Ion Channel Defects Cause Hyperexcitability in Huntington's Disease Skeletal Muscle

Huntington's disease is a progressive and fatal degenerative disorder with devastating cognitive and motor defects. It is estimated to afflict 5.70 per 100,000 individuals. The motor defects include chorea (irregular jerky movements), rigidity, and dystonia (atypical tonicity often resulting in abnormal positioning of the head and limbs). The disease is caused by an expanded CAG repeat in the huntingtin gene and is one of several trinucleotide repeat disorders. Although the huntingtin gene is widely expressed throughout the body, it is generally believed that the defects of the disease are the result of neurodegeneration. However, no previous study has examined the membrane properties that control contraction in Huntington's disease muscle. We show defects in ex vivo adult skeletal muscle from the R6/2 transgenic mouse model of Huntington's disease. All the results are compared to muscle from wild-type age-matched littermates. Using two intracellular microelectrodes we demonstrate that action potentials in diseased fibers are more easily-triggered and prolonged. Furthermore, some action potentials in the diseased fibers self-trigger. These defects occur because of decreased currents through ClC-1 chloride channels and inward rectifying potassium (Kir) channels. Consistent with this, analysis with real time quantitative RT-PCR shows reduced levels of the normal mature mRNA for Clcn1 (gene for ClC-1) and Kcnj2 (gene for Kir2.1) in diseased muscle. We also found a nearly 3-fold increase in the proportion of aberrantly spliced Clcn1 mRNA (containing exon 7a) in disease muscle. A similar disruption of mRNA splicing has been shown to cause a decrease in ClC-1 expression in myotonic dystrophy type 1, another trinucleotide repeat disorder. The defects we found in the disease muscle cause a striking hyperexcitability. The resulting involuntary and prolonged contractions may help explain the chorea, rigidity, and dystonia that characterize Huntington's disease.