EXCESSIVE INTRACELLULAR ACIDOSIS OF SKELETAL MUSCLE ON EXERCISE IN A PATIENT WITH A POST-VIRAL EXHAUSTION/FATIGUE SYNDROME: A 31P Nuclear Magnetic Resonance Study

doi:10.1016/S0140-6736(84)91871-3

The Lancet

Volume 323, Issue 8391, 23 June 1984, Pages 1367-1369

https://doi.org/10.1016/S0140-6736(84)91871-3 Get rights and content

Abstract

A patient with prolonged post-viral exhaustion and excessive fatigue was examined by ³¹P nuclear magnetic resonance. During exercise, muscles of the forearm demonstrated abnormally early intracellular acidosis for the exercise performed. This was out of proportion to the associated changes in high-energy phosphates. This may represent excessive lactic acid formation resulting from a disorder of metabolic regulation. The metabolic abnormality in this patient could not have been demonstrated by traditional diagnostic techniques.

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It would also result in an increased disturbance of the sympathetic nerve fibers, which regulate several functions in skeletal muscles, such as blood flow, metabolism, movements of ions through membranes, and contractility [109–114]. There are some indications that the removal of the H+ ions (acid) from the muscle cells is impaired in ME/CFS patients [115–117], and that this impairment may be associated with the disturbance of the sympathetic nerves [115]. If this is correct, it could have a profound impact on the ME/CFS-patients’ physical capacity [118–121].
According to the hypothesis presented here, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops over 3 steps: Step 1 is characterized by the aggregation of lymphoid cells in dorsal root ganglia or other nervous structures. The cause of this formation of ectopic lymphoid aggregates may be an acute infection, asymptomatic reactivations of a common neurotropic virus, exposure to a neurotoxin, or physical injury to peripheral nerves. In step 2, Epstein-Barr virus (EBV)-infected lymphocytes or monocytes bring EBV from the circulation to one or several of these lymphoid aggregates, whereupon cell-to-cell transmission of EBV and proliferation of latently EBV-infected lymphocytes lead to the presence of many EBV-infected cells in the lymphoid aggregates. The EBV-infected cells in the aggregates ignite an inflammation in the surrounding nervous tissue. This local inflammation elicits, in turn, a wave of glial cell activation that spreads from the EBV-infected area to parts of the nervous system that are not EBV-infected, disturbing the neuron-glial interaction in both the peripheral – and central nervous system. In step 3, immune cell exhaustion contributes to a consolidation of the pathological processes. There might be a cure: Infusions of autologous EBV-specific T-lymphocytes can perhaps remove the EBV-infected cells from the nervous system.
A model of the mitochondrial basis of bipolar disorder
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Calcium ions also participate in mechanisms that regulate ATP production which are independent of ΔΨm, which we will now consider. The allosteric ATP-inhibition of cytochrome c oxidase (CcO), often described as complex IV, which is activated by cAMP dependent phosphorylation constitutes an ΔΨm-independent mechanism for the regulation of mitochondrial respiration (Arnold et al., 1984; Kadenbach et al., 2009; Lee et al., 2009b). This is perhaps unsurprising given the fact that CcO acts as the rate-limiting enzyme in the mitochondrial electron transport chain (Huttemann et al., 2012; Li et al., 2006).
Bipolar disorder phenomenologically is a biphasic disorder of energy availability; increased in mania and decreased in depression. In consort, there is accumulating evidence indicating increased mitochondrial respiration and ATP production in bipolar mania which contrasts with decreased mitochondrial function in patients in the euthymic or depressive phase of the illness. Consequently, the central thesis of this paper is that bipolar disorder is due to a phasic dysregulation of mitochondrial biogenergetics. The elements responsible for this dysregulation may thus represent critical treatment targets for mood disorders, and are the subject of this paper.
