Purpose of Review
Here, we review potential causes of muscle dysfunction seen in many patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) such as the effects of oxidative and nitrosative stress (O&NS) and mitochondrial impairments together with reduced heat shock protein production and a range of metabolic abnormalities.
Several studies published in the last few years have highlighted the existence of chronic O&NS, inflammation, impaired mitochondrial function and reduced heat shock protein production in many patients with ME/CFS. These studies have also highlighted the detrimental effects of chronically elevated O&NS on muscle functions such as reducing the time to muscle fatigue during exercise and impairing muscle contractility. Mechanisms have also been revealed by which chronic O&NS and or impaired heat shock production may impair muscle repair following exercise and indeed the adaptive responses in the striated muscle to acute and chronic increases in physical activity.
The presence of chronic O&NS, low-grade inflammation and impaired heat shock protein production may well explain the objective findings of increased muscle fatigue, impaired contractility and multiple dimensions of exercise intolerance in many patients with ME/CFS.
A recent study identified 20 case definitions of chronic fatigue syndrome (CFS) in common use . The widest definition of CFS is favoured in the UK and only mandates the presence of idiopathic fatigue of variable severity . The narrowest definition favoured in other countries, notably the USA, mandates the presence of severe incapacitating fatigue, pain, neurocognitive disability, compromised sleep, symptoms suggestive of autonomic dysfunction and a worsening of global symptoms following minor increases in physical and/or cognitive activity . Importantly, while the use of narrow selection criteria identifies patients with far higher levels of physical and cognitive disability than the use of wide criteria [4,5,6], thus far no diagnostic approach has been shown to uniquely identify patients with a single illness as evidenced by a common pathogenesis and pathophysiology. Moreover, criteria variance has been identified as the most common confounding variable largely accounting for the huge variation in study results and lack of replicated data supplied by researchers in this field .
Such results include evidence of activated but dysregulated immune pathways, neuroimaging abnormalities chronic oxidative and nitrosative stress (O&NS) and mitochondrial dysfunction when patients are enrolled into studies via the use of restrictive criteria or no evidence of any biological abnormalities whatsoever when patients are recruited by the most permissive schema [7,10,, 8•, 9–11, 12•]. However, it is also fair to say that results are highly inconsistent even with the use of narrow criteria, and there is now considerable scientific evidence in support of the view that a diagnosis of ME/CFS represents a group of illnesses with a distinct biological aetiology with a very similar phenotype often referred to as CFS subtypes [13,14,15]. This is perhaps unsurprising given that this would appear to be a common theme in other diagnostic categories reliant on purely phenotypic inclusion criteria .
However, despite the well-documented difficulties in the reliance of purely symptomatic classifications in scientific research, the use of restrictive criteria allied with multivariate statistical techniques is increasing the probability of identifying patients displaying evidence of activated immune-inflammatory and O&NS pathways discussed briefly above [17•, 18]. There is also accumulating evidence demonstrating that the cause of such abnormalities in many patients is increased intestinal permeability and bacterial translocation into the bloodstream [19•, 20•, 21, 22, 23•]. Several studies published in the last few years have highlighted the detrimental effects of chronically elevated O&NS on muscle functions such as reducing the time to muscle fatigue during exercise and impairing muscle contractility. There are currently no curative treatment options for patients diagnosed with this illness according to any criteria. The evidence for cognitive behaviour therapy (CBT) and graded exercise in reducing fatigue is mixed and is not better than self-help advice [24, 25].
Here, we will focus on mechanisms which may be responsible for increased muscle fatigue, impaired contractility and exercise intolerance in patients diagnosed according to internationally agreed guidelines and we will provide suggestions for treatment.
