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The influence of metallothionein treatment and treadmill running exercise on disease onset and survival in SOD1G93A amyotrophic lateral sclerosis mice

Lewis, KEA ORCID: 0000-0003-1264-464X, Bennett, W ORCID: 0000-0002-1559-3027, Blizzard, CL ORCID: 0000-0002-9541-6943, West, AK, Chung, RS and Chuah, MI 2020 , 'The influence of metallothionein treatment and treadmill running exercise on disease onset and survival in SOD1G93A amyotrophic lateral sclerosis mice' , European Journal of Neuroscience , pp. 1-19 , doi: 10.1111/ejn.14682.

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterised bythe degeneration of motor neurons innervating skeletal muscle. The mechanisms underlying neurodegeneration in ALS are not yet fully elucidated, and with current therapeuticsonly able to extend lifespan by a matter of months there is a clear need for novel therapiesto increase lifespan and patient quality of life. Here, we evaluated whether moderate-intensity treadmill exercise and/or treatment with metallothionein-2 (MT2), a neuroprotectiveprotein, could improve survival, behavioural or neuropathological outcomes in SOD1G93Afamilial ALS mice. Six-week-old female SOD1G93A mice were allocated to one of fourtreatment groups: MT2 injection, i.m.; moderate treadmill exercise; neither MT2 norexercise; or both MT2 and exercise. MT2-treated mice survived around 3% longer thanvehicle-treated mice, with this mild effect reaching statistical significance in Cox proportional hazards analysis once adjusted for potential confounders. Mixed model body weighttrajectories over time indicated that MT2-treated mice, with or without exercise, reachedmaximum body weight at a later age, suggesting a delay in disease onset of around 4%compared to saline-treated mice. Exercise alone did not significantly increase survival ordelay disease onset, and neither exercise nor MT2 substantially ameliorated gait abnormalities or muscle strength loss. We conclude that neither exercise nor MT2 treatmentwas detrimental in female SOD1G93A mice, and further study could determine whetherthe mild effect of peripheral MT2 administration on disease onset and survival could beimproved via direct administration of MT2 to the central nervous system.

Item Type: Article
Authors/Creators:Lewis, KEA and Bennett, W and Blizzard, CL and West, AK and Chung, RS and Chuah, MI
Keywords: antioxidant, metallothionein-2, mixed modelling, neurodegeneration, treadmill exercise
Journal or Publication Title: European Journal of Neuroscience
Publisher: Blackwell Publishing Ltd
ISSN: 0953-816X
DOI / ID Number: 10.1111/ejn.14682
Copyright Information:

© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

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