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Keywords:

  • acylcarnitine;
  • carnitine;
  • carnitine palmitoyltransferase;
  • chronic fatigue syndrome;
  • fatty acid

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Abstract.  Reuter SE, Evans AM (School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, SA, Australia; Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia). Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitine palmitoyltransferase-I activity. J Intern Med 2011; 270: 76–84.

Objective.  The underlying aetiology of chronic fatigue syndrome is currently unknown; however, in the light of carnitine’s critical role in mitochondrial energy production, it has been suggested that chronic fatigue syndrome may be associated with altered carnitine homeostasis. This study was conducted to comparatively examine full endogenous carnitine profiles in patients with chronic fatigue syndrome and healthy controls.

Design.  A cross-sectional, observational study.

Setting and subjects.  Forty-four patients with chronic fatigue syndrome and 49 age- and gender-matched healthy controls were recruited from the community and studied at the School of Pharmacy & Medical Sciences, University of South Australia.

Main outcome measures.  All participants completed a fatigue severity scale questionnaire and had a single fasting blood sample collected which was analysed for l-carnitine and 35 individual acylcarnitine concentrations in plasma by LC-MS/MS.

Results.  Patients with chronic fatigue syndrome exhibited significantly altered concentrations of C8:1, C12DC, C14, C16:1, C18, C18:1, C18:2 and C18:1-OH acylcarnitines; of particular note, oleyl-l-carnitine (C18:1) and linoleyl-l-carnitine (C18:2) were, on average, 30–40% lower in patients than controls (P < 0.0001). Significant correlations between acylcarnitine concentrations and clinical symptomology were also demonstrated.

Conclusions.  It is proposed that this disturbance in carnitine homeostasis is reflective of a reduction in carnitine palmitoyltransferase-I (CPT-I) activity, possibly a result of the accumulation of omega-6 fatty acids previously observed in this patient population. It is hypothesized that the administration of omega-3 fatty acids in combination with l-carnitine would increase CPT-I activity and improve chronic fatigue syndrome symptomology.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Chronic fatigue syndrome (also known as myalgic encephalomyelitis) is a term used to describe a heterogeneous condition that is primarily characterized by persistent debilitating fatigue that cannot be attributed to any alternative condition [1–4]. Despite being widely recognized, it remains one of the most perplexing conditions in medical science as there is little understanding of its pathogenesis and aetiology. Consequently, there remains no universally effective treatment option and diagnosis is based on the presence of a number of poorly understood signs and symptoms. Additional research to ascertain the underlying pathology of chronic fatigue syndrome is vital to establish appropriate diagnostic criteria as well as effective treatment protocols.

It is estimated that the prevalence of chronic fatigue syndrome is approximately 0.2–0.7% in the community and 0.5–2.5% in primary care [4] with the condition predominantly affecting young adults (onset 20–40 years) with a higher incidence in women (female–male ratio 3 : 1) [1–4]. Chronic fatigue syndrome has been associated with a significant loss in productivity [5] and a high total annual cost burden [4, 6, 7]. However, it is important to note that the impact of chronic fatigue syndrome is not merely economic with reports that sufferers experience a heavy psychosocial burden and a substantially reduced quality of life [8].

A variety of factors have been attributed to the pathophysiology of chronic fatigue syndrome, including immunologic, biochemical, psychiatric and neurological [2, 3]; however, at this time, no firm associations can be drawn. Numerous studies have emphasized a viral cause of chronic fatigue syndrome [2, 3] and recently a link between chronic fatigue syndrome and infection with certain retroviruses has been reported [9], although this result remains controversial [10–14].