There are many potential mediators of mitochondrial function which collectively are implicated in bipolar disorder. Levels of oxidative stress, pro-inflammatory cytokines and intracellular calcium ions are all higher in bipolar mania than in the euthymic and depressive phases of the illness. Increased levels of calcium ions can partly account for increased oxidative phosphorylation via well documented pathways such as the modulation of the F₁–F_O elements of ATP synthase. Likewise, increased levels of oxidative stress and pro-inflammatory cytokines lead to the upregulation of AMPK, SIRT-1, SIRT-3 and NAD⁺ which directly stimulate oxidative phosphorylation. Uric acid and melatonin are also differentially elevated in bipolar mania and both molecules stimulate the production of ATP. The pro-apoptotic, neurotoxic and mitotoxic effects of elevated glutamate, dopamine and GSK-3 in bipolar mania may be counterbalanced by higher basal levels and activity of p53, Bcl-2, PI3K and Akt in an environment of elevated uric acid and decreased BDNF.
Details of these pathways are discussed as an explanatory model for the existence of increased ATP generation in mania. We also offer a model explaining the biphasic nature of mitochondrial respiration in bipolar disorder and the transition between mania and depression based on increasing levels of TNFα, ROS, NO, AMPK and SIRT-1 together with the antagonistic relationship between p53 and NF-κB.
Increased risk of chronic fatigue syndrome in patients with migraine: A retrospective cohort study
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Vermeulen et al. showed that low oxygen uptake by muscle cells causes exercise intolerance in CFS, suggesting that an insufficient metabolic adaptation to exercise may underlie the mechanism of CFS [9]. Compared with controls, CFS patients examined using magnetic resonance spectroscopy (MRS) displayed higher intracellular lactate levels with exercise [10], abnormal increases in lactate with minor exercise [11], lower ATP resynthesis rates during recovery [11],and reduced intracellular ATP in muscles [12]. These findings suggest that mitochondrial dysfunction may underlie the pathophysiology of reduced physical endurance in CFS patients.
The common concurrence of migraine and chronic fatigue syndrome (CFS) has been reported but whether migraine poses a higher risk of CFS remains unknown. In this retrospective case–control study, we examined the association between the 2 disorders by using a nationwide, population-based database in Taiwan.
The data were retrieved and analyzed from the National Health Insurance Research Database (NHIRD) of Taiwan; 6902 newly diagnosed migraine cases from 2006–2010 were identified in a subset of the NHIRD, and 27,608 migraine-free individuals were randomly selected as the comparison cohort. The multivariate Cox proportional hazards regression model was used to investigate the risk of CFS in migraineurs after adjustment for demographic characteristics and comorbidities.
After adjustment for the covariates, the risk of CFS was 1.5-fold higher in the migraine cohort than in the comparison cohort (52.72 vs. 28.85 per 10,000 person-years). Intriguingly, the risk was most prominent in the oldest group (≥ 65 years), with a 2.11-fold increased risk (95% confidence interval 1.31–3.41) of CFS. In addition, the adjusted cumulative incidence of CFS in the follow-up years was higher in the migraine group (log-rank test, P < .0001), and CFS incidence appeared to increase with the frequency of migraine diagnoses.
The current study demonstrated an increased risk of CFS in migraineurs. Proposed mechanisms in previous studies such as mitochondrial dysfunction and central sensitization may underlie the shared pathophysiology of these seemingly distinct but potentially overlapping disorders.
In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome
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Differences in the lactate accumulation and the anaerobic threshold were also reported in experimental studies [1,4]. As shown in Fig. 5E and Suppl. Fig. 2E, the CFS simulations exhibit an increased acidosis during exercise with a maximal pH difference to the control simulations of 0.056 and a slightly prolonged pH recovery, which concurs with experimental observations [1,25]. As a consequence of the lower pH both, the lactate accumulation (Fig. 5F and Suppl. Fig. 2F) and the lactate efflux from the cell during recovery, were increased up to 15% and 20%, respectively, compared to controls.
