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

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 1

AR113Q males are smaller and weaker than WT littermates.

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AR113Q males are smaller and weaker than WT littermates. (A) Body mass (...
(A) Body mass (mean ± SD) reported by age of WT (red line, n = 9), AR113Q (blue line, n = 5–22 depending on age, due to early death), and castrated AR113Q males (C-AR113Q) (green line, n = 9). AR113Q males were significantly smaller than WT (P < 0.001), and castration further decreased body mass (P < 0.05 by ANOVA with the Neuman-Keuls multiple comparison test). Inset shows body mass of AR48Q (n = 7) and WT (n = 5) males at 22–23 months (P > 0.05 by unpaired Student’s t test). (B) Forelimb grip strength (mean ± SD) of WT (red line, n = 13), AR113Q (blue line, n = 5), and castrated AR113Q males (green line, n = 9) evaluated monthly beginning at 11–13 months. The 3 curves are significantly different from each other (P < 0.001 by ANOVA with the Neuman-Keuls multiple comparison test). Implantation of testosterone pellets into castrated AR113Q males at 17–19 months is indicated by arrow. Inset shows grip strength of AR48Q (n = 7) and WT (n = 5) males at 22–23 months (P > 0.05 by unpaired Student’s t test).