Pursuant to our interest in O&NS as a potential cause of documented muscle dysfunction in many patients afforded a diagnosis of ME/CFS according to international consensus guidelines, a MEDLINE search was carried out using the keywords of reactive oxygen species, nitric oxide, oxidative, nitrosative, striated muscle and chronic fatigue syndrome. The results obtained from this initial search were processed, and the conclusions reached formed the basis of a second keyword search using the terms, heat shock proteins, reactive oxygen and nitrogen species (ROS/RNS), nuclear factor-κB, muscle metabolic sensors, VO2max, mitochondrial dysfunction, criteria variance, physical function, immune, exercise intolerance and post-exercise fatigue. The information obtained from the latter searches was then organised into a review aimed at detailing the potential causes of muscle pathology in many ME/CFS patients and aimed at proposing mechanisms underpinning perhaps the most distinctive diagnostic elements of ME/CFS namely intolerance to mild increases in activity and excessively prolonged post-exercise muscle fatigue.
Evidence of Muscle Dysfunction and Physical Impairments in ME/CFS Patients
There is now copious evidence of profound physical disability  , exercise intolerance [28, 29•] and multidimensional muscle pathology [30, 31•] in many individuals afforded a diagnosis of ME/CFS. The development of widespread muscle fatigue and weakness following trivial increases in activity is one of the primary symptoms of ME/CFS diagnosed according to internationally agreed criteria which occurs after relatively mild activity [32,33,34]. Conflicting data exists in relation to objective measures of physiological exercise capacity of ME/CFS patients, but a systematic review of the published evidence in this domain by Nijs and others  concluded that the weight of evidence indicates an impaired physiological exercise capacity in at least some patients afforded a ME/CFS diagnosis . Indeed, most sedentary, but otherwise healthy, individuals recover from a maximal exercise test within 24 h and display few if any signs of prolonged post-exercise muscle fatigue. However, profound post-exercise muscle fatigue persisting at similar levels those reported in the immediate aftermath of aerobic exercise for 24 h or more [36,37,38]. Many ME/CFS patients also lack the ability to reproduce workload and measurements on repeat maximal cardio-pulmonary exercise testing (CPET) [36,37,38]. This phenomenon was recently demonstrated by Snell et al.  who conducted a CPET on ME/CFS patients diagnosed according to Fukuda criteria reporting that there were no significant differences between the responses of healthy controls and ME/CFS patients at maximal effort for the first CPET. However, the latter group of patients displayed significantly reduced values for workload and oxygen consumption at maximal exercise and at the anaerobic or ventilator threshold . These results were confirmed by Keller et al. [29•] who also noted that using the data from a single CPET would result in an overestimation of the functional capacity of their study participants [29•, 39]. It is worth noting, however, that while there are multiple lines of empirical evidence demonstrating muscle dysfunction in ME/CFS patients, this level of pathology is likely to have different causes in different patients and is not present in all patients afforded this diagnosis and one such element could be impaired heat shock protein (Hsp) production during and immediately after aerobic exercise.
Impaired Exercise Induced Heat Protein Production in ME/CFS
One of the most puzzling phenomenon reported by authors investigating skeletal muscle metabolic abnormalities in ME/CFS patients during an immediately following exercise is an excessive increase in markers of oxidative stress together with the failure of the Hsp response compared to healthy controls [30, 31•, 40, 41]. Elevated serum Hsp-70 levels is indicative of systemic inflammation and oxidative stress  which may reflect the conserved role of this Hsp in inhibiting the development of systemic inflammation by inhibiting the activation of NF-κB and its cyto-protective role in increasing cellular resistance to inflammatory mediators such as tumour necrosis factor (TNF)α and ROS . Importantly, Hsp-70 is elevated in muscles in an environment of increased ROS and RNS  and plays a major role in muscle repair following exercise-induced damage [45, 46]. There are a number of routes whereby Hsp-70 aids muscle repair including the inhibition of NF-κB and Forkhead Box O which drive muscle inflammation and atrophy and perhaps more importantly this Hsp recruits immune cells into muscles following injury which in turn engage in a reparative inflammatory response . This restorative mechanism involves a complex interplay between macrophages and Toll-like receptors (TLRs) and macrophages which produce a subtle balance between pro-inflammatory and anti-inflammatory cytokines, and readers interested in the fine details of these processes are invited to consult excellent explanations provided by Novak et al.  and Hindi and Kumar . Unsurprisingly, there is now robust evidence that impaired Hsp-70 activity leads to the loss of this reparative response, which results in significantly delayed healing , and hence could account for the prolonged muscle fatigue and weakness experienced by some ME/CFS patients following even gentle exercise.
