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 alpha-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Androgens / metabolism*
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Androgens / pharmacology
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Animals
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Chloride Channels / genetics
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Chloride Channels / metabolism
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Disease Models, Animal*
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Female
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Gene Expression / genetics
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Glial Cell Line-Derived Neurotrophic Factor / genetics
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology*
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Muscular Atrophy, Spinal / genetics
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Muscular Atrophy, Spinal / metabolism
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Muscular Atrophy, Spinal / pathology*
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Mutation / genetics
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Myogenin / genetics
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NAV1.4 Voltage-Gated Sodium Channel
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Nerve Growth Factors / genetics
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Orchiectomy
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Receptors, Cholinergic / genetics
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Sodium Channels / genetics
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Sodium Channels / metabolism
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Spinal Cord / metabolism
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Spinal Cord / pathology
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Survival Analysis
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Testis / pathology
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Testosterone / pharmacology
Substances
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Androgens
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CLC-1 channel
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Chloride Channels
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Glial Cell Line-Derived Neurotrophic Factor
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Myogenin
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NAV1.4 Voltage-Gated Sodium Channel
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Nerve Growth Factors
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Receptors, Androgen
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Receptors, Cholinergic
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Scn4a protein, mouse
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Sodium Channels
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Testosterone
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neurotrophin 4