l-carnitine is an endogenous compound, found in all mammalian species [15]. Adequate levels of l-carnitine are achieved from dietary sources, in particular from red meat, as well as via biosynthesis in the kidneys, liver and to some extent in the brain [15]. The principal biological role of carnitine is in the transport of fatty acids across the inner mitochondrial membrane for fatty acid oxidation via the reversible binding of acyl groups from Coenzyme A (CoA) (Fig. 1) [16]. It has also been established that carnitine has a role in regulating the cellular to mitochondrial ratio of free CoA to AcylCoA, in the transport of short and medium acyl groups from the peroxisome to the mitochondria and in the removal of unwanted acyl groups from the body [15, 17]. Alterations in carnitine homeostasis can have a detrimental effect on human health [18, 19]. In its severest form, carnitine deficiency is associated with progressive cardiomyopathy, encephalopathy and muscle weakness, resulting in death from heart failure [19, 20].

image

Figure 1. The role of l-carnitine in fatty acid oxidation. CoA, Coenzyme A; CPT, Carnitine Palmitoyltransferase.

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In the light of carnitine’s critical role in fatty acid oxidation, it has been suggested that chronic fatigue syndrome may be associated with alterations in l-carnitine and acylcarnitine homeostasis [21]. Previous studies have reported a reduction in endogenous plasma l-carnitine (free carnitine), total carnitine and/or acylcarnitine levels in patients with chronic fatigue syndrome [22–26]; however, these results have not been replicated in other studies [27, 28]. Whilst these studies have provided useful information on the composition of the endogenous carnitine pool in chronic fatigue syndrome, they have only examined free carnitine and total acylcarnitine levels (i.e. the sum of all individual acylcarnitines) and consequently alterations in the levels of some individual acylcarnitines may be effectively ‘cancelled out’ by relatively normal levels of other acylcarnitines in these patients. Recently, tandem mass spectrometry methods have been developed which are capable of quantifying individual acylcarnitine levels in human plasma [29, 30] and therefore provide a more adequate representation of the full carnitine profile.

One previous study examined individual plasma acylcarnitine concentrations in patients with chronic fatigue syndrome [31] in which the authors reported no significant differences in acylcarnitine levels between 25 patients and 25 healthy controls. However, it should be noted that in this study, only 20 individual acylcarnitines were quantified, and consequently, the individual acylcarnitines reported accounted for less than two-thirds of the reported total acylcarnitine levels. In addition, the lower limit of quantification of the assay used was well above the levels reported for all of the medium- and long-chain acylcarnitines quantified. Consequently, no firm conclusions regarding carnitine pool composition in patients with chronic fatigue syndrome can be drawn from this study.

The present study was conducted to examine the levels of endogenous plasma l-carnitine and 35 individual acylcarnitines in patients with chronic fatigue syndrome compared with age- and gender-matched healthy controls.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Study design

This study was reviewed and approved by the Human Research Ethics Committee of the University of South Australia. Participants were fully informed of the study procedures and provided written informed consent prior to study initiation. The study was conducted in accordance with the Declaration of Helsinki and the National Statement on Ethical Conduct in Human Research issued by the National Health and Medical Research Council (Australia).

Patients with chronic fatigue syndrome were recruited via the Chronic Fatigue Syndrome Society of South Australia [ME/CFS Society (SA) Inc]. Patients had been previously diagnosed with chronic fatigue syndrome by a physician according to the standard diagnostic criteria [4]. Age- and gender-matched healthy subjects, with no significant illnesses, were recruited from the general population via advertising. Neither patients nor subjects had received any carnitine supplementation within 2 months of assessment.

On the study assessment day, each participant completed a fatigue severity scale questionnaire and had a single fasting blood sample collected via venepuncture for carnitine profiling.

Fatigue severity scale

The fatigue severity scale is a validated functional measure which comprises nine items that are rated according to a Likert-type rating scale from 1 to 7, with ‘1’ indicating no impairment and ‘7’ indicating severe impairment (Table 1) [32]. The fatigue severity scale has been shown to be an appropriate and accurate measure of fatigue severity and symptomology and is able to distinguish between individuals with chronic fatigue syndrome-like symptomology and those individuals with no or varying levels of general fatigue [33].

