Pre-clinical symptoms of SBMA may not be androgen-dependent: implications from two SBMA mouse models

Abstract

A distinguishing aspect of spinal and bulbar muscular atrophy (SBMA) is its androgen-dependence, possibly explaining why only males are clinically affected. This disease, which impairs neuromuscular function, is linked to a polyglutamine expansion mutation in the androgen receptor (AR). In mouse models of SBMA, motor dysfunction is associated with pronounced defects in neuromuscular transmission, including defects in evoked transmitter release (quantal content, QC) and fiber membrane excitability (based on the resting membrane potential, RMP). However, whether such defects are androgen-dependent is unknown. Thus, we recorded synaptic potentials intracellularly from adult muscle fibers of transgenic (Tg) AR97Q male mice castrated pre-symptomatically. Although castration largely protects both QC and the RMP of fibers, correlating with the protective effect of castration on motor function, significant deficits in QC and RMP remained. Surprisingly, comparable defects in QC and RMP were also observed in pre-symptomatic AR97Q males, indicating that such defects emerge early and are pre-clinical. Exposing asymptomatic Tg females to androgens also induces both motor dysfunction and comparable defects in QC and RMP. Notably, asymptomatic Tg females also showed significant deficits in QC and RMP, albeit less severe, supporting their pre-clinical nature, but also raising questions about the androgen-dependence of pre-clinical symptoms. In summary, current evidence indicates that disease progression depends on androgens, but early pathogenic events may be triggered by the mutant AR allele independent of androgens. Such early, androgen-independent disease mechanisms may also be relevant to females carrying the SBMA allele.

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

“…However, Chrne mRNA was appreciably lower in the synaptic region of diseased muscle relative to WT controls (97Q: −2.02 ± 0.34, p = 0.003; myogenic: −2.98 ± 0.64, p = 0.004). In contrast, Chrne transcript level was comparable in the extrasynaptic region of diseased and WT muscle (97Q: 2.02 ± 0.67, p = 0.064; myogenic: −1.27 ± 0.40, p = 0.463), consistent with earlier published work on these models indicating that diseased muscles are not denervated in end-stage mice [14,15,29], and that denervation per se does not cause a progressive loss of motor function in SBMA. Thus, the disease-related downregulation of this transcript, previously reported for whole muscle [14], reflects a loss specifically in the synaptic region, presumably contributing to the decline in synaptic strength seen in these models.…”

“…SBMA has classically been considered a “motoneuron” disease, but data from genetically engineered mouse models make it clear that AR acting solely in skeletal muscles can instigate significant, if not the full spectrum of neuromuscular pathology in SBMA [5,8,9]. Toxic AR in muscle induces three notable disease outcomes: (1) a profound loss of intrinsic muscle force that is independent of muscle mass [10,11], (2) impaired retrograde axonal transport in innervating motoneurons [12,13], and (3) defects in neuromuscular transmission involving impairments in neurotransmitter release [14,15]. Thus, it is critical to understand which genes in muscle underlie muscle dysfunction on the one hand, and motoneuron dysfunction on the other.…”

“…These models include the “97Q” model, characterized by ubiquitous expression of a mutant human AR [3], the 113Q knock-in (KI) model expressing a humanized mouse AR with an expanded glutamine tract [6], and the “myogenic” model characterized by muscle-specific expression of wild-type (WT) rat AR [5]. SBMA mice in each model exhibit common disease traits that include an androgen-dependent loss of motor function in the absence of motoneuronal cell death that is associated with perturbed expression of neurotrophic factors in muscle, impaired motoneuronal retrograde axonal transport, and synaptic and muscle electrophysiological dysfunction [12,14,15].…”

“…Using quantitative real-time PCR, we examined the expression of a number of genes with known function. Our primary interest was in the neurotrophic factors, since such factors are implicated in SBMA and are critical for proper synaptic and muscle function, both of which are profoundly impaired in models of SBMA [5,6,10,11,14,15,22,23,24,25,26,27,28]. While skeletal muscles are well known to express numerous neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and other related neurotrophins, it not known whether their expression is regionally regulated across the length of the fiber, particularly in the context of neuromuscular disease.…”

Molecular Mechanisms and Therapeutics for SBMA/Kennedy's Disease

“…Indeed, new discussions regarding the role of hormone in SBMA have been driven by the fact that clinical trials aimed at suppressing hormone production in SBMA patients have had modest effects on disease progression [4,187], despite the fact that chemical or surgical castration completely abolishes (and even reverses) disease in mouse models [177,178,185,191]. It has recently been suggested that some subclinical phenotypes in SBMA mouse models may be hormone independent [216], although the authors of this study note that prenatal androgen exposure during development [217] represents an important caveat. Nevertheless, a conversation regarding the role of hormone in disease is worthwhile as efforts to knock down mutant AR mRNA in SBMA patients gain traction based on promising preclinical studies [169,218].…”