Disease Affects Bdnf Expression in Synaptic and Extrasynaptic Regions of Skeletal Muscle of Three SBMA Mouse Models

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.

Exercise-Induced Elevated BDNF Level Does Not Prevent Cognitive Impairment Due to Acute Exposure to Moderate Hypoxia in Well-Trained Athletes

“…Moreover, there are also suggestions that the negative impact on cognitive function in hypoxia can be at least partially explained by the simultaneous decrease of BDNF [ 79 , 80 ]. Studies with animal models have shown that this neurotrophin is produced, among other tissues, in brain by motor neurons [ 81 ] and intermittent hypoxia increases BDNF levels in neurons of the primary motor cortex [ 82 ]. Also, central BDNF cannot be measured in living humans.…”

Androgen Therapy in Neurodegenerative Diseases

“…Interdomain interactions of AR transcription factors involve a variety of nuclear receptors [ 100 ]. In SBMA animal models, a downregulation of genes that regulate the expression of VEGF, IGF-1, glial cell line-derived neurotrophic factor [ 105 ], and transforming growth factor-beta type II receptor [ 106 ] has been reported. Importantly, IGF-1 mediates the inactivation of mutant AR, reducing muscle and spinal cord pathology in SBMA.…”

Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and avenues for treatment

“…This and other evidence suggests that skeletal muscle may be a therapeutic target in SBMA patients. SBMA mouse muscle has been found to have disruption of neurotrophic factors such as brain derived growth factor (BDNF), suggesting a potential therapeutic role for growth factor support [24]. The alteration in SBMA mouse muscle is associated with glycolytic-to-oxidative fiber-type switching and mitochondrial dysfunction, and dependence on the age at which mutant AR is expressed [25].…”