Mitochondrial dysfunction and the role of cytokines in ME/CFS: Preliminary results from research being funded by The MEA Ramsay Research Fund and the Medical Research Council | 2 April 2015

From The FASEB Journal, published by the Federation of American Societies for Experimental Biology, April 2015.

The Role of Cytokines in Muscle Fatigue in Patients with Chronic Fatigue Syndrome (CFS).

Kate Earl(1), Giorgos Sakellariou(1), Daniel Owens(2), Melanie Sinclair(1), Manuel Fenech(1), Graeme Close(2), Clare Lawton(3), Louise Dye(3), Micheal Beadsworth(1) and Anne McArdle(1)
1) Institute of Ageing and Chronic Disease University of Liverpool United Kingdom
2) RISES Liverpool John Moores University United Kingdom
3) Psychological Sciences University of Leeds United Kingdom

Abstract

CFS is characterized by profound levels of persistent/recurrent fatigue. It is proposed that chronic, low level inflammation may play a role in this fatigue.

We recruited 100 untreated patients with CFS (average age 33±12) and 100 age and sex matched healthy controls (HCs).

Serum levels of TNF-α were assessed using ELISA. Subjective fatigue was determined by questionnaire and muscle function tests were undertaken in subgroups in which maximal voluntary contraction (MVC), electrically stimulated muscle force generation and rate of fatigue were assessed in the quadriceps muscle.

Subjective fatigue was higher in patients with CFS compared with HCs. Preliminary analyses showed that serum TNF-α was undetectable in 97% of HCs, whereas 15% of patients with CFS had detectable (4.4+/-0.18pg/ml) serum TNF-α. MVC was significantly reduced in subjects with CFS compared with HCs.

No difference was seen in stimulated muscle fatigue between groups.

This preliminary data suggests that a sub-group of patients with CFS may have low level inflammation and analyses are underway to further characterise other inflammatory markers in serum and muscle of these patients and to determine whether such changes could affect indices of muscle function or central fatigue.

Funded by MRC, BBSRC and the ME Association.


COMMENT FROM DR CHARLES SHEPHERD, MEDICAL ADVISER, ME ASSOCIATION


These are important preliminary results from research into the role of mitochondrial dysfunction in ME/CFS that we are funding Professor Anne McArdle et al to carry out at the University of Liverpool.

Mitochondria are key cellular components that are responsible for the production of energy and the hypothesis underlying this research, which also involves the role of cytokines and low level inflammation, is as follows:

We hypothesise that the application of these newly developed techniques (at the University of Liverpool) will demonstrate that skeletal muscle mitochondria in patients with CFS are dysfunctional and that this results in muscle fatigue.

The dysfunctional mitochondria then activate a process which leads to a chronic, low grade inflammation, commonly reported in patients with CFS, which in turn results in further mitochondrial abnormalities and the establishment of a vicious circle of events.

Understanding the processes by which muscle fatigue occurs will lead to optimal interventions that break this vicious circle and improve muscle function and wellbeing of individuals.

These preliminary results from Liverpool add further support to research that has already been published, some of which has also been funded by the MEA Ramsay Research Fund, which indicates that there are abnormalities in skeletal muscle in at least a sub-group of people of that are not the result of deconditioning.

The preliminary results also support a role for cytokine induced inflammation in ME/CFS – as has been reported in the recently published research from Mady Hornig et al which has found important changes in certain specific cytokines in the early stages of ME/CFS in both blood and cerebrospinal fluid:

www.meassociation.org.uk/2015/03/scientists-find-clues-into-cognitive-dysfunction-in-chronic-fatigue-syndrome-medical-xpress-31-march-2015/

Among the other components to this muscle mitochondrial research we are funding is an examination of possible therapeutic interventions.

The MEA RRF is also helping to fund a study which is looking at mitochondrial DNA (= genetic material) in ME/CFS.

And we will be shortly announcing funding for a third mitochondrial function study.

