Why is understanding hypermetabolism important in ALS outcomes?

Why is understanding hypermetabolism important in ALS outcomes?

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This blog is part of our Symposium Spotlight series, where we’re looking back on some of the research that was presented at the 33rd International Symposium on ALS/MND. Today we’re taking a closer look into plenary speaker Associate Professor Shyuan Ngo’s talk that she gave at the 33rd symposium’s session on metabolism and nutrition. ALS is the most common form of MND and these terms are used interchangeably in this blog.

Shyuan Ngo - plenary speaker

Day 2 of the Symposium began with a session on Metabolism and a presentation from plenary speaker Associate Prof Shyuan Ngo from the University of Queensland, Australia.

Shyuan’s talk was titled ‘Investigating the role of hypermetabolism in ALS’ (C06 in the abstract book) and discussed the research being carried out by her team to try and understand the mechanisms driving hypermetabolism in ALS and what hypermetabolism means clinically for people living with the disease. This blog details Shyuan’s work and looks closely at her observations on hypermetabolism in relation to ALS.

What do we mean by hypermetabolism?

Metabolic balance is dictated by the amount of energy we take into our bodies (from calories in the food we eat) against the energy we use. The body uses energy in three ways:

  • 70% of the energy we consume is used when the body is at rest – known as resting energy expenditure.
  • 20% of our energy expenditure is related to exercise.
  • 10% is used to break down food.

When energy intake is balanced with energy expenditure you would expect to see weight maintenance in individuals. But it has been reported that people living with ALS have an increased resting energy expenditure, which is called hypermetabolism, and this commonly leads to weight loss because more energy is being used than is being taken in.

Is hypermetabolism seen in people with ALS?

ALS is described as a heterogenic disease, which means it has many possible causes or drivers. This heterogeneity makes it difficult to develop new therapies and, if we had a better understanding of these drivers, it would improve our chances of developing new therapies and improving the quality of life for people living with ALS.

It has become apparent through research that a person’s ability to tolerate the metabolic impact of the disease is something that might contribute to the heterogeneity of ALS. We now know that weight loss, whether it’s before symptom onset, at the time of diagnosis or during the course of the disease, is associated with worse outcomes.

Hypermetabolism in people with ALS has been reported in studies in the last two decades or so, with high numbers of people with sporadic MND being reported as hypermetabolic. One study in 2009 found that all the people with inherited ALS that were involved in the study were hypermetabolic. However, despite these findings none of these studies showed a direct link between hypermetabolism and weight loss, nor did they show the clinical significance of hypermetabolism in terms of the disease.

In 2015, Shyuan and her team began a study looking at hypermetabolism in people with ALS. The study’s aim was to answer one very important question – what is the relevance of hypermetabolism to the outcomes of people living with ALS? Fifty-eight people living with ALS and 58 healthy controls took part. All participants underwent tests to predict how much resting energy they should be using. Further tests were performed to see how much resting energy each person was actually using, and the results were compared to see if anyone was hypermetabolic.

The results, published in 2018, showed that just over 40% of the participants with ALS were hypermetabolic and that people with ALS were five times more likely to be hypermetabolic compared to the non-ALS controls.

When the measures of hypermetabolism were compared against the ALSFRS-R, participants that were hypermetabolic showed a faster decline in their scores compared to those with normal metabolism. This was important as it showed that hypermetabolic individuals were at greater risk of earlier death.

Are these findings supported?

Another study, also published in 2018 by Jesus and colleagues, supported these findings and, since 2018 there have been many studies that have reported hypermetabolism in people with ALS. In 2022 alone, three studies have shown that some people with ALS are hypermetabolic and that this is associated with faster disease progression and earlier death.

The question remains – what causes hypermetabolism in ALS and can it be targeted for therapy?

Over the years, the team in Australia have also considered hypermetabolism in relation to the gut microbiome, (the gut microbiome is made up of trillions of bacteria, fungi and other microbes and is critical to a person’s health and wellbeing), whether individuals have a loss of appetite or not, and if there is a relationship with the size of the hypothalamus, which is an area in the brain crucial in controlling metabolic balance. To date, they have not found any association between hypermetabolism and any of these factors.

