Frequent Strenuous Exercise Increases the Risk of Developing ALS in Certain People

Summary: Researchers have identified a causal link between strenuous exercise and ALS in people with genetic risk factors for the neurodegenerative disease. The study reports intense physical exercise contributes to motor neuron injury in those susceptible to ALS.

Source: University of Sheffield

Frequent strenuous exercise increases the risk of developing motor neuron disease (MND)/ALS in certain people, new research from the University of Sheffield has found.

The findings, published in the journal EBioMedicine, show a causal relationship between exercise and MND, with high intensity physical activity likely to contribute to motor neurone injury, but only in individuals with a predisposing genetic profile.

Scientists at the University of Sheffield believe the pioneering study represents a significant step towards unravelling the link between high levels of physical activity and the development of the neurodegenerative condition which affects approximately 5,000 people in the UK.

Over recent years a number of professional sportsmen across the world have shared their experience of living with MND. The condition is commonly referred to as ALS, or Lou Gehrig’s disease in North America in memory of a professional baseball player for the New York Yankees who developed the condition in his 30’s.   

The life-time risk of developing MND is approximately 1 in 400.  Previous research has reported an estimated six-times increased risk of MND in professional football players compared to the general population. 

Co-author of the study, Dr Johnathan Cooper-Knock from the University of Sheffield’s Neuroscience Institute and Senior Lecturer in Neurology, said: “Complex diseases such as MND are caused by an interaction between genetics and the environment. We urgently need to understand this interaction in order to discover pioneering therapies and preventative strategies for this cruel and debilitating disease.  

“We have suspected for some time that exercise was a risk factor for MND, but until now this link was considered controversial. This study confirms that in some people, frequent strenuous exercise leads to an increase in the risk of MND.

“It is important to stress that we know that most people who undertake vigorous exercise do not develop MND. Sport has a large number of health benefits and most sportsmen and women do not develop MND. The next step is to identify which individuals specifically are at risk of MND if they exercise frequently and intensively; and how much exercise increases that risk.”

Senior author of the study, Professor Dame Pamela Shaw Director of the Neuroscience Institute and NIHR Sheffield Biomedical Research Centre at the University of Sheffield, said: “This research goes some way towards unravelling the link between high levels of physical activity and the development of MND in certain genetically at-risk groups.  We studied the link using three different approaches and each indicated that regular strenuous exercise is a risk factor associated with MND. 

“There are three important key findings of the study. Firstly those who have a genetic make-up favouring strenuous physical activity have an increased risk of developing MND.  Many of the 30 plus genes known to predispose to MND change in their levels of expression during intense physical exercise and individuals who have a mutation in the C9ORF72 gene, which accounts for 10 percent of MND cases, have an earlier age of disease onset if they have a lifestyle which includes high levels of strenuous physical activity. 

“Clearly most people who undertake strenuous exercise do not develop motor neurone injury and more work is needed to pin-point the precise genetic risk factors involved.  The ultimate aim is to identify environmental risk factors which can predispose to MND, to inform prevention of disease and life-style choices.” 

MND, or Amyotrophic Lateral Sclerosis (ALS) as it is also known, is a disorder that affects the nerves – motor neurones – in the brain and spinal cord that form the connection between the nervous system and muscles to enable movement of the body. The messages from these nerves gradually stop reaching the muscles, leading them to weaken, stiffen and eventually waste.  The progressive disease affects a person’s ability to walk, talk, use their arms and hands, eat and breathe.

Approximately 10 percent of MND cases are inherited, but the remaining 90 percent are caused by complex genetic and environmental interactions which are not well understood – this is known as sporadic MND.

The new research will have a significant impact on the global research effort to identify which individuals based on their genetics are at risk of MND. In time it is hoped that this work will help medical professionals to be able to offer advice to family members of MND patients about the risks so they can make personal decisions about their exercise habits.

This shows a woman doing crossfit exercise
The life-time risk of developing MND is approximately 1 in 400. Image is in the public domain

Dr Brian Dickie, Director of Research Development at the Motor Neuron Disease Association said: “In recent years, understanding of the genetics of MND has advanced, but there has been little progress in identifying the environmental and lifestyle factors that increase the risk of developing the disease.

“This is, in part, because the genetic and the environmental studies tend to be carried out in isolation by different research teams, so each is only working with part of the jigsaw. The power of this research from the University of Sheffield comes from bringing these pieces of the puzzle together.

“We need more robust research like this to get us to a point where we really understand all the factors involved in MND to help the search for more targeted treatments.”

About this ALS and exercise research news

Source: University of Sheffield
Contact: Amy Huxtable – University of Sheffield
Image: The image is in the public domain

Original Research: Open access.
Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes” by Pamela Shaw et al. EBioMedicine


Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes


Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease. ALS is determined by gene-environment interactions and improved understanding of these interactions may lead to effective personalised medicine. The role of physical exercise in the development of ALS is currently controversial.


First, we dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. Next we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity questionnaire in a small cohort of genetically selected ALS patients.


We present MR evidence supporting a causal relationship between genetic liability to frequent and strenuous leisure-time exercise and ALS using a liberal instrument (multiplicative random effects IVW, p=0.01). 

Transcriptomic analysis revealed that genes with altered expression in response to acute exercise are enriched with known ALS risk genes (permutation test, p=0.013) including C9ORF72, and with ALS-associated rare variants of uncertain significance.

Questionnaire evidence revealed that age of onset is inversely proportional to historical physical activity for C9ORF72-ALS (Cox proportional hazards model, Wald test p=0.007, likelihood ratio test p=0.01, concordance=74%) but not for non-C9ORF72-ALS.

Variability in average physical activity was lower in C9ORF72-ALS compared to both non-C9ORF72-ALS (F-test, p=0.002) and neurologically normal controls (F-test, p=0.049) which is consistent with a homogeneous effect of physical activity in all C9ORF72-ALS patients.


Our MR approach suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS.


We acknowledge support from the Wellcome Trust (JCK, 216596/Z/19/Z), NIHR (PJS, NF-SI-0617-10077; IS-BRC-1215-20017) and NIH (MPS, CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01-HL122939, S10OD025212, P30DK116074, and UM1HG009442).

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