Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model
Zhigang Yu, Nahid Dadgar, Megan Albertelli, Kirsten Gruis, Cynthia Jordan, Diane M. Robins, Andrew P. Lieberman
Zhigang Yu, Nahid Dadgar, Megan Albertelli, Kirsten Gruis, Cynthia Jordan, Diane M. Robins, Andrew P. Lieberman
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Research Article Neuroscience

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

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 4

Testosterone-treated AR113Q females exhibit normal life span.

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Testosterone-treated AR113Q females exhibit normal life span. (A–D) Test...
(A–D) Testosterone-dependent effects on heterozygous AR113Q females. AR113Q females were implanted with testosterone (+T, n = 8) or vehicle control (–T, n = 7) pellets at 2–4 months. Serum testosterone levels, determined at 4–7 months, were significantly increased in hormone-treated mice compared with controls (P < 0.001) (A). Excretion of major urinary proteins (B) was compared in AR113Q–T and AR113Q+T females. AR113Q+T females showed a small but significant deficit in forelimb grip strength (C) (P = 0.01 by unpaired Student’s t test) but unchanged body mass (D) (P = 0.3 by unpaired Student’s t test) compared with AR113Q–T females at 16 months. (E) Survival curves of AR113Q+T (n = 8) and AR113Q–T (n = 7) (overlapping green lines), untreated AR113Q females (blue line, n = 11), and WT females (red line, n = 19) were similar (P > 0.05). None of the AR113Q+T or AR113Q–T females died during the study; half were euthanized at 16–19 months, and the remainder were euthanized at 23–26 months.