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Hum Mol Genet. 2018 May 15;27(10):1723-1731. doi: 10.1093/hmg/ddy077.

A genetic modifier suggests that endurance exercise exacerbates Huntington's disease.

Author information

Mammalian Genetics Unit, Harwell Institute, Medical Research Council, Oxfordshire, UK.
Department of Biology, University of York, York, UK.
Institute of Medical Sciences, University of Aberdeen, Scotland, UK.
Department of Cell and Developmental Biology, University College London (UCL), London, UK.
Department of Sport and Health Sciences, Technical University of Munich (TUM), Exercise Biology, Munich, Germany.
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, UK.
UK Dementia Research Institute, University of Cambridge, Cambridge, UK.
Unidad de Investigación, Hospital Universitario de Canarias, Fundación Canaria de Investigación Sanitaria e Instituto de Tecnologías Biomédicas, La Laguna, Spain.


Polyglutamine expansions in the huntingtin gene cause Huntington's disease (HD). Huntingtin is ubiquitously expressed, leading to pathological alterations also in peripheral organs. Variations in the length of the polyglutamine tract explain up to 70% of the age-at-onset variance, with the rest of the variance attributed to genetic and environmental modifiers. To identify novel disease modifiers, we performed an unbiased mutagenesis screen on an HD mouse model, identifying a mutation in the skeletal muscle voltage-gated sodium channel (Scn4a, termed 'draggen' mutation) as a novel disease enhancer. Double mutant mice (HD; Scn4aDgn/+) had decreased survival, weight loss and muscle atrophy. Expression patterns show that the main tissue affected is skeletal muscle. Intriguingly, muscles from HD; Scn4aDgn/+ mice showed adaptive changes similar to those found in endurance exercise, including AMPK activation, fibre type switching and upregulation of mitochondrial biogenesis. Therefore, we evaluated the effects of endurance training on HD mice. Crucially, this training regime also led to detrimental effects on HD mice. Overall, these results reveal a novel role for skeletal muscle in modulating systemic HD pathogenesis, suggesting that some forms of physical exercise could be deleterious in neurodegeneration.

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