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Genetics, physical activity and fruit flies: unraveling the potential link between strenuous exercise and the development of MND

22 November 2023

We recently visited the Sheffield Institute of Translational Neuroscience (SITraN), to hear the latest updates from a research project looking at the potential link between strenuous exercise and MND. The research, led by Professor Dame Pamela Shaw with support from co-investigators Dr Johnathan Cooper-Knock and Dr Ryan West, looks to unravel whether strenuous exercise could be linked to the development of MND in people with a specific gene mutation.

It is important to note here that there is no evidence that taking part in exercise alone is enough to increase the risk of developing MND and the majority of people who take part in strenuous exercise will not go on to develop MND. In general, the benefits of taking part in exercise far outweigh any potential risk associated with developing the disease. However, Professor Shaw and her team are aiming to unravel whether people who have a particular mutation in a gene called C9orf72 are “genetically predisposed” to develop the disease, if they also take part in strenuous exercise. 

They propose three mechanisms for how this might work:

  1. Genetic make-up could make someone good at or enjoy exercise, therefore they pursue exercise, and the exercise increases the risk of developing MND;
  2. Genetic make-up could make someone good at exercise but also make them predisposed to MND, completely independently of each other;
  3. Genetic make-up could predispose someone to MND but MND only manifests after participation in strenuous exercise.

The team began this research in 2022 by conducting a detailed review of the current evidence surrounding the topic and they found that some studies did identify strenuous anaerobic physical activity (relying on energy sources other than oxygen - typically short bursts of intense energy e.g. sprinting) as a risk factor for developing MND, but concluded that additional larger-scale studies focusing on specific at-risk genes are required to confirm the finding. The work we are funding at SITraN uses several different approaches to investigate the link.

Genetic approaches to exercise

Approximately 10% of people living with MND will have familial disease i.e. it will run through their family, and the most common mutation to cause familial disease is in the C9orf72 gene (C9orf72-MND). The mutation, characterised as an incorrectly repeated section of the gene, causes the resulting protein to have toxic effects on motor neurons that ultimately lead to motor neuron death. It has been suggested in previous work that the mutation in this gene may be more strongly linked to MND in people who have previously taken part in strenuous exercise and, in particular, that high levels of exercise in adult life appear to cause MND to develop at an earlier age.

To understand the mechanism of this relationship between genetics, exercise and MND, Dr Johnathan Cooper-Knock and Dr David O’Brien are conducting a study of approximately 50 individuals with C9orf72-MND. They will use a validated questionnaire called the HAPAQ (Historical Adulthood Physical Activity Questionnaire) that was designed in partnership with the MRC Epidemiology Unit at Cambridge University, to accurately measure the levels of physical activity over the course of an adult life. 

This research could enable healthcare professionals to provide people who have a C9orf72 mutation information about their personal level of risk of developing MND, so that they can make informed decisions about whether or not to take part in strenuous exercise.

Modeling the effects of exercise at a cellular level

During strenuous exercise, our cells initiate a “stress response”, which can be replicated in the lab. Dr Kriti Gupta and Megha Madhu have been exposing skin cells of people living with C9orf72-MND to “stressors” such as hypoxic (low oxygen) and low nutrient environments to monitor if these cells have a diminished stress response which might contribute to cell death when individuals with the mutation take part in strenuous exercise.

Skin cells, that are more robust than motor neurons, provided an ideal tool to optimise the assays for the measurement of stress response, which Dr Gupta and Ms Madhu have now done. They will now use induced pluripotent stem cells (iPSCs, human skin cells that have been reprogrammed into motor neurons) from people living with C9orf72-MND so that they can measure the stress response specifically in motor neurons to understand the mechanism by which strenuous exercise may contribute to motor neuron death, specifically in individuals with this mutation.

Modeling MND in fruit flies

It may be surprising to know that several researchers use fruit flies to model human disease. They are a particularly good model because 75% of “disease-causing” genes in humans are also found in flies and, particularly good for MND, is the presence of a central and peripheral nervous system with many similarities to the human nervous system.

Dr Ryan West and Dr Debarati Bhattacharya are exercising fruit flies to study the effect of the C9orf72 mutation on their mobility and to determine the effects of exercise on the molecular pathways identified in Dr Gupta’s and Ms Madhu’s cellular work, explained above.

We would like to thank the members of Professor Shaw’s lab for hosting us at SITraN, and The Netherby Trust and supporters of the Foundation whose generous donations allow us to fund this important work. Finally, we’re grateful to all those affected by MND who support our researchers by donating tissue samples that are essential to this research.

Please visit our How to Donate page for information on how you can donate and fundraise.

Genetics, physical activity and fruit flies: unraveling the potential link between strenuous exercise and the development of MND
Genetics, physical activity and fruit flies: unraveling the potential link between strenuous exercise and the development of MND

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