Journal: J Intern Med., 2005 Mar;257(3):299-310.
Authors: Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S.
Affiliations: From the Laboratoire de Physiopathologie Respiratoire (UPRES EA 2201), Faculte de Medecine, Institut Federatif de Recherche Jean Roche, and Service des Explorations Fonctionnelles Respiratoires, Hopital Nord, Assistance Publique-Hopitaux de Marseille, Marseille, France.
NLM Citation: PMID: 15715687
Design. This case-control study compared 15 CFS patients to a gender-, age- and weight-matched control group (n = 11) of healthy subjects.
Interventions. All subjects performed an incremental cycling exercise continued until exhaustion.
Main outcome measures. We measured the oxygen uptake (Vo(2)), heart rate (HR), systemic blood pressure, percutaneous O(2) saturation (SpO(2)), M-wave recording from vastus lateralis, and venous blood sampling allowing measurements of pH (pHv), PO(2) (PvO(2)), lactic acid (LA), and three markers of the oxidative stress (thiobarbituric acid-reactive substances, TBARS, reduced glutathione, GSH, and ascorbic acid, RAA).
Results. Compared with control, in CFS patients (i) the slope of Vo(2) versus work load relationship did not differ from control subjects and there was a tendency for an accentuated PvO(2) fall at the same exercise intensity, indicating an increased oxygen uptake by the exercising muscles; (ii) the HR and blood pressure responses to exercise did not vary; (iii) the anaerobic pathways were not accentuated; (iv) the exercise-induced oxidative stress was enhanced with early changes in TBARS and RAA and enhanced maximal RAA consumption; and (v) the M-wave duration markedly increased during the recovery period.
Conclusions. The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability. These two objective signs of muscle dysfunction are sufficient to explain muscle pain and postexertional malaise reported by our patients.
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The present study in CFS patients shows that their maximal aerobic capacity was lowered because they stopped pedalling earlier than the age-, weight- and gender-matched control individuals. However, the slope of V o 2 versus work load relationship did not significantly differ from control and the simultaneous measurements of SpO2 and PvO2 even suggested the occurrence of an accentuated arterio-venous O2 difference and thus of an elevated oxygen uptake in exercising muscles. By contrast, the resting PvO2 level, measured in comfortably seated subjects before they were equipped to exercise, was higher in resting CFS patients, suggesting a reduced baseline oxygen uptake by tissues. There was no intergroup difference between resting V o 2 values but they were measured in subjects standing on the bicycle and wearing the complete equipment (face mask, SpO2 device, ECG leads...), that is in a stressing condition which often increased both ventilation and HR. In contrast, the cardiac and systolic blood pressure response to incremental exercise was the same than in control. We also found that the time course of pHv and LA changes during the exercise did not differ from control and that the peak LA variations were the same in the two groups. Despite no difference in resting levels of TBARS and antioxidants between CFS and control groups, in CFS patients the exercise-induced oxidative stress occurred sooner, that is at the maximal work rate, lasted more, and there was a significant enhanced maximal postexercise decrease in RAA level. This accentuated postexercise oxidative stress was associated with marked alterations in muscle excitability (lengthened M-wave duration), these M-wave changes being totally absent in our control subjects.
Our observations of the absence of impaired aerobic metabolism in our CFS patients corroborate several previous observations based on nearly the same exercise protocol [14-19]. These physiological data are supported by the absence of ultrastructural mitochondrial abnormalities in CFS patients . A study by Fulcher and White  even reported an accentuated aerobic metabolism in their CFS patients. We cannot come to the same conclusion but the present observation of higher arterio-venous oxygen difference in exercising CFS patients partly supports the conclusions by Fulcher and White . In addition, we did not report any intergroup differences between the progressive blood acidosis (pHv fall, LA increase) during the exercise bout, corroborating previous observations by Barnes et al.  who did not observe any abnormalities of glycolysis or pH regulation in a large group of CFS patients (n = 46) explored using 31P NMR spectroscopy. By contrast, Wong et al. , who also used 31P NMR spectroscopy in the gastrocnemius muscle, found that the changes in PCr and intramuscular pH occurred more rapidly in CFS patients than in control subjects suggesting an acceleration of glycolysis. However, there may be marked interindividual differences in the metabolic profiles of CFS patients because in their study Barnes et al.  clearly showed that an increased acidification relative to PCr depletion occurred in six of 46 subjects.
