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

Silvia Corrochano,Abraham Acevedo-Arozena,Jessica Wettstein,Michelle Simon,David C Rubinsztein,Thomas Agnew,Michelle Stewart,Saumya Kumar,Henning Wackerhage,Vassilios N Kotiadis,Lee Moir,Debbie Williams,Steve D M Brown,Michael R Duchen,Allison Landman,Gonzalo Blanco

doi:10.1093/hmg/ddy077

Abstract

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.

Highlights

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by pathogenic poly-glutamine expansions in the huntingtin gene (HTT) [1]
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
As Scn4a is primarily expressed in skeletal muscle, analysis of the modifier effect highlighted a novel critical role of the periphery in modulating systemic HD pathogenesis

Summary

Introduction

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by pathogenic poly-glutamine expansions in the huntingtin gene (HTT) [1]. Primarily a neurodegenerative disorder, HD causes pathological changes in many peripheral tissues and organs including skeletal muscle [3, 4]. Changes in skeletal muscle homeostasis, including those induced by physical exercise or by pathological abnormalities, can in turn affect whole body metabolism, affecting the brain. In this sense, physical exercise has been tested as a possible treatment for HD [7]. Studies in different HD mouse models have shown potential beneficial effects of moderate exercise, especially observed in hippocampal neurogenesis [9,10]. There are several reports evidencing detrimental effects of exercise regimes in HD mice, as well as inconclusive studies in HD patients [11]

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Results

Conclusion