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Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model
Zhigang Yu, … , Diane M. Robins, Andrew P. Lieberman
Zhigang Yu, … , Diane M. Robins, Andrew P. Lieberman
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2663-2672. https://doi.org/10.1172/JCI28773.
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Research Article Neuroscience

Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model

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Abstract

Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length–dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2–4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel α-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line–derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non–cell autonomous toxicity of lower motor neurons.

Authors

Zhigang Yu, Nahid Dadgar, Megan Albertelli, Kirsten Gruis, Cynthia Jordan, Diane M. Robins, Andrew P. Lieberman

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Figure 7

Electrophysiologic and gene expression changes demonstrate myopathy in AR113Q males.

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Electrophysiologic and gene expression changes demonstrate myopathy in A...
(A) Composite images from sequential video frames of needle electromyography on levator ani/bulbocavernosus and hind-limb muscles from WT and AR113Q males at 3–5 months. Abnormal spontaneous and insertional activities were observed in both muscle groups of AR113Q males, as indicated by positive, downward deflections of the tracing, but not in WT males. Each horizontal division is equal to 10 ms. (B) Relative NT-4 and GDNF mRNA expression levels in hind-limb muscle, determined as in Figure 6. Differences between WT and AR113Q are significant at P < 0.05.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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