Metabolic and Sensory Abnormalities Reported in the Peripheral Musculature of ME/CFS Patients
Several research teams have reported the presence of impaired nociceptive inhibition in some ME/CFS patients undertaking aerobic exercise evidenced by a significantly reduced pain threshold during and in the post-exercise phase rather than the increase in pain thresholds experienced by healthy individuals [49,50,51]. There is also some evidence to suggest the presence of widespread hyperalgesia [52, 53]. This phenomenon may be a result of sensitised nociceptors within injured peripheral muscle tissue (trapezius, quadriceps and deltoid) but can also be detected in asymptomatic areas  suggesting the existence of central sensitisation. Other research teams have highlighted abnormal increases in the expression of a range of metabolite detecting receptors including ASIC3, P2X4 and P2X5 and sympathetic nervous system receptors alpha-2A, beta-1, beta-2 and COMT during and in the post-exercise phase in their study cohorts suggestive of widespread peripheral pathology . Interestingly, these authors also reported immunological abnormalities in their patients during exercise such as increased production of interleukin (IL)-10 and expression of TLR-4 [54, 55].
The presence of immune abnormalities within the striated muscle of ME/CFS patients during exercise was confirmed by a recent meta-analysis . However, Kent-Braun and fellow workers  reported findings suggestive of impaired central activation of voluntary muscle as a cause of abnormal muscle fatigue in their study subjects  which is a finding replicated by Schillings et al. . Vermeulen et al.  conducted repeat exercise tests 24 h apart on a group of patients afforded a diagnosis of ME/CFS and reported that during both exercise tests, the patients reached the anaerobic threshold and the maximal exercise at a much lower oxygen consumption than the controls and this worsened in the second test. The authors interpreted their data as evidence for the increase of lactate levels, the product of anaerobic glycolysis and a decrease of the mitochondrial ATP production in the patients .
Bioenergetic Abnormalities in the Skeletal Muscle of ME/CFS Patients
There is now a considerable body of evidence indicating that mitochondrial dysfunction plays a crucial role in the aetiology of the symptoms displayed by many but by no means all patients diagnosed with ME/CFS using internationally agreed or very narrow definitions. Lowered production of ATP, impaired oxidative phosphorylation and mitochondrial abnormalities have all been reported [60, 61, 62•]. Moreover, there is also accumulating data suggesting that the intracellular acidosis and the abnormally high levels of lactate in the musculature of ME/CFS patients following very mild increases in activity stem from impaired mitochondrial function and oxidative phosphorylation [63, 64]. The characteristic pattern of sustained intracellular acidosis in exercising muscle coupled with a decreased anaerobic threshold (AT) has been repeatedly reported by research teams utilizing NMR spectroscopy [65, 66]. ME/CFS patients show significantly lower intracellular ATP concentrations than healthy control participants upon exercising to the point of exhaustion indicative of oxidative metabolism . It is also interesting to note that the response to exercise of many ME/CFS patients is typical of the pattern commonly reported in individuals with syndromic mitochondrial diseases . It should be stressed however that studies examining muscle bioenergetics in ME/CFS patients using magnetic resonance spectroscopy (MRS) techniques have produced mixed results. Some authors have reported distinctive muscle bioenergetic abnormalities in patients diagnosed with ME/CFS according to Fukuda 1994 criteria following initial or repeat exercise tests [65, 66, 68, 69]. Interestingly, Jones et al. reported that their entire group displayed a significantly reduced VO(2) peak and peak work, heart rate and anaerobic threshold compared to controls which is a very similar finding to the CPET results discussed above . However, such bioenergetic abnormalities were not seen in all studies with Lane et al.  reporting evidence of impaired oxidative metabolism in 50% of their patients, and Barnes et al.  reporting evidence of such pathology in only 20% of their study population. One well-documented cause of mitochondrial dysfunction and impaired ATP generation is the presence of chronic oxidative stress which has been repeatedly demonstrated in the musculature of ME/CFS patients [30, 31•, 40, 41, 53, 64, 72]. It should be stressed however that O&NS together with chronic inflammation are well-documented causes of muscle fatigue and impaired muscle contractility via mechanisms which are independent of their deleterious effects on mitochondrial function particularly in chronic inflammatory illnesses [73, 74]. ROS and RNS modulate numerous biochemical processes including gene expression, glucose uptake, calcium signalling and muscle contractility [75, 76]. In pathological conditions, however, excessive or dysfunctional ROS and RNS signalling promotes contractile dysfunction and myopathy in the striated muscle .