Table 1. Fatigue severity scale [32]
Indicate your agreement/disagreement with the following statements on a scale of 1 to 7, with a score of 1 indicating strongly disagree and a score of 7 indicating strongly agree
My motivation is lower when I am fatigued1234567
Exercise brings on my fatigue1234567
I am easily fatigued1234567
Fatigue interferes with my physical functioning1234567
Fatigue causes frequent problems for me1234567
My fatigue prevents sustained physical functioning1234567
Fatigue interferes with me carrying out certain duties and responsibilities1234567
Fatigue is among my three most disabling symptoms1234567
Fatigue interferes with my work, family or social life1234567

Carnitine profiling

A single fasting blood sample was collected from each study participant for analysis of plasma l-carnitine and individual acylcarnitine concentrations. Analysis was conducted by the Department of Genetic Medicine, Women’s and Children’s Hospital (Adelaide, SA, Australia) using a MDS-SCIEX API4000 triple quadrupole tandem mass spectrometer (Applied Biosystems Inc, Foster City, CA, USA) with sample delivery using a 1100 HPLC system (Agilent Technologies, Santa Clara, CA, USA). Aliquots (2 μL) of each plasma sample were applied to 3-mm punches of filter paper (Whatman BFC-180; Whatman Inc, Fairfield, NJ, USA) and allowed to dry at room temperature. Once dry, filter papers were shipped to the analytical laboratory for analysis.

Samples were extracted from the filter paper using a solution of pure methanol containing known concentrations of stable isotopically enriched acylcarnitines (synthesized in-house). After a 15-minute extraction period, samples were dried under nitrogen. Samples were then esterified using acidified butanol to form the butyl-ester of each acylcarnitine followed by drying under nitrogen to remove excess butanolic HCl. The butyl-esters were determined by precursor scan of 85.1 amu. The levels of acylcarnitines were determined against the respective deuterated stable isotope using Analyst® software (Applied Biosystems Inc).

Individual carnitines analysed are given in Table 2. Total acylcarnitine levels were taken as the sum of all individual acylcarnitine concentrations, and total carnitine levels were calculated as the sum of l-carnitine and total acylcarnitine concentrations. It should be noted that, because of the nature of the tandem mass spectrometry method, some assay results represent the sum of 2 or 3 carnitine esters; for example, C4 represents the sum of 2 structural isomers with a four carbon-chain acyl group (butyryl-l-carnitine and isobutyryl-l-carnitine).

Table 2. Endogenous plasma carnitine concentrations (μmol L−1) for patients with chronic fatigue syndrome (n = 44) and healthy controls (n = 49)
Endogenous Plasma CarnitineHealthy ControlsChronic Fatigue Syndrome Patients
  1. Data are expressed as mean ± standard deviation; *P < 0.05.

