Corrochano 2018 Hum Mol Genet

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Corrochano S, Blanco G, Williams D, Wettstein J, Simon M, Kumar S, Moir L, Agnew T, Stewart M, Landman A, Kotiadis VN, Duchen MR, Wackerhage H, Rubinsztein DC, Brown SDM, Acevedo-Arozena A (2018) A genetic modifier suggests that endurance exercise exacerbates Huntington's disease. Hum Mol Genet 27:1723-31.

» PMID: 29509900

Corrochano S, Blanco G, Williams D, Wettstein J, Simon M, Kumar S, Moir L, Agnew T, Stewart M, Landman A, Kotiadis VN, Duchen MR, Wackerhage H, Rubinsztein DC, Brown SDM, Acevedo-Arozena A (2018) Hum Mol Genet

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.


Bioblast editor: Kandolf G O2k-Network Lab: UK London Duchen MR


Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Exercise physiology;nutrition;life style  Pathology: Neurodegenerative 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 


Coupling state: OXPHOS, ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k 

Labels, 2018-04