Investigating strenuous exercise in MND

Summary

While major progress has been made in understanding genetic risk factors for MND, potential environmental factors, such as physical activity, are less well understood. Some evidence indicates an increased risk of MND may be linked to strenuous exercise in elite athletes, though results remain inconsistent.

Led by Professor Dame Pamela Shaw in Sheffield, a multidisciplinary team have previously discovered that extreme levels of exercise combined with mutations in a specific gene linked to MND, C9ORF72, increased the risk of developing the disease. The results of this project, which we funded, have been published and you can read more about it here.

Building on this body of work, the team will start a new project, using large genetic datasets (UK Biobank and the US Million Veterans Programme) to investigate how other genes and strenuous physical activity interact to trigger MND. These interactions will then be studied in fruit flies and cellular models of MND, with the researchers developing new ways to model the effects of physical activity. Specifically, motor neurons will be grown in a dish together with - and connect to - muscle cells. This in vitro system will be stimulated to mimic the effects of exercise. Together, the genetic data and the models of physical activity will allow the researchers to investigate the mechanisms by which the identified genes may predispose to MND, and how risk may be increased when those genes are combined with high levels of physical activity.

In parallel, the team will seek to validate and build on their previous findings for a potential therapeutic target, GRM4, which they found could be protective for exercise-induced motor neuron damage.

Why this research is important

Understanding what causes MND, especially for non-inherited cases, remains a priority for our community. Incorporating lifestyle factors into this effort, such as physical activity, is crucial and may lead to the identification of new therapeutic targets and the future development of prevention strategies.