Post-exertional malaise is commonly observed in patients with myalgic encephalomyelitis/chronic fatigue syndrome, but its mechanism is not yet well understood. A reduced capacity for mitochondrial ATP synthesis is associated with the pathogenesis of CFS and is suspected to be a major contribution to exercise intolerance in CFS patients. To demonstrate the connection between a reduced mitochondrial capacity and exercise intolerance, we present a model which simulates metabolite dynamics in skeletal muscles during exercise and recovery. CFS simulations exhibit critically low levels of ATP, where an increased rate of cell death would be expected. To stabilize the energy supply at low ATP concentrations the total adenine nucleotide pool is reduced substantially causing a prolonged recovery time even without consideration of other factors, such as immunological dysregulations and oxidative stress. Repeated exercises worsen this situation considerably. Furthermore, CFS simulations exhibited an increased acidosis and lactate accumulation consistent with experimental observations.
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Chronic fatigue syndrome (CFS) patients show a persistent fatigue condition with muscle pain and impairment of concentration, memory, and sleep. Presently, the physiological basis of CFS remains unclear. In this study, spectroscopic differences in the thumb were compared between 103 CFS patients and 122 healthy controls to examine possible changes of levels of oxygenated or deoxygenated hemoglobin.
Visible and near-infrared (Vis–NIR) spectroscopy was used to examine possible changes in the region of 600–1100 nm.
Vis–NIR spectra showed sharp peaks at 694, 970 and 1060 nm and broad peaks in the regions of 740–760 and 830–850 nm. As these peaks are possibly related to oxyhemoglobin, cytochrome c oxidase and water, levels of these factors were compared between the two groups. Statistical analysis of the absorbance of Vis–NIR spectra showed a significant decrease in water content, a significant increase in oxyhemoglobin content, and a significant increase in the oxidation of heme a + a₃ and copper in cytochrome c oxidase in CFS patients.
These changes imply accelerated blood flow and energy metabolism in the thumbs of CFS patients.
Non invasive investigation of muscle function using <sup>31</sup>P magnetic resonance spectroscopy and <sup>1</sup>H MR imaging
2006, Revue Neurologique
Le caractère non invasif et non traumatique des techniques de spectrométrie et d’imagerie de résonance magnétique et leur simplicité de mise en œuvre en font maintenant des outils de choix pour l’exploration de la fonction musculaire in vivo. L’exploration par SRM du P-31 des pathologies ayant une incidence directe ou indirecte sur le métabolisme musculaire entre progressivement dans le champ des explorations cliniques de routine. Pour être pleinement efficace, cette exploration doit s’accompagner du choix d’un protocole standardisé adapté aux patients et de la définition de critères de normalité prenant en compte l’hétérogénéité inter-individuelle caractéristique de toute population distribuée de façon « normale ». L’analyse des résultats de la littérature et notre expérience acquise à partir de l’exploration de 4 000 patients et témoins sur une période de quinze ans permettent dès à présent de tirer un certain nombre de conclusions claires sur les indications, les limites et les perspectives de ce nouveau mode d’exploration du muscle. Les glycogénoses et les myopathies mitochondriales présentent des anomalies métaboliques spécifiques. Il est cependant à souligner que les patients souffrant de désordres mitochondriaux présentent des profils métaboliques variables dont seules certaines constantes sont systématiquement retrouvées. Un autre domaine où l’apport de la SRM du P-31 est significatif concerne l’analyse des désordres métaboliques musculaires secondaires à certaines pathologies (inflammatoires, infectieuses, hormonales, etc.). Dans le cadre de la susceptibilité à l’hyperthermie maligne, les anomalies affectant le transport du calcium se traduisent par un profil métabolique anormal qui permet l’exploration systématique de tous les membres d’une famille à risque. De nouveaux développements technologiques (IRM et spectrométrie couplées) font leur apparition et leur place dans un contexte clinique