Cara Tomas, Joanna L Elson, Julia L Newton & Mark Walker
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Scientific Reports, 2020 Oct 26; 10(1):18232
Key findings
- Muscle cells from people with ME/CFS are less able to use glucose as a fuel to produce energy
- This impairment in energy production may underlie the muscle fatigue that is characteristic of the illness
- These results help narrow down where in the metabolic pathway the abnormality occurs
Background
Muscle fatigue is among the most common symptoms experienced by people with ME/CFS, with a huge impact on their quality of life, and it is a key element of existing ME/CFS diagnostic criteria. So it makes perfect sense to focus research on the biological mechanisms underlying this symptom.
And that is what scientists at Newcastle University have been doing over the last decade or so, in a series of projects funded by ME Research UK and led by Prof. Julia Newton.
In recent years, Dr Cara Tomas has taken the reins on this research, and the valuable work of the team has led to important insights into the cellular metabolism of people with ME/CFS, including abnormalities in AMPK activation, glucose uptake, mitochondrial function and cellular bioenergetics.
In this latest paper, published in Scientific Reports, Cara has been looking more closely at how skeletal muscle cells produce energy from the different fuel sources (or substrates) available, and how this differs between people with ME/CFS and healthy individuals.
Importantly, she has built on the team’s previous work by using cultured muscle cells rather than the white blood cells used in some of the earlier experiments.
Findings
The cells of the body – including muscle cells – produce energy by breaking down glucose (a sugar that we get from our food) and converting it into the molecule ATP, which is used to transport energy for use within the cell.
There are four steps to this process: glycolysis, pyruvate oxidation, the citric acid cycle and oxidative phosphorylation (OXPHOS). In this study, Cara concentrated on glycolysis and OXPHOS.
Using a technique called extracellular flux analysis, Cara measured glycolysis in the skeletal muscle cells of nine people with ME/CFS and eleven healthy control subjects.
When glucose was introduced as the primary fuel for these cells, there was no difference in glycolysis between the two groups. This is similar to previous results in blood cells.
Next, OXPHOS was assessed using either glucose or galactose (another sugar) as the primary fuel.
With glucose as the fuel source, OXPHOS was reduced in skeletal muscle cells from people with ME/CFS compared with cells from healthy control subjects; this was the case both at baseline and when stimulated with oxygen.
Interestingly, OXPHOS was restored when the cells were treated with compound 991 (which activates AMPK).
However, with galactose as the fuel source, there was no difference in OXPHOS between cells from patients and those from healthy controls. There was also no difference between patients and controls in the ability of skeletal muscle cells to use fatty acids as a source of fuel.
Relevance
In summary, therefore, skeletal muscle cells from people with ME/CFS had a reduced ability to use glucose as a fuel to produce energy via OXPHOS, while they were able to use galactose and fatty acids normally, and glycolysis was also normal.
This is important because glucose is one the body’s preferred sources of fuel, and cells rely on OXPHOS as the final step in generating ATP for energy.
Furthermore, the results help narrow down where in the pathway this dysfunction occurs. Cara suggests that it could be in the pyruvate oxidation step which links glycolysis with the citric acid cycle (not the first time this has been implicated).
The results are similar to those reported previously in white blood cells, but it is significant that the same abnormality is present in muscle cells, and strengthens the idea that ME/CFS affects multiple organs.
As part of the extended programme of metabolic research in Newcastle over the last decade, these findings bring us another step closer to understanding fully the abnormalities in metabolism that underlie the muscle fatigue experienced by people with ME/CFS.