In Shyuan’s 2018 study, it was noted that hypermetabolism seemed to be higher in people who had greater involvement of motor neurons that were in the spinal cord (lower motor neurons, which connect the spinal cord to the muscles). By comparison, they found no association between hypermetabolism and features associated with the motor neurons in the brain (upper motor neurons, which connect the brain to the spinal cord). Different forms of motor neurone disease, that affect different parts of the body, are caused by involvement of either the upper or lower motor neurons or both.

This led them to question if hypermetabolism was something specifically relevant to the loss of the motor neurons in the spinal cord which leads to the muscle weakness seen in ALS. Skeletal muscle (muscles that are joined to the skeleton and are controlled by the individual to make limbs and other body parts move) is a highly metabolic tissue, and it usually uses glucose (sugar) as it’s energy source. However, it appears that in the course of the disease skeletal muscle has a change in its preference for glucose as its energy source to fat and this might be driving the onset of hypermetabolism that we see in ALS.

Using a particular SOD1 mouse model of ALS and samples collected from muscle biopsies from people living with ALS and normal controls, the team have been able to show that skeletal muscle does have an increased dependence on fat as an energy source as the disease progresses. In the SOD1 mouse model, this happens in the mid-stage of the disease. This is also the time when significant loss of motor neurons in the spinal cord is seen in the SOD1 mice compared to mice without ALS. Higher dependency on fat is also seen in muscle fibres grown from samples taken from people with ALS compared to those samples from people without the disease. This presumably happens because fat is a much richer energy source, and the muscle is trying to find the best way to maintain function in the face of losing its connections to the neurons in the spinal cord.

But this is somewhat counter-productive. Although fat is a richer energy source, it takes more oxygen to break down each molecule of fat than it does to break down a molecule of glucose, leading to an overall increase in energy use. Is this, then, presenting as hypermetabolism?

And if the change in fuel source is really to sustain proper functioning and survival of the cells, but this change also underpins hypermetabolism, why would people with hypermetabolism have a worse prognosis?

One explanation could be that because there is this change in energy source as the disease progresses, those individuals with ALS who have a faster progressing type of the disease would encounter this switch much earlier, and present in clinic with hypermetabolism.

Can we turn the ‘switch’ off?

If this switch in fuel source is indeed the driver, or cause, of hypermetabolism could the way in which cells access energy be ‘tweaked’ to prevent hypermetabolism and improve outcomes in ALS?

This question was answered in a collaborative study by Shyuan and other research teams using a drug called Trimetazidine, currently approved as a treatment for angina. Trimetazidine is a partial fatty acid oxidation inhibitor, which means it hampers the way cells access fat and improves their ability to access glucose to sustain their energy supply.

Using a SOD1 mouse model of ALS, the study showed that Trimetazidine slowed down energy expenditure, prevented hypermetabolism and extended survival in mice treated with the drug compared to mice who received no treatment.

Although these results appear promising, it must be remembered that these were seen in a mouse model of the disease. Would it be as beneficial to people living with ALS? The MetFlex clinical trial, currently underway at sites in Australia (recruiting), the Netherlands and at King’s College London in the UK (not yet recruiting), is seeking to answer this question. It is hoped the trial will finish in June 2023.

What’s next?

Although there has been a lot of progress made in recognising hypermetabolism in ALS over recent years, there are still may questions left unanswered. We know that hypermetabolism is higher in people with the disease than in those without, but we don’t yet fully understand why. Shyuan presented evidence to suggest that it might be due to changes in cellular metabolism in the muscle but there is also evidence emerging that there may be changes in metabolism in the motor neurons, and in the astrocytes and glial cells (the cells that provide nourishment and support to the motor neurons) that could contribute to this hypermetabolism. And while there is some evidence to suggest that hypermetabolism is associated with worse clinical outcomes, Shyuan suggests there are two things we need to do to be able to decipher the cause and clinical significance of hypermetabolism:

  • First, studies must be conducted in larger groups of people to see if the trend in hypermetabolism is true in larger populations of people with ALS.
  • Secondly, the approaches used to define hypermetabolism must be standardised as different estimation models (used to estimate a person’s resting energy expenditure) produce different results. Although all models show that hypermetabolism is more common in ALS, one model may show someone as hypermetabolic, and another will show them as having normal metabolism. This work is currently ongoing around the world.

This is an important area of research and more work is needed to fully understand the relationship between hypermetabolism and survival outcomes in people with ALS. We hope that Prof Ngo’s talk inspires more researchers to study this vital area of science and that beneficial targets for therapy are identified soon.