The Role of O&NS in the Genesis of Muscle Dysfunction Seen in ME/CFS Patients
While low and physiological levels of ROS play an indispensable role in ensuring normal force production in the skeletal muscle [78, 79], elevated levels of superoxide anions or hydrogen peroxide may result in contractile dysfunction, muscle weakness and fatigue . This Janus-faced property of ROS is seen during exercise where modest increases in ROS, which is an invariant co-occurrence during submaximal exercise in healthy people, have a beneficial effect on force generation and muscle strength . However, further increases during maximal exercise or due to the presence of oxidative stress result in a depression of force generation in a concentration and time-dependent manner . This phenomenon is often described as the ROS muscle paradox [77, 82•]. The mechanisms by which excessive ROS levels exert these detrimental effects are not fully understood but are thought to involve the redox modification of cysteine thiol groups on proteins which regulate the normal performance of the striated muscle during exercise and at rest .
Mechanisms Underpinning the Detrimental Effects of Excessive ROS on Muscle Force and Contractility
Thiol oxidation can alter protein function by interfering with biochemical reactions or by altering protein structure and the availability of regulatory sites. Numerous proteins undergo reversible thiol-disulphide interactions. Many functional and regulatory proteins engaged in the cooperative regulation of muscle performance contain thiol groups which are potential targets of ROS-mediated changes in muscle performance in an environment of acute or chronic oxidative stress. These include the ryanodine-sensitive calcium release channel (RYR), SR calcium ATPase (SERCA), SR Ca2+-ATPase, tropomyosin, troponin, actin, myosin and the Na+/K+-ATPase pump among other ion transporters [80, 83]. Chronically elevated levels of ROS potentiates the opening of the ryanodine-sensitive calcium release channel, resulting in increased calcium release from the SR, and inhibits ATPase (SERCA) activity [84, 85] and these effects were originally considered to be prime causes of ROS-mediated muscle fatigue [86, 87]. However, subsequent in vitro and in vivo evidence has unequivocally disproved this hypothesis [82•, 88]. Although it must be stressed that the causes of impaired muscle contractility induced by prolonged elevations are not completely understood, the current consensus position is that this phenomenon is mediated at least in part by changes in the myofibrillar Ca2+ sensitivity [89, 90].
Prolonged elevation of ROS levels leads to the oxidation of a range of essential myofilament proteins leading to impaired function [91, 92]. For example, molecules of the myosin heavy chain are vulnerable to ROS-mediated oxidation, which leads to impaired myosin function [85, 91]. Troponin C is another myofilament protein with a high sensitivity to ROS-induced oxidation and subsequent conformational changes which negatively impacts its normal function [93, 94]. It is thought that these structural and functional modifications lie at the heart of calcium ion insensitivity induced by excessive levels of ROS, but there is also some data to support the view that a major mechanism underpinning this phenomenon is impaired cross-bridge kinetics secondary to oxidative disruption of disulphide bonds . A subset of thiol-regulated proteins appears to mediate ROS-induced muscle fatigue. Much of the experimental evidence has been provided by the administration of N-acetyl cysteine (NAC), for example, McKenna et al. have demonstrated that pretreatment with oral NAC leads to enhanced muscle glutathione and cysteine and preserves the activity of the Na+/K+ pump significantly delaying fatigue during prolonged cycling exercise [83, 96]. Given the relative paucity of effective treatments for patients afforded a diagnosis of ME/CFS, the potential treatment application of this molecule will be discussed in a later section of this paper.
