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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.

SUBMITTER: Johansen JA

PROVIDER: S-EPMC4209964 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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

Johansen Jamie A JA Yu Zhigang Z Mo Kaiguo K Monks D Ashley DA Lieberman Andrew P AP Breedlove S Marc SM Jordan Cynthia L CL

Neurobiology of disease 20081231 1

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 androg ...[more]

PMID: 19211034

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Project description:BackgroundSpinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by the expansion of trinucleotide cytosine-adenine-guanine (CAG) repeats, which encodes a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. Recent evidence suggests that, in addition to motor neuron degeneration, defective skeletal muscles are also the primary contributors to the pathogenesis in SBMA. While benefits of physical exercise have been suggested in SBMA, underlying mechanism remains elusive.MethodsWe investigated the effect of running exercise in a transgenic mouse model of SBMA carrying human AR with 97 expanded CAGs (AR97Q). We assigned AR97Q mice to exercise and sedentary control groups, and mice in the exercise group received 1-h forced running wheel (5 m/min) 5 days a week for 4 weeks during the early stage of the disease. Motor function (grip strength and rotarod performance) and survival of each group were analysed, and histopathological and biological features in skeletal muscles and motor neurons were evaluated.ResultsAR97Q mice in the exercise group showed improvement in motor function (~40% and ~50% increase in grip strength and rotarod performance, respectively, P < 0.05) and survival (median survival 23.6 vs. 16.7 weeks, P < 0.05) with amelioration of neuronal and muscular histopathology (~1.4-fold and ~2.8-fold increase in motor neuron and muscle fibre size, respectively, P < 0.001) compared to those in the sedentary group. Nuclear accumulation of polyQ-expanded AR in skeletal muscles and motor neurons was suppressed in the mice with exercise compared to the sedentary mice (~50% and ~30% reduction in 1C2-positive cells in skeletal muscles and motor neurons, respectively, P < 0.05). We found that the exercise activated 5'-adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibited mammalian target of rapamycin pathway that regulates protein synthesis in skeletal muscles of SBMA mice. Pharmacological activation of AMPK inhibited protein synthesis and reduced polyQ-expanded AR proteins in C2C12 muscle cells.ConclusionsOur findings suggest the therapeutic potential of exercise-induced effect via AMPK activation in SBMA.

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

Publications

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

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