Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Neuroscience

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

  • Text
  • PDF
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

×

Figure 6

Androgen-dependent decrease of CLCN1 and SCN4A expression in AR113Q skeletal muscle.

Options: View larger image (or click on image) Download as PowerPoint
Androgen-dependent decrease of CLCN1 and SCN4A expression in AR113Q skel...
(A) Indirect immunofluorescence demonstrates CLCN1 protein expression (red) in levator ani/bulbocavernosus (LA/BC) and hind-limb muscles of WT, AR113Q, and castrated AR113Q males. Nuclei were stained with DAPI. (B–D) Relative CLCN1 (B and C) and SCN4A (D and E) mRNA expression levels in levator ani/bulbocavernosus (B and D) and hind-limb (C and E) muscles of WT (n = 8), AR113Q (n = 9), and castrated WT males (n = 6) at 3–5 months and castrated AR113Q males at 18 months (n = 4). Data are reported as mean ± SD relative to expression of 18s rRNA. Differences between WT and AR113Q are significant different in hind-limb (P < 0.01 for CLCN1) and levator ani/bulbocavernosus muscles (P < 0.001 for CLCN1 and SCN4A) as determined by ANOVA with the Neuman-Keuls multiple comparison test. SCN4A levels in hind-limb muscle are not significantly different.

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

Sign up for email alerts