The Role of NO and Other RNS in the Development of Muscle Dysfunction and Fatigue
There is copious evidence demonstrating that excessive levels of endogenous NO production depresses force production in the skeletal muscle via mechanisms involving cGMP-mediated signalling, reversible S-nitrosylation and modification of peroxynitrite levels [73, 81, 95, 97]. The mechanisms underpinning this phenomenon are varied and unlike the situation with excessive levels of ROS, there is considerable evidence that the deleterious effect of excessive NO concentrations on skeletal muscle contractility is due in part to disrupted calcium regulation in the SR . Chronically elevated NO inhibits the activity of SERCA via the inactivation of functional sulfhydryl groups  and nitration of key tyrosine residues  resulting in impaired calcium uptake in the SR and increased calcium levels in the cytosol. NO also exerts dose-dependent effects on the activity of the RyR  with physiological levels providing a protective effect against RYR oxidation, via superoxide scavenging , while excessive levels lead to inhibition of RYR activity and blocks calcium release [102, 103]. RyR1 possesses a cysteine residue at position 3635 (Cys3635) that is highly susceptible to be S-nitrosylated by chronically elevated levels of NO [104, 105] leading to loss of contraction force, increased skeletal muscle protein breakdown and, consequently, reduced abilities of skeletal muscles to adapt to physical exercise stimuli . It is interesting that nitrosylation of RYR1 is affected by increased inducible NO synthase (iNOS) activity rather than neuronal nitric oxide , which is the main source of NO in striated muscles, as high levels of RNS secondary to inducible NO synthase upregulation cause weakness and dysfunction in inflammatory states [107, 108]. There is also evidence that the inhibition of SERCA, myosin and calcium-dependent activation of myosin in an environment of chronic NO elevation is as a result of S-nitrosylation of specific cysteine thiols [109,110,111]. Excessive levels of NO also inhibit actin-myosin cross-bridge cycling, lessen the activity of cytochrome-c oxidase, diminish mitochondrial oxygen utilization and inhibit the activity of key enzymes of the mitochondrial electron transport chain and the tricarboxylic acid cycle [67, 112]. It is noteworthy that the majority of these inhibitory effects on mitochondrial function and energy production are affected by S-nitrosylation [23•, 112]. Given this evidence, it is tempting to conclude that this post-translational modification is also the cause of accelerated muscle fatigue in an environment of chronic nitrosative stress reported by several research teams [113,114,115]. However, it must be stressed that the current consensus view is that the deleterious effects on muscle function caused by pathological levels of NO is confined to impaired contractility and possibly increased muscle atrophy, and that there is not enough evidence to support the view that NO levels directly contribute to the development of muscle fatigue [77, 80].
S-nitrosylation also regulates a plethora of processes and signalling pathways involved in the physiological function of the striated muscle [116, 117] and in the adaption of muscle function during exercise . The relative importance of cGMP signalling and S-nitrosylation in the redox regulation of striated muscle function is a matter of debate, but it is worth noting that there is now considerable evidence indicating that the vast bulk of NO signalling in a cellular environment is effected by the latter process [23•]. This is an important point as the mechanisms regulating the reversibility of S-nitrosylation and maintaining the balance of nitrosylation and denitrosylation break down in an environment of chronic O&NS leading to a state described as hypernitrosylation and consequent dysregulation of NO-based regulation of protein function . This phenomenon can have dire consequences for the function of unloaded muscle and the adaptation of muscle function during chronic and long-term exercise as we will now briefly explain.
