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Title: Skeletal muscle fatigue : investigating the role of cytokines, ROS and mitochondrial function
Author: Earl, K. E.
ISNI:       0000 0004 6059 0524
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Skeletal muscle dysfunction and increased rate of fatigue is observed in a number of disorders. An increase in systemic and/or local pro-inflammatory cytokines has been proposed to modulate the ability of skeletal muscle to generate force, alter mitochondrial bioenergetics and induce reactive oxygen species (ROS) generation in muscle. Evidence suggests cytokines such as Tumour necrosis factor-a (TNF-a) play a major role in modulating the function of muscle cells. Muscle contraction and fatigue is a multidimensional concept which can be defined through both physical and psychological concepts, thus systemic changes in cytokine levels may alter both central and peripheral fatigue. Increased levels of dietary polyphenols have been associated with a reduction in systemic inflammation and may therefore alleviate muscle dysfunction. The aim of this work was to use cell-based studies to validate TNF-a induced cytokine production and examine the potential effects of targeted polyphenol interventions on cytokine release by skeletal muscle cells. Moreover, the aim of this study was to investigate in a human clinical population the role of cytokines in subjective fatigue and peripheral function of skeletal muscle. The human study focussed on patients with chronic fatigue syndrome (CFS), a condition associated with enhanced and chronic perceived fatigue. Patients with CFS report symptoms of post exertion malaise and general widespread fatigue in the outer limbs. The cellular mechanisms associated with perceived muscle weakness in CFS are poorly characterised. The hypothesis of this thesis was that altered circulating levels of cytokines and chemokines may play a major role in the pathogenesis of CFS. A cell model of increased cytokine release through TNF-a exposure of muscle cells was validated. C2C12 myotubes treated with 25ng/ml TNF-a released increased levels of IL-6, CCL2, CCL5 and CXCL1. Pre-treatment with polyphenol compounds followed by TNF-a exposure showed that resveratrol attenuated TNFinduced release of IL-6, CCL2, CCL5 and CXCL1 cytokines from C2C12 myotubes. These data suggest that resveratrol may inhibit the actions of TNF-a, thus can potentially modulate local environment and potentially affecting muscle function. These findings are clinically relevant and have widespread implications for the understanding of diverse scientific areas, including the potential effect of polyphenol compounds on muscle function as well as inflammatory human muscle diseases in which cytokines may alter both central and peripheral muscle fatigue. This study showed that maximum voluntary contractions (MVC) were significantly reduced in patients with CFS compared with Healthy Controls (HCs). No difference was seen in electrically stimulated muscle tetanic forces or fatigue or single muscle fibre force measurements between groups. There was no difference in circulating cytokine levels or cytokine gene expression within the muscle in CFS compared with HCs although there was a suggestion of an increase in IP-10 and CCL2. Muscle mitochondrial respiratory function and ROS generation were not significantly different between patients with CFS and HCs although mitochondria in muscles of patients with CFS showed a blunted response to substrates compared with HCs. Overall these data suggest that patients with CFS do not show grossly altered muscle ROS generation, mitochondrial function or altered systemic levels of cytokines. Further investigations are required to determine the cause of reduced MVC and elevated perception of fatigue in patients with CFS and to examine the effect of stratification of these data from patients with CFS.
Supervisor: McArdle, A. ; Lightfoot, A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral