title: Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction.
abstract: Huntington disease is a progressive and fatal genetic disorder with debilitating motor and cognitive defects. Chorea, rigidity, dystonia, and muscle weakness are characteristic motor defects of the disease that are commonly attributed to central neurodegeneration. However, no previous study has examined the membrane properties that control contraction in Huntington disease muscle. We show primary defects in ex vivo adult skeletal muscle from the R6/2 transgenic mouse model of Huntington disease. Action potentials in diseased fibers are more easily triggered and prolonged than in fibers from WT littermates. Furthermore, some action potentials in the diseased fibers self-trigger. These defects occur because of decreases in the resting chloride and potassium conductances. Consistent with this, the expression of the muscle chloride channel, ClC-1, in Huntington disease muscle was compromised by improper splicing and a corresponding reduction in total Clcn1 (gene for ClC-1) mRNA. Additionally, the total Kcnj2 (gene for the Kir2.1 potassium channel) mRNA was reduced in disease muscle. The resulting muscle hyperexcitability causes involuntary and prolonged contractions that may contribute to the chorea, rigidity, and dystonia that characterize Huntington disease.
authors.affiliation: Department of Biological Sciences, California State Polytechnic University, Pomona, CA 91768, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Waters
authors.forename: Grigor
authors.initials: G
authors.lastname: Varuzhanyan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Talmadge
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Voss
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D053447:Channelopathies / Q000378:metabolism / Q000503:physiopathology*; D018118:Chloride Channels / Q000378:metabolism*; D017097:Electric Impedance; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D015221:Potassium Channels
keywords: channelopathy; electrophysiology; myopathy; myotonia; trinucleotide repeat