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What is the understanding muscle dysfunction study?

Led by: Dr Phil Manning and Prof Julia Newton at Newcastle University.

Aims: This PhD studentship will establish in vitro approaches to exploring the inter-relationship between muscle function, acidosis and fatigue expression with a view to developing treatments to be used in subsequent clinical trials.

Cost: £25,000

Length of study: Three years

Study began: May 2012

Background information: The funding provided by Action for M.E. is being matched by Newcastle University’s Faculty of Medical Sciences to establish the Action for M.E. PhD Studentship. A top science graduate, Gina Rutherford, is being trained and employed to work on this study over three years.

The study hypothesises that M.E./CFS patients show abnormalities in their anaerobic metabolism pathways following a standard level of peripheral muscle exercise when assessed using fMRI and that this energetic abnormality is a significant contributing factor to the fatigue experienced by people living with M.E./CFS and that targeting this will reduce the amount of fatigue they experience. In vitro studies will directly study muscle mitochondrial function, pH (utilising a novel nanosensor approach developed by the applicants) and responsivity to alteration in pyruvate dehydrogenase function. 

Project summary: By Gina Rutherford, Newcastle University

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/M.E.) is a debilitating disorder of unknown aetiology and is characterised by severe disabling fatigue in the absence of an alternative diagnosis. Historically, there has been a tendency to draw psychological explanations for the origin of fatigue. However, this model is at odds with patient descriptions of their fatigue, with many citing difficulty in maintaining muscle activity due to perceived lack of energy and discomfort.

Studies have demonstrated that when CFS/M.E. patients complete relatively low-level repeat exercise, they experience profound muscle dysfunction which is accompanied by acidity in the muscle. This has been speculated to be due to abnormalities within the muscle.[1],[2]

These abnormalities may lead to patients using anaerobic energy-producing pathways, rather than aerobic energy pathways that enable the muscle to function for longer without excessive fatigue. Studies that have reported abnormality have used magnetic resonance spectroscopy (MRS) to measure internal pH of the lower limb musculature in patients.

In this project, muscle samples were obtained from CFS/M.E. patients in an attempt to investigate muscle function in more detail. This involved using novel approaches to measure pH at rest and following electrical impulse stimulation which functioned to experimentally mimic muscular contraction and simulate exercise. Furthermore, other approaches were used to investigate specific energy producing pathways such as glycolysis (anaerobic respiration) and mitochondrial oxidative phosphorylation (aerobic respiration).

During each experiment, the cells were treated with key drug compounds to test the capacity of new drugs to modulate cellular energy production and to investigate the capacity of these drugs to treat peripheral muscle fatigue in CFS/M.E.

Fluorescent dye was used to measure the pH inside the muscle. Interestingly, there was no difference in pH when CFS/M.E. muscle samples were compared to healthy control sample, which contrasts previous work conducted when CFS/M.E. patients performed an exercise intervention .

When specifically measuring glycolytic (anaerobic) activity there was no significant difference in lactate which is produced at a rate comparable to glycolysis or any of the glycolytic parameters measured.

Mitochondrial (aerobic) function was also assessed using a technique called extracellular flux analysis, which measures the rate of cellular oxygen consumption. Data revealed there to be no differences in the mitochondrial function of CFS/M.E. muscle cells compared to healthy control samples. Thus, it can be determined that mitochondrial dysfunction is not the cause of muscle fatigue symptomology experienced by CFS/M.E. patients.

Free radical generation in CFS/M.E. muscle samples was also investigated in this project. Briefly, free radicals are atoms that contain an unpaired electron in their outermost ring, this results in a highly reactive configuration which will readily interact with other molecules to become stabilised, which is potentially damaging to key components of the cell and could lead to cellular dysfunction.

However, the results demonstrated there to be no evidence of elevated free radical generation when compared to control samples. This would suggest that the muscle fatigue phenotype exhibited in CFS/M.E. patients is not related to elevated oxidative stress at the isolated muscle cell level.

This research project did not find any evidence of biochemical or metabolic dysfunction in muscle cell samples obtained from CFS/M.E. patients. This contrasts previous work that has reported muscle dysfunction in CFS/M.E. patients following exercise. Further investigations are required to determine the biological basis of fatigue in CFS/M.E. patients.

[1] Jones DJ, Hollingsworth KG, Jakovijevic DG, Fattahova G, Pairman J, Blamire AM, Trennel MI and Newton JL (2012) Loss of capacity to recover from acidosis on repeat exercise in CFS/M.E. patients-a case control study. European Journal of Clinical Investigation. 42(92):186-194

[2] Jones DJ, Hollingsworth KG, Taylor R, Blamire AM and Newton JL (2010) Abnormalities in pH handling by peripheral muscle and potential regulation of the autonomic nervous system in chronic fatigue syndrome. Journal of Internal Medicine. 267(4):394-401