LCl-Carnitine45.2 ± 9.7945.0 ± 11.3
TCTotal Carnitine59.5 ± 12.958.8 ± 13.6
AcylLCTotal Acylcarnitines14.3 ± 4.1313.8 ± 3.45
C2Acetyl-l-Carnitine10.6 ± 3.3710.2 ± 2.72
C3Propionyl-l-Carnitine0.502 ± 0.1530.489 ± 0.199
C3DCMalonyl-l-Carnitine0.0447 ± 0.02170.0416 ± 0.0166
C4Butyryl-l-Carnitine0.255 ± 0.09260.250 ± 0.107
C4-OHHydroxy-Butyryl-l-Carnitine0.0239 ± 0.01170.0252 ± 0.0130
C4DCSuccinyl-l-Carnitine0.0750 ± 0.01350.104 ± 0.135
C5Isovaleryl-l-Carnitine0.111 ± 0.04080.103 ± 0.0424
C5:1Tiglyl-l-Carnitine0.0276 ± 0.007870.0285 ± 0.0110
C5-OHHydroxy-Isovaleryl-l-Carnitine0.0352 ± 0.007890.0392 ± 0.0103
C5DCGlutaryl-l-Carnitine0.129 ± 0.04190.132 ± 0.0575
C6Hexanoyl-l-Carnitine0.0602 ± 0.02490.0605 ± 0.0213
C6:1Hexenoyl-l-Carnitine0.0211 ± 0.008180.0222 ± 0.00988
C6DCAdipyl-l-Carnitine0.0947 ± 0.01210.0971 ± 0.0277
C8Octanoyl-l-Carnitine0.0994 ± 0.06550.0953 ± 0.0553
C8:1Octenoyl-l-Carnitine 0.178 ± 0.117 0.132 ± 0.0752 * P = 0.0201
C8DCSuberyl-l-Carnitine0.0549 ± 0.007730.0601 ± 0.0177
C10Decanoyl-l-Carnitine0.161 ± 0.1130.154 ± 0.106
C10:1Decenoyl-l-Carnitine0.105 ± 0.05200.109 ± 0.0536
C10:2Decadienoyl-l-Carnitine0.0374 ± 0.01840.0395 ± 0.0216
C10DCSebacyl-l-Carnitine0.0970 ± 0.01180.0999 ± 0.0162
C12Lauroyl-l-Carnitine0.0668 ± 0.03640.0633 ± 0.0276
C12:1Dodecenoyl-l-Carnitine0.0681 ± 0.04240.0707 ± 0.0437
C12DCDodecanedioyl-l-Carnitine 0.0782 ± 0.0124 0.108 ± 0.0489* P  < 0.0001
C14Myristoyl-l--Carnitine 0.0751 ± 0.0248 0.0612 ± 0.0269* P  = 0.0023
C14:1Myristoleyl-l-Carnitine0.0694 ± 0.04350.0651 ± 0.0324
C14:2Tetradecadienoyl-l-Carnitine0.0390 ± 0.01640.0398 ± 0.0177
C14-OHHydroxy-Myristoyl-l-Carnitine0.0149 ± 0.006670.0157 ± 0.00605
C16Palmitoyl-l--Carnitine0.352 ± 0.1480.404 ± 0.220
C16:1Palmitoleyl-l-Carnitine 0.0586 ± 0.0276 0.0472 ± 0.0212* P  = 0.0383
C16-OHHydroxyl-Palmitoyl-l-Carnitine0.0104 ± 0.003610.0114 ± 0.00570
C16:1-OHHydroxy-Palmitoleyl-l-Carnitine0.0193 ± 0.007640.0211 ± 0.0111
C18Stearoyl-l-Carnitine 0.103 ± 0.0350 0.0874 ± 0.0326* P  = 0.0104
C18:1Oleyl-l-Carnitine 0.401 ± 0.170 0.279 ± 0.159* P  < 0.0001
C18:2Linoleyl-l-Carnitine 0.232 ± 0.111 0.146 ± 0.0911* P  < 0.0001
C18:1-OHHydroxy-Oleyl-l-Carnitine 0.0178 ± 0.00858 0.0228 ± 0.0116* P  = 0.0191

Statistical analysis

Unless otherwise indicated, data are expressed as mean ± standard deviation. Carnitine concentrations and demographic characteristics (i.e. age and fatigue severity scale results) obtained from patients with chronic fatigue syndrome were statistically compared to those obtained from healthy subjects using an analysis of variance (anova). Statistical examination of the relationship between carnitine pool composition and fatigue severity was conducted using linear regression of fatigue severity scale results versus endogenous carnitine levels. Gender distribution between the groups was compared using Pearson’s Chi-Squared (χ2) cross-tabulation analysis.

Significance was set at an α-level of 0.05. WinNonlin® Professional Version 5.3 (Pharsight Corporation, Mountain View, CA, USA) was used for anova analysis. spss for Windows Version 16.0 (SPSS Inc, Chicago, IL, USA) was used for conduct of the linear regression and Pearson’s Chi-Squared cross-tabulation analyses.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Forty-four patients with chronic fatigue syndrome (17 men; 27 women), with an average age of 49.9 ± 15.0 years, participated in the study. In addition, 49 healthy subjects (20 men; 29 women), aged 45.6 ± 11.6 years, were recruited to serve as controls. Average fatigue severity scale scores for the chronic fatigue syndrome group were 6.22 ± 0.660, compared with scores of 3.04 ± 1.23 for the healthy control group (P < 0.0001). There were no significant differences in age or gender distribution between the groups.

