What’s going on inside? Possible mechanisms associated with physical activity and MND

UPDATE  – The question of whether exercise causes, or contributes towards MND is still very much unanswered. But a recent study by Julian and colleagues (2021) has attempted to provide answers using huge data sets of genetic information, bioinformatics and validated questionnaires for physical exercise in specific genotypes to shed more light on a potential association between exercise and MND, in a way that is claimed to remove much of the potential issues with bias reporting. You can read more about this in a more recent blog post here.

Physical activity and MND – part 3

This is the final blog article in our trio of blogs that are looking at physical activity and MND. The first two have addressed the questions ‘did the amount of physical activity I undertook before my diagnosis cause my MND?’ and ‘can I continue with physical activity after my diagnosis, or will this make my MND worse?’

Despite the evidence reported by Visser and colleagues, which showed an increase of 6% in the risk of developing MND in people with high activity levels (discussed in the first of these blogs), there is limited evidence to support a relationship between physical activity and the development of MND, that is, what exactly is it about physical activity that would lead to MND-specific neurodegeneration. The available evidence tends to suggest it is more likely that there are other, as yet unidentified, factors associated with physical activity that might drive the risk. However, several credible explanations for how exercise could directly cause MND have been proposed and studied and we are going to take a more in-depth look at some of these here.

Athleticism and MND

It has been suggested that some people are genetically predisposed to athleticism and that this make them more susceptible to developing MND. They have a gene, or collection of genes, that predisposes them to be physically more active than people without this  ‘genetic equipment’, and the same combination of genes may also contribute to MND.

However, it is doubtful that this athletic predisposition is the only reason a person develops MND and other, as yet unknown, environmental factors are likely to ‘tip the balance’ and MND develops. These could include repeated head injuries, use of performance-enhancing drugs or chemicals (such as pesticides) used to treat sports fields. These, together with the athletic genetic make-up, may make an individual more susceptible to setting off the ‘neurological cascades’ that may lead to MND.

A study carried out by researchers in Sheffield in 2016, funded by the MND Association, suggests that individual risk might be due to an inherent genetic predisposition. If this could be identified, advice ensuring that an active lifestyle could be maintained without, perhaps, increasing the risk of developing MND could be given. It could also help to clarify whether physical activity is a direct MND risk factor for people with a tendency to athleticism and MND.

In 2013, researchers suggested that this predisposition to athleticism may have its roots in evolution. It would have been advantageous for our very (very) distant ancestors to be physically fit, for hunting and survival. This genetic determinant may predispose to neurodegeneration, without there being a direct causal link between MND and exercise. This has, however, only manifested itself as a disease because of relatively recent increases in life expectancy. Given the fact that these diseases usually emerge in older age, they might represent an unintended consequence of this increased longevity for a minority of people.

Oxidative stress

It has been suggested that, in a minority of the population, physical activity may be harmful to people with a complex genetic profile that gives rise to adverse effects to the metabolic response to vigorous muscle activity. A metabolic response is any reaction by the body to a specific action, like exercise. It occurs in individual cells, glands, organs or a whole system, such as the respiratory system.

Oxidative stress is one effect of an adverse metabolic response. Oxidative products are the results of oxidative stress. Oxidative stress occurs when the body is unable to keep up the detoxification of free radicals, which can damage cells in the body. If left unchecked by antioxidants, this can result in the development of disease. Oxidative stress is thought to be one of the factors generally associated with the development of MND.

Exercise produces a ‘pleiotropic adaptive response’ in skeletal muscles (skeletal muscles produce all the movements of body parts and are under voluntary control). This means it changes the form, structure, and the chemical processes in the muscle that help to regulate the production of some antioxidants found in the cells mitochondria, the cells ‘powerhouse’. Antioxidants inhibit the oxidation of other molecules which can lead to cell damage. Mitochondrial impairment, caused by oxidative stress, is thought to be a possible disease-causing mechanism of neurodegeneration.

In 2016 Italian researchers found that during exercise higher levels of oxidative products were found in people with MND. An ‘allele’ is one of many forms of a gene, located in the same position on a chromosome. The study compared 197 people with sporadic MND with 197 healthy controls to evaluate whether the allele ‘Gly482Ser’ is involved in oxidative stress during physical exercise. In this case Gly482Ser is a specific variant of the PGC-1a gene which regulates energy metabolism in mitochondria.

The participants in the Italian study were split into groups depending on whether they had the Gly482Ser variation. During exercise higher levels of oxidative products were found in people with MND who had the variation, suggesting that oxidative stress is involved in the biological progression of the disease, and that the Gly482Ser variation in the PGC-1a gene is related to lower resistance to exercise-related oxidative stress in MND. If it is known that a person with MND has this variation, appropriate exercise regimes aimed at maintaining the functionality of the skeletal muscle for as long as possible could be developed.

Oxidative stress and the potentiation of environmental toxins could possibly be the common aspect of many studied environmental risk factors. Potentiation is the action of a substance, at a dose that does not in itself have an adverse reaction, in enhancing the effect of another substance. In simple terms, this means that vigorous exercise could lead to oxidative stress. This would then exacerbate the effects of other environmental risks, such as pesticides or head trauma that, on their own, would not be adverse.

Cardiovascular fitness

Being lean and athletic could be an expression of genetic susceptibility to MND. This might be supported by the finding that cardiovascular fitness was found to be associated with MND in a 2012 study by researchers from Oxford.

Because there is persistent anecdotal evidence that people who develop MND are often physically ‘fitter’ before diagnosis than the general population, identification of those at risk is important for early intervention. The researchers from Oxford suggested that hospital admission for coronary heart disease (CHD) might serve as a marker of reduced cardiovascular fitness. Using data from two large databases of hospital admissions, the researchers calculated the ratio of the rate of MND in people without a history of CHD to that in those with a history of CHD.

Those without a record of CHD were at a modestly higher risk of developing MND. This supports the theory that MND is more prevalent in those who may have higher levels of cardiovascular fitness.

What’s next for research?

As we have discussed in the two previous blog articles about physical activity and MND, it is still very unclear if physical activity is a cause of MND or not, and that the increased risk is probably not due to physical activity itself but to unknown factors that tip the balance towards developing the disease. However, there remains a clinical impression that people who develop MND frequently have a higher than average level of physical activity or fitness. This is exacerbated by media coverage of high-profile sports people who have developed the disease, but it should be remembered that most elite sports people do not develop MND.

Although, in recent years, the understanding of the possible mechanisms of MND has advanced, the challenge to identify the actual causes of this devastating disease remains. Because of this, the search for possible external and internal risk factors continues. Current evidence for physical activity as a risk factor for MND is limited and conflicting, and the positive association reported between physical activity and the development of MND has not been disproved beyond doubt.

Identifying the complex genetic and environmental interactions at play in MND may lead to the development of screening methods for those in ‘at-risk’ environmental and lifestyle conditions which, in turn, could help to identify future therapies.