O&NS as a Cause of Impaired Exercise Tolerance and the Development of Excessive Post-exercise Fatigue or Muscle Pain
Prime mediators of the adaptive responses to exercise in the striated muscle are the adenosine monophosphate-activated protein kinase (AMPK), the PI3K/Akt pathway and the NF-κB family of transcription factors, together with the MAP kinases notably p38 MAPK, and several members of the FoxO transcription factor family [119,120,121], which are all activated by increasing levels of superoxide, hydrogen peroxide and other ROS during exercise. These pathways promote adaptation by increasing expression of antioxidant enzymes genes such as Mn-SOD and Cu, Zn-SOD, CAT and GPX1, which are essential players in counteracting the tissue damaging effects of dramatic increases in ROS . High antioxidant capacities then diminish the deleterious effects of subsequent increases in ROS .
ROS-induced activation of NF-κB and p38/MAPK is also needed for the exercise-induced upregulation of PGC-1 alpha [124, 125], which is also a major driver of muscle adaptation to exercise in the medium and longer term and acts to prevent the development of muscle atrophy [126, 127]. PGC-1α has been demonstrated to regulate lipid and carbohydrate metabolism and to improve the oxidative capacity of the muscle fibres by promoting their change towards a slow twitch phenotype, increasing the activity and amount of mitochondria via increased production of the master regulator of cellular anti-oxidant defences nuclear respiratory factors (NRF-1, NRF-2) and upregulation of mitochondrial transcription factor A (TFAM) [128, 129].
It is clear from the above that activation of NF-κB, the p38/MAPK pathway, AMPK and the Forkhead box protein O family of transcription factors are essential elements in the short- and long-term adaptations of the skeletal muscle to exercise. Importantly, NF-κB activation and DNA binding, PI3K /AKT signalling and MAPK /p38 activity are inhibited in an environment of nitrosative stress by S-nitrosylation of a range of thiol groups whose redox state determines the function of these proteins [23,131,132,•, 130–133]. Consequently, one would expect impaired adaptation to exercise and exercise intolerance in patients displaying high levels of O&NS in their peripheral musculature which is a phenomenon observed in some ME/CFS patients especially when diagnosed according to narrow or internationally recognised criteria as discussed above. This is also a plausible mechanism which may explain the relatively poor results, or frank harm, following prolonged GET in ME/CFS study populations [24, 134, 135].
Many patients diagnosed with ME/CFS using internationally agreed diagnostic criteria display objective evidence of profound physical disability. Such evidence includes significant muscle weakness, prolonged post-exercise muscle fatigue and reduced VO2max and a lower anaerobic threshold compared to healthy unaffected controls which is generally more apparent on repeat exercise testing. There are a number of observations that could explain the presence of muscle dysfunction and exercise intolerance in CFS patients although it is likely that the causes may vary as a diagnosis of ME/CFS does not represent a single illness with a unitary pathogenesis and pathophysiology. Increases in the expression of genes responsible for metabolite sensing and abnormal immune signatures in the exercising muscle of patients afforded a diagnosis of ME/CFS compared to unaffected controls and has been repeatedly reported although the origin of such observations remains obscure. Elevated oxidative stress and impaired Hsp production is a highly replicated finding in ME/CFS patients. This is highly significant as Hsp production protects muscle cells from the damaging effects of exercise-induced oxidative stress and inflammation during exercise and is an indispensable player in facilitating post-exercise muscle repair. Similarly, increased levels of ROS and RNS are well-documented causes of increased muscle fatigue and impaired muscle contractility. The presence of chronic oxidative stress may also explain evidence demonstrating impairments in oxidative phosphorylation and other dimensions of mitochondrial performance, and it is also noteworthy that chronically upregulated levels of ROS and RNS are known to impair mechanisms responsible for the adaptation of the striated muscle to exercise.
Recently published papers of particular interest have been highlighted as: • Of importance
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Maes M, Twisk FN, Johnson C. Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res. 2012;200(2-3):754–60.
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The authors declare that they have no conflict of interest.
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This article is part of the Topical Collection on Chronic Pain
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Gerwyn, M., Maes, M. Mechanisms Explaining Muscle Fatigue and Muscle Pain in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a Review of Recent Findings. Curr Rheumatol Rep 19, 1 (2017). https://doi.org/10.1007/s11926-017-0628-x
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