Endogenous plasma l-carnitine, total carnitine, total acylcarnitine and individual acylcarnitine concentrations for the chronic fatigue syndrome and healthy control groups are presented in Table 2. There were no significant differences in l-carnitine, total carnitine or total acylcarnitine levels between the groups, whereas patients with chronic fatigue syndrome had significantly lower C8:1, C14, C16:1, C18, C18:1 and C18:2 concentrations and significantly higher C12DC and C18:1-OH levels than healthy subjects. In most of these cases, endogenous acylcarnitine levels differed by approximately 20% between the groups; however, of particular note, C18:1 and C18:2 were 30–40% lower in patients with chronic fatigue syndrome than in healthy controls (Fig. 2) (P < 0.0001).

image

Figure 2. Endogenous plasma oleyl-l-carnitine (C18:1) and linoleyl-l-carnitine (C18:2) concentrations (μmol L−1) in patients with chronic fatigue syndrome (•) and healthy controls (○).

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Significant negative correlations between the results of the fatigue severity scale and endogenous plasma concentrations of C8:1, C14, C16:1, C18:1 and C18:2 were observed. Importantly, there were highly significant associations between fatigue severity and C18:1 (P = 0.0009, R = −0.3547) and C18:2 (P < 0.0001, R = −0.4191) levels. Significant positive correlations between fatigue severity and concentrations of C12DC, C16 and C18:1-OH were demonstrated; however, it should be noted that the data for C12DC was skewed because of two patients with chronic fatigue syndrome who exhibited highly elevated levels.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

On account of carnitine’s critical role in energy metabolism, a number of previous studies have investigated endogenous plasma carnitine levels in patients with chronic fatigue syndrome, with equivocal results. Some studies have suggested that chronic fatigue syndrome is associated with a reduction in endogenous plasma l-carnitine [22, 25, 26] and total carnitine levels [26]; however, these findings have not been replicated in other studies [23, 24, 27, 28, 31]. Similarly, chronic fatigue syndrome has also been associated with a reduction in endogenous plasma (total) acylcarnitine concentrations [22–24, 26], whilst other studies have reported no differences in levels between patients with chronic fatigue syndrome and healthy controls [27, 28, 31]. For instance, Plioplys & Pliopys [26] reported significantly lower endogenous levels of l-carnitine, total carnitine and total acylcarnitines in 35 patients with chronic fatigue syndrome compared with normative data obtained from the Mayo Clinic, whereas in a series of experiments conducted by Kuratsune et al. [22–24], the authors reported no differences in l-carnitine and total carnitine levels between patients with chronic fatigue syndrome and healthy controls in their earlier studies whilst their later study noted a significant reduction in l-carnitine levels in the patient population. Significantly lower total acylcarnitine levels in patients with chronic fatigue syndrome were reported in all three studies conducted by Kuratsune et al. [22–24]. In contrast, Jones et al. [27] reported no significant differences in l-carnitine, total carnitine and total acylcarnitine levels between 31 patients with chronic fatigue syndrome and 31 healthy controls.

Previous studies have predominantly used enzymatic assays for the quantification of l-carnitine, total carnitine and total acylcarnitine levels. This analysis, whilst useful, does not provide information on individual acylcarnitine levels; it is therefore possible that chronic fatigue syndrome is associated with alterations in the levels of only some acylcarnitines and consequently potential differences may be missed in the examination of total acylcarnitine levels in these studies. Only one previous study has investigated individual acylcarnitine levels in patients with chronic fatigue syndrome [31]. The study reported no significant differences in individual acylcarnitine levels between 25 female patients with chronic fatigue syndrome and 25 female healthy controls; however, only a limited number of individual acylcarnitines were quantified and no firm conclusions can be made. The present study was therefore conducted to examine the levels of endogenous plasma l-carnitine and 35 individual acylcarnitines in patients with chronic fatigue syndrome compared with age- and gender-matched healthy controls.

