Recovery of function in a myogenic mouse model of spinal bulbar muscular atrophy

Abstract

With this paper, we deliberately challenge the prevailing neurocentric theory of the etiology of spinal bulbar muscular atrophy (SBMA). We offer data supporting an alternative view that androgen receptor (AR) acts in skeletal muscles to cause the symptoms of SBMA. While SBMA has been linked to a CAG repeat expansion in the AR gene and mutant AR is presumed to act in motoneurons to cause SBMA, we find that over-expression of wild type AR solely in skeletal muscle fibers results in the same androgen-dependent disease phenotype as when mutant AR is broadly expressed. Like other recent SBMA mouse models, transgenic (tg) females in our model exhibit a motor phenotype only when exposed to androgens, and this motor dysfunction is independent of motoneuronal or muscle fiber cell death. Muscles from symptomatic females also show denervation-like changes in gene expression comparable to a knock-in model of SBMA. Furthermore, once androgen treatment ends, tg females rapidly recover motor function and muscle gene expression, demonstrating the strict androgen-dependence of the disease phenotype in our model. Our results argue that SBMA may be caused by AR acting in muscle.

Subcellular effects of myocyte-specific androgen receptor overexpression in mice

“…More direct evidence comes from studies of genetic manipulation of AR in myocytes. We find that HSA-AR rats and mice have increased RMR and ETC activity (Fernando et al 2010; Tables 1 and 2) and that HSA-AR mice have increased NADH/diaphorase staining (Monks et al 2007, Johansen et al 2009) and increased mitochondrial density, number, and/or size (Figs 1, 3, 4 and 6). Increases in oxidative metabolism of HSA-AR mice and rats are not secondary to increases in muscle mass, indicating hypermetabolism.…”

“…However, the pathology of HSA-AR mice (Monks et al 2007, Johansen et al 2009) complicates this interpretation, raising the possibility that any changes seen are secondary to a pathological process. Although, we may be at least assured that these changes are independent of the most severe pathology (e.g.…”

“…Pathology in HSA-AR mice presents somewhat differently in male and testosteronetreated HSA-AR females (Monks et al 2007), and it may be that the increased glycogen is related to pathology rather than an exaggeration of normal function of AR in myocytes. However, the fact that the severe muscular atrophy, motor deficits, and muscle weakness in testosterone-treated L141 females (Monks et al 2007, Johansen et al 2009) is not obviously accompanied by increases in glycogen (Fig. 5) argues against this last possibility.…”

“…However, in laboratory mice and rats, we do not typically see alterations in myofiber size in limb muscles following androgen manipulations (Monks et al 2004, Johansen et al 2009, although perineal muscles such as the levator ani do show marked reductions in myofiber size following androgen deprivation (Monks et al 2004, which is associated with myofibril disassembly (Venable 1966). For this reason, and given the dose and duration of testosterone treatment, we were not surprised that testosterone treatment had no significant effect on any measure in Wt females, consistent with our previous observations (Monks et al 2007, Table 2 Respiratory complexes in skeletal muscle of testosterone-treated female mice.…”

“…Nonetheless, a straightforward function of myocyte AR in increasing myofibrillar width would predict that HSA-AR mice, which have increased AR signaling in myocytes, would also have greater myofibrillar width, whereas the opposite result was found. It seems likely then that this reduction in myofibrillar width in HSA-AR mice is related to pathology in these mice, which results in muscular atrophy, motor deficits, and weakness (Monks et al 2007, Johansen et al 2009). Interestingly, myofibrillar disruption is observed in muscle-specific ARKO mice , which may indicate a paradoxical loss of normal AR function in HSA-AR mice.…”