in the androgen receptor (AR) gene [2]. Men carrying the mutation develop the disease, while women carriers do not, subclinical symptoms such as muscle cramping are common among female carriers. This sex difference in disease susceptibility is likely related to sex differences in circulating androgens, with male-typical levels driving the disease [3,4,5,6,7]. It is critical to understand which genes in muscle underlie muscle dysfunction on the one hand, and motoneuron dysfunction on the other
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