The present study confirmed that chronic fatigue syndrome is not associated with alterations in l-carnitine, total carnitine or total acylcarnitine levels; however, significant differences in levels between patients and healthy subjects were demonstrated for eight of the 35 of individual acylcarnitines quantified. Of particular note was the substantial reduction in oleyl-l-carnitine (C18:1) and linoleyl-l-carnitine (C18:2) levels in chronic fatigue syndrome, a result that has not been previously demonstrated. Soetekouw et al. [31] failed to find a significant difference in levels between patients and controls for five of the eight acylcarnitines which were found to be altered in this study (the remaining 3/8 were not analysed); this may be contributed to a lack of power. For example, whilst the levels reported for C8:1 are similar to those observed in this study, Soetekouw et al. [31] examined carnitine profiles in just 25 patients and 25 controls and, based on these subject numbers, we estimate that their study only had 45% power to determine a difference between the groups.

This study has also demonstrated significant relationships between severity of fatigue and endogenous plasma acylcarnitine levels. Importantly, highly significant associations were demonstrated for oleyl-l-carnitine and linoleyl-l-carnitine, with lower levels associated with greater fatigue severity as estimated by the fatigue severity scale. The relationship between fatigue severity and individual acylcarnitine levels in chronic fatigue syndrome has not been previously investigated. Plioplys & Plioplys [26] demonstrated significant negative relationships between l-carnitine and total carnitine concentrations and fatigue severity, but not total acylcarnitine levels. In keeping with the findings of our study, Kuratsune et al. [21] reported that an improvement in the condition of chronic fatigue syndrome patients was associated with a concurrent increase in endogenous plasma acylcarnitine levels, indicating the importance of carnitine homeostasis in the symptomology of chronic fatigue syndrome.

Based on the l-carnitine/acylcarnitine pathway in fatty acid oxidation, it is conceivable that the observed deficiency in long-chain acylcarnitines in chronic fatigue syndrome may be reflective of either (i) an increase in the activity of l-carnitine/acylcarnitine translocase or (ii) a reduction in the activity of carnitine palmitoyltransferase-I (CPT-I) (Fig. 1). An increase in l-carnitine/acylcarnitine translocase activity would result in enhanced long-chain acylcarnitine transfer across the inner mitochondrial membrane and hence an increase in substrate availability for muscle β-oxidation; a scenario that is improbable given the symptomology of chronic fatigue syndrome. More likely is that the deficiency in long-chain acylcarnitines in these patients is suggestive of reduced formation via CPT-I; in principle, this would result in less acylcarnitines available for transport across the inner mitochondrial membrane. Consequently, there would be a reduction in the amount of acylcarnitines within the mitochondria available for reverse transesterification by carnitine palmitoyltransferase-II (CPT-II) and hence a reduction in long-chain fatty acid oxidation (Fig. 1). In keeping with this, previous research has established that mitochondrial long-chain fatty acid oxidation is reduced in patients with chronic fatigue syndrome [34, 35]. In further support, patients diagnosed with CPT-II deficiency (in which less substrate is available for β-oxidation within the mitochondria) exhibit remarkably similar symptoms to chronic fatigue syndrome patients including myalgia, cramps, muscle stiffness, painful muscles and muscle weakness [19]. As long-chain fatty acids are the most energy-rich substrates for β-oxidation, it is plausible that small changes in acylcarnitine levels would have a significant impact on energy production, leading to fatigue.