Oxidative stress is highly expressed in skeletal muscles because their antioxidant defences are poor . We already described the changes in the same blood markers (TBARS, RAA and GSH) in response to exactly the same protocol of incremental cycling exercise . In our previous study in a large number of healthy sedentary subjects, we showed that a significant exercise-induced increase in TBARS and consumption of blood antioxidants (RAA and GSH) never occurred before the 5th min of the recovery period and that the three blood markers recovered their resting levels within a maximum of 20 min. Our present data confirm these observations in control subjects. Thus, the early changes in blood redox status here measured in CFS patients during the exercise bout have a real significance. These differences prevail for the changes in plasma RAA concentration. In humans, RAA is the only endogenous antioxidant that completely protects the plasma lipids from any detectable damage induced by the formation of hydroperoxide radicals [38, 39], trapping all hydroperoxide radicals in the aqueous phase before they can reach the plasma lipids. Data in the literature also indicate an increased blood oxidative stress in resting CFS patients [24, 25]. Another observation  is in favour of an increased activity of intramuscular antioxidants (catalase, glutathione peroxidase and transferase) in resting CFS patients. Our study only showed a tendency (nonsignificant) for elevated baseline levels of TBARS, RAA and GSH. The present observations of an accentuated exercise-induced oxidative stress in CFS patients are supported by experimental data in a mouse model of CFS. Indeed, Singh et al.  reported that antioxidants markedly reduced the increased lipid peroxidation and catalase levels in the whole brain of mice which were forced to swim every day for a 7-day session. Such an accentuated exercise-induced oxidative stress in CFS patients could explain the enhanced oxygen uptake by the exercising muscles suggested by our measurement of an elevated arterio-venous oxygen difference. Indeed, recent data [41, 42] show that superoxide activates the mitochondrial uncoupling proteins and uncoupling processes enhance oxygen uptake through their influence on the mitochondrial respiratory chain.
Recording the compound-evoked muscle action potentials (M-wave) with surface electrodes (SEMG) is a noninvasive means to explore peripheral muscle fatigue in exercising humans. An impaired excitation of the muscle fibres is suspected when the M-wave declines and becomes broader . After an incremental cycling exercise, we observed that the M-wave duration was modestly lengthened in sedentary subjects [29, 30]. The present study in CFS patients reports no change in the neuromuscular transmission (conduction time) but it shows marked alterations of muscle excitability which began early after the exercise had stopped and culminated at the end of the 30-min recovery period. Only Kent-Braun et al.  recorded the M-wave and analysed its changes in amplitude in CFS patients executing intermittent submaximal contractions of the tibialis anterior muscle. These authors did not measure any significant differences in the M-wave variations between CFS and control subjects but their protocol was limited to a small muscle group and thus cannot be compared with an incremental cycling exercise until V o 2max which involves the participation of large muscle groups. The postexercise-altered muscle membrane excitability reported here in CFS is not explained by any impairments of the potassium outflow during muscle excitation or of the potassium inflow during the recovery period. As already demonstrated by Marcos and Ribas , an extracellular potassium accumulation can act as a negative feedback signal for sarcolemma excitability and this may constitute a possible mechanism for the postexercise M-wave alterations. In CFS patients, the accentuated and prolonged postexercise oxidative stress may be responsible for muscle membrane alterations (for example the formation of lipid hydroperoxides) with the consequence of the impaired membrane excitability described here. To explain their data of altered excitation-contraction coupling in skeletal muscle of CFS patients, Fulle et al.  suggested that the deregulation of pump activities could result from an increased sarcoplasmic reticulum membrane fluidity and the role played by the formation of lipid hydroperoxides in this process is already well documented .
Thus, as in inherited muscular dystrophy in which a variety of cellular abnormalities can be accounted for by free radical-mediated damages including abnormal functions of the sarcolemma and an altered activity of membrane-bound enzymes involved in excitation-contraction coupling, an increased level of free radical damage in CFS may be a contributor to the underlying functional defects and symptom presentation. This should promote further researches towards the goal of an effective treatment of CFS-suffering patients.
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