Key research findings in ME/CFS relating to muscle and immunology are summarised and referenced in the Research section of the MEA purple booklet: ME/CFS/PVFS: An Exploration of the Key Clinical Issues:

www.meassociation.org.uk/2014/07/our-purple-booklet-clear-clinical-guidance-and-the-latest-research-all-wrapped-up-in-52-pages/


MORE INFORMATION ON THIS RESEARCH AT THE MEDICAL RESEARCH COUNCIL WEBSITE


MR/J002895/1
PI: Professor Anne McArdle, University of Liverpool
Title: Determination of mitochondrial function and cytokine production in skeletal muscle of patients with CFS.
Start Date: 01/05/2012
End Date: 30/04/2015
Award Amount: £252,030.40 (co funded between Medical Research Council and MEA Ramsay Research Fund)

Lay Summary

Chronic fatigue syndrome (CFS) is a severely debilitating illness of uncertain cause.

CFS is characterised by prolonged, debilitating fatigue that can be triggered by minimal activity (NICE, 2010).

The fatigue is accompanied symptoms which can include painful muscles and joints, disordered sleep, gastric disturbances and cognitive impairment and is sometimes associated with depression.

CFS can affect people of any age but is most common between the ages of 25 and 45.

Evidence suggests between 150,000 and 250,000 people are affected in the UK.

The effect of CFS on quality of life is substantial, with some individuals becoming housebound, employment becoming difficult or impossible, disrupted education in younger sufferers and thus represents a substantial effect on the quality of life for people with the condition, their families and carers.

The mechanisms by which an initial event leads to the chronic debilitating muscle fatigue and pain are unknown. The time required for diagnosis (typically 4 – 6 months) further complicates the identification of the factor(s) responsible for initiation of the illness. Irrespective of the factor(s) which initiates the illness, reversal of the severely debilitating fatigue which ensues remains the most promising form of treatment.

A number of studies have suggested that there is a defect in the energy producing components of muscle cells, known as mitochondria but, although this is core to understanding muscle fatigue in patients with CFS, the presence of abnormal mitochondria in muscle of patients with CFS remains the subject of considerable debate as other studies have failed to demonstrate a defect.

The reasons for such different findings are likely due to the previously limited methods of analysis for mitochondrial function with a lack of availability of appropriate and sensitive techniques to determine mitochondrial function directly in human muscle fibres. However, a new technique to study mitochondria in muscle fibres in situ from humans has now been developed and is established in our laboratory.

We hypothesise that the application of these newly developed techniques will demonstrate that skeletal muscle mitochondria in patients with CFS are dysfunctional and that this results in muscle fatigue. The dysfunctional mitochondria then activate a process which leads to a chronic, low grade inflammation, commonly reported in patients with CFS, which in turn results in further mitochondrial abnormalities and the establishment of a vicious circle of events.

Understanding the processes by which muscle fatigue occurs will lead to optimal interventions that break this vicious circle and improve muscle function and wellbeing of individuals.

Technical Summary

Chronic Fatigue Syndrome (CFS) is a severely debilitating illness of uncertain cause, characterised by prolonged, debilitating fatigue.

Reversal of the severely debilitating fatigue which ensues remains the most promising treatment.

The presence of abnormal mitochondria in muscle of patients with CFS remains the subject of considerable debate. The reasons for such different findings are likely due to the previous lack of availability of appropriate and sensitive techniques to determine mitochondrial function directly in muscle fibres.

However, to study mitochondrial function in muscle fibres in situ from humans, a method of isolating bundles of muscle fibres and permeablisation with saponin has been developed. This technique is established in our laboratories and will lead to a definitive answer regarding a mitochondrial defect in muscles of patients with CFS.

Chronic ROS generation by muscle mitochondria is proposed to result in chronic activation of NFkB and subsequent lowgrade inflammation.

We further hypothesise that activation of NFkB results in muscle becoming a major source of systemic pro-inflammatory cytokines, resulting in further mitochondrial abnormalities and the establishment of a vicious circle of events. Interventions that modify mitochondrial ROS generation or NFkB activation in muscles will reduce systemic inflammation, break this vicious circle and improve muscle function.

This application is a new collaboration between basic scientists at the University of Liverpool, experts on diet and cognitive function at the University of Leeds and a consultant in Infectious disease and Tropical medicine with a special interest in CFS/ME.

We will apply a novel technique to examine mitochondrial function in muscle cells in situ and determine the role of muscle in the production of inflammatory mediators.