Modulation of aberrant mitochondrial function and cytokine production in skeletal muscle of patients with CFS by supplementary polyphenols

Lead Research Organisation: University of Liverpool
Department Name: Institute of Ageing and Chronic Disease

Abstract

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. Nutritional interventions that modify mitochondrial function or modify the systemic inflammation will break this vicious circle and improve muscle function and improvement in muscle function and or the direct effects of polyphenols will result in improved 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. Nutritional 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 to examine mitochondrial function in muscle cells in situ, determine the role of muscle in the production of inflammatory mediators and undertake a polyphenol intervention to modify ROS generation and inflammation and improve fatigue and wellbeing in CFS patients.

Planned Impact

Who will benefit from this research?

Evidence suggests between 150,000 and 250,000 people in the UK are affected with CFS and these individuals will be one of the main beneficiaries of the research.

Clinical practitioners will benefit from the research.

Industry may also benefit from optimisation of and potential development of novel formulations of polyphenol-enriched foods targeted at improving mitochondrial function, muscle function and reducing chronic inflammation.

Staff working directly on the project will also benefit from the research.


How will they benefit from this research?

The potential impact of this research is extensive. 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 a substantial effect on the quality of life for people with the condition, their families and carers. Development of optimal therapy will have a major impact on quality of life for these patients and their carers. Similarly, clinical practitioners will benefit from the additional research knowledge of the role of mitochondrial dysfunction and chronic inflammation in the development of CFS and thus the use of more targeted interventions.

In the longer term the project may lead to a diet-based improvement in prevention of fatigue in the wider community such as our ageing population.

We anticipate that the design of the current study is such that information provided at the end of the study will have an immediate and direct application to the UK population.

Staff working directly on the project will benefit from the development of skills which are applicable to a number of employment sectors.

Publications

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Description Role of defective mitochondrial function in the loss of skeletal muscle and weakness that occurs in patients with chronic renal failure
Amount £120,000 (GBP)
Organisation Mersey Kidney Research 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2011 
End 02/2013
 
Title CFS cytokine database 
Description Cytokine protein array data from 90 CFS patients and 93 Healthy Control subjects/ 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact The work is currently being prepared for publication. The database comprises a large dataset of cytokine profiles from patients with Chronic Fatigue Syndrome and matched Healthy Control subjects which will be in a format searchable by others. 
 
Description BBC news on-line 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Asked to comment on news reports. Although not directly related to outputs form this research, relevant in general terms.

Some contact from other organisations to advise regarding glutamine supplementation in ITU (RDG) or general muscle function and ageing (AMcA)
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Engagement with ME/CFS paient groups and funders 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Scientific presentations to patients with CFS, targetted funders and carers.
Year(s) Of Engagement Activity 2014,2015,2016
 
Description Public Engagement at World Museum Liverpool 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact A large set of activities aimed at engagement of children with science, with focus on funded research areas within the Department/Institute.
Year(s) Of Engagement Activity 2014
 
Description School placements 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact School sixth form work experience in laboratories.

Led to a better understanding of the support or lack of support provided to inner-city schoolchildren with no background in higher education in their family.
Year(s) Of Engagement Activity 2012,2013,2014