reste à évaluer. L’IRM quant à elle fournit des informations anatomiques et fonctionnelles sur le muscle au repos, mais également sur le muscle travaillant. Il devient ainsi possible de combiner des mesures anthropométriques de qualité et une identification précise des muscles sollicités au cours d’un effort. De plus, dans le domaine pathologique, l’utilisation de séquences dédiées permet de détecter la présence de processus inflammatoires et/ou œdémateux, de quantifier un éventuel envahissement graisseux, une hypotrophie ou une hypertrophie musculaire. La place actuelle des explorations par SRM et IRM dans le bilan diagnostique et pronostique des maladies musculaires est claire. Compte tenu de leur caractère non invasif, elles constituent, l’examen de première intention dans le cadre d’une suspicion d’une myopathie. La normalité des explorations par SRM et par IRM permet d’éliminer pratiquement la plupart des diagnostics de myopathie métabolique (diagnostic d’exclusion). L’utilisation complémentaire de techniques invasives plus classiques, biochimiques ou histo-enzymologiques demeure nécessaire pour étayer un profil métabolique peu spécifique. En ce qui concerne le versant thérapeutique, la SRM du P-31 a prouvé son utilité dans le suivi au long cours des traitements palliatifs et dans l’évaluation pharmacologique de nouvelles molécules. Dans un proche avenir, la SRM du P-31 représentera vraisemblablement un outil méthodologique privilégié pour étudier les effets réparateurs de la thérapie génique et de la thérapie cellulaire.
³¹P MRS and 1H MRI of skeletal muscle have become major new tools allowing a complete non invasive investigation of muscle function both in the clinical setting and in basic research. The comparative analysis of normal and diseased muscle remains a major requirement to further define metabolic events surrounding muscle contraction and the metabolic anomalies underlying pathologies. Also, standardized rest-exercise-recovery protocols for the exploration of muscle metabolism by P-31 MRS in healthy volunteers as well as in patients with intolerance to exercise have been developed. The CRMBM protocol is based on a short-term intense exercise, which is very informative and well accepted by volunteers and patients. Invariant metabolic parameters have been defined to characterize the normal metabolic response to the protocol. Deviations from normality can be directly interpreted in terms of specific pathologies in some favorable cases. This protocol has been applied to more than 4 000 patients and healthy volunteers over a period of 15 years. On the other hand, MRI investigations provide anatomical and functional information from resting and exercising muscle. From a diagnostic point of view, dedicated pulse sequences can be used in order to detect and quantify muscle inflammation, fatty replacement, muscle hyper and hypotrophy. In most cases, MR techniques provide valuable information which has to be processed in conjunction with traditional invasive biochemical, electrophysiological and histoenzymological tests. P-31 MRS has proved particularly useful in the therapeutic follow-up of palliative therapies (coenzyme Q treatment of mitochondriopathies) and in family investigations. It is now an accepted diagnostic tool in the array of tests which are used to characterize muscle disorders in clinical routine. As a research tool, it will keep bringing new information on the physiopathology of muscle diseases in animal models and in humans and should play a role in the metabolic characterization of gene and cell therapy.

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EXCESSIVE INTRACELLULAR ACIDOSIS OF SKELETAL MUSCLE ON EXERCISE IN A PATIENT WITH A POST-VIRAL EXHAUSTION/FATIGUE SYNDROME: A 31P Nuclear Magnetic Resonance Study

Abstract

J Biol Chem

J Biol Chem

J Biol Chem

Bioenergetics of intact human muscle. A 31P nuclear magnetic resonance study

Mol Biol Med

Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values

Scand J Clin Lab Invest

Extra- and intracellular water spaces in muscles of man at rest and with dynamic exercise

Am J Physiol

EXCESSIVE INTRACELLULAR ACIDOSIS OF SKELETAL MUSCLE ON EXERCISE IN A PATIENT WITH A POST-VIRAL EXHAUSTION/FATIGUE SYNDROME: A ³¹P Nuclear Magnetic Resonance Study

Bioenergetics of intact human muscle. A ³¹P nuclear magnetic resonance study