The findings of a previous study by Maes et al. [36] further support our hypothesis. In their study, endogenous levels of fatty acids were examined in 22 patients with chronic fatigue syndrome and 12 healthy controls, and it was demonstrated that chronic fatigue syndrome was accompanied by increased levels of omega-6 poly-unsaturated fatty acids and mono-unsaturated fatty acids. Interestingly, of the fatty acids measured by Maes et al. [36] for which the corresponding acylcarnitine was quantified in the present study (C14, C16, C16:1, C18, C18:1, C18:2), for five of the six cases there was a significant reduction in acylcarnitine levels and an increase in corresponding free fatty acid levels (C14, C16:1, C18, C18:1 & C18:2). In fact, when our findings are linked with those of Maes et al. [36], it can be speculated that the ratio of free fatty acid to acylcarnitine for these acyl groups is approximately 2- to 3-fold higher in patients with chronic fatigue syndrome than in healthy controls, indicating a substantial disruption in fatty acid/carnitine homeostasis in these patients. This may be because of either (i) a reduction in the activity of AcylCoA synthase required for the conversion of free fatty acid to AcylCoA or (ii) reduced activity of CPT-I. As CPT-I is the rate-controlling enzyme in mitochondrial fatty acid oxidation [37], it is hypothesized, based on these findings, that a reduction in CPT-I activity contributes to the symptomology of chronic fatigue syndrome.

In keeping with this, high levels of omega-6 fatty acids (such as C18:2 seen in this patient group) have been shown to inhibit CPT-I activity [38] in rats, whereas an increase in the ratio of omega-3 to omega-6s has been shown to increase CPT-I activity in both rats [39] and healthy volunteers [40, 41]. As l-carnitine is also known to increase CPT-I activity [42], it is proposed that administration of omega-3 fatty acids in combination with l-carnitine would improve CPT-I activity in chronic fatigue syndrome, thereby decreasing the ratio of free fatty acid to acylcarnitine and theoretically normalizing mitochondrial fatty acid oxidation in these patients.

No studies have been conducted to investigate the impact of administration of l-carnitine in combination with essential fatty acids on chronic fatigue syndrome symptomology. Preliminary exploratory studies have determined the impact of carnitine supplementation (alone) on chronic fatigue syndrome severity; however, no double-blind, placebo-controlled studies have been conducted. In an open-label study, Plioplys & Plioplys [43] demonstrated that l-carnitine supplementation (1 g t.i.d p.o) resulted in significant improvements in fatigue severity after 2 months of supplementation. Similarly, in an open-label, randomized study, investigating the effect of administration of acetyl-l-carnitine and/or propionyl-l-carnitine in chronic fatigue syndrome, Vermeulen & Scholte [44] noted that supplementation with acetyl-l-carnitine (2 g daily p.o. for 24 weeks) resulted in significant improvements in mental fatigue and attention concentration, whilst administration of propionyl-l-carnitine (2 g daily p.o. for 24 weeks) resulted in significant improvements in general and physical fatigue. Although the present study has demonstrated that endogenous levels of these carnitines (i.e. l-carnitine, acetyl-l-carnitine and propionyl-l-carnitine) are not altered in chronic fatigue syndrome, we propose that their administration alters the equilibrium balance between l-carnitine and acylcarnitines via CPT-I, thereby impacting positively on the levels of acylcarnitines which have been shown to be depleted in this patient population. Previous studies have also demonstrated that administration of essential fatty acids (alone) results in a significant improvement in chronic fatigue syndrome symptomology [45–47].

Whilst the cause of this proposed impairment of mitochondrial fatty acid oxidation in patients with chronic fatigue syndrome is unknown, it is possible that this may be linked to the recent finding that chronic fatigue syndrome is associated with an increase in the incidence of viral infection [2, 3, 9]. Previous research has indicated that viral infection may result in altered fatty acid oxidation [48], and therefore, it is feasible that the condition may be triggered by a viral infection which leads to a disruption in free fatty acid and carnitine homeostasis, thereby impacting on the clinical condition of these patients. This hypothesis warrants further investigation.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

The authors thank the ME/CFS Society [SA] Inc for their contribution to this study.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References
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