During constant work-rate exercise above the lactic acidosis threshold, oxygen consumption fails to plateau by 3 minutes, but continues to rise slowly. This slow component correlates closely with the rise in lactate in normal subjects. We investigated if oxygen consumption during constant work-rate exercise could rise after 3 minutes in the absence of a rise in lactate. We studied five patients with McArdle's disease, one patient with phosphofructokinase deficiency and six normal subjects. Subjects performed two 6-minute duration constant work-rate exercise tests at 40 and 70% of peak oxygen consumption. During low-intensity exercise, oxygen consumption reached steady state by 3 minutes in both groups. Lactate rose slightly in control subjects but not in patients. During high-intensity exercise, oxygen consumption rose from the third to the sixth minute by 144 (21-607) ml/minute (median and range) in control subjects and by 142 (73-306) ml/minute in patients (p = not significant, Mann-Whitney U test). Over the same period, lactate (geometric mean and range) rose from 2.68 (1.10-5.00) to 5.39 (2.70-10.00) mmol/L in control subjects, but did not rise in patients (1.20 [0.64-1.60] to 0.70 [0.57-1.20] mmol/L). We conclude that the slow component of oxygen consumption during heavy exercise is not dependent on lactic acidosis.
Keywords: glycogen storage disease; exercise; acidosis, lactic; oxygen consumption
In normal subjects, when constant work-rate exercise is performed below the lactic acidosis threshold V O^sub 2^ rises quickly to reach a steady state at or before 3 minutes. However, during constant work-rate exercise above the lactic acidosis threshold, V O^sub 2^ does not achieve a plateau but continues to rise slowly as exercise proceeds (1, 2). This 'slow component' may reach values of 1 L/minute or more (3, 4) and causes V O^sub 2^ to increase well above that expected for the particular work rate. A slow V O^sub 2^ component is evident in patients suffering from primary pulmonary hypertension (5), chronic obstructive pulmonary disease (6, 7), and heart failure (8). This increased demand for oxygen may have important consequences for exercise intolerance in disease states. The etiology of the slow V O^sub 2^ component in subjects performing relatively high constant work-rate exercise is unclear. The slow component has been shown to correlate closely with an increase in plasma lactate in normal subjects and patients with heart failure (8-10), suggesting that lactate may be important in its causation. Several mechanisms have been postulated to account for the correlation between lactate and the slow component. Additional V O^sub 2^ could result from the conversion of lactate to glucose in the liver (11) and to glycogen in skeletal muscle (12). Lactate is oxidized by exercising and nonexercising muscle (13), and lactate infusion has been found to increase V O^sub 2^ in resting skeletal muscle (14). Lactate-induced vasodilatation and an acidosis-mediated Bohr effect could increase oxygen delivery and permit V O^sub 2^ to increase within exercising muscle for other reasons (e.g., to repay an oxygen deficit incurred earlier in exercise) (15). An alternative possibility for the correlation between lactate and the slow component is that the relationship is purely associative and that lactate increase is a marker for another mechanism underlying the slow component.
We wished to determine if the slow V O^sub 2^ component during high constant work-rate exercise was present in subjects who cannot produce lactate in skeletal muscle during exercise. Patients with the rare conditions of McArdle's disease (myophosphorylase deficiency or type V glycogenosis) and phosphofructokinase deficiency (Tarui's disease or type VII glycogenosis) cannot increase plasma lactate during exercise because they cannot convert glycogen to lactate in skeletal muscle. McArdle's disease was first described in 1951 (16), and the defect in the skeletal muscle enxyme, myophosphorylase, was identified in 1959 (17, 18). We and others have shown that these patients have severely impaired exercise capacity (19, 20) and, in addition, do not exhibit a lactic acidosis threshold (20). Phosphofructokinase deficiency was first described by Tarui and coworkers (21). It is caused by a deficiency in phosphofructokinase in erythrocytes and in muscles. The clinical picture is similar to McArdle's disease but with the addition of hemolytic anemia and gout.
If lactic acidosis is responsible, or necessary, for the appearance of a slow V O^sub 2^ component during heavy exercise, then failure to produce lactic acid should abolish the slow component. We hypothesized that V O^sub 2^ would not continue to rise after 3 minutes of high-intensity constant work-rate exercise in patients with McArdle's disease or phosphofructokinase deficiency.
Some of the results of these studies have been previously reported in the form of an abstract (22).
METHODS
Five patients with McArdle's disease and one with phosphofructokinase deficiency were studied (Table 1). Six healthy age-, sex-, and weight-matched control subjects were recruited. Further details are given in an online supplement.
Tests were performed in two centers. The patients with McArdle's disease and their matched control subjects were studied in Belfast. The patient with phosphofructokinase deficiency (F.K.) and his control (B.Y.) were studied at Harbor-University of California at Los Angeles. all tests were performed on an electronically braked cycle ergometer. After an initial familiarization test, subjects returned on a separate day for a symptom-limited maximal incremental test. Two 6-minute duration constant work-rate tests were then performed on further separate days in random order; a low-intensity test at 40% peak V O^sub 2^ and a high-intensity test at 70% peak V O^sub 2^. Further details are given in the online supplement.
Ethics
Ethical approval for the study was given by the Ethics Committee of the Queen's University of Belfast and the Harbor-University of California at Los Angeles Human Subjects in Research Review Committee. Written informed consent was obtained from all subjects.
Maximal Incremental Protocol
Work-rate increments (Table 1) were individually chosen so as to aim for a total exercise duration in the range 8-12 minutes (23).
Constant Work-Rate Protocol
The work-rates for the high- and low-intensity work-rate tests for each subject (Table 2) were determined from the maximal incremental test. Blood samples for lactate, pyruvate, pH, ammonia, and catecholamines were drawn before exercise, at 3 and 6 minutes of exercise, and after 3 and 6 minutes of recovery.
Gas Analysis
Respired gas exchange was measured throughout. In Belfast a proprietary system was used (Cosmed Quark b^sup 2^, Rome, Italy). The system at Harbor-University of California at Los Angeles used a combination of a volume turbine transducer and mass spectrometer (24). Further details are given in the online supplement.
Analysis of gas exchange data.
Maximal test. Peak exercise variables were calculated by averaging the final 30 seconds of exercise. A gas exchange lactic acidosis threshold was sought using the method of Beaver and coworkers. (25).
Constant work-rate tests. Variables at the end of the exercise tests were determined by averaging the final 30 seconds. Resting measurements were defined as the average of the final 60 seconds of rest. The magnitude of the slow V O^sub 2^ component was assessed by calculating the change in V O^sub 2^ from the end of the third minute to the end of the sixth minute of exercise ([Delta]V O^sub 2^ [6 - 3]) (9). Further details are provided in the online supplement. In patient A.M., who completed only 4 minutes and 54 seconds of exercise at the high-intensity work-rate, the change in V O^sub 2^ was computed from the end of the third minute until the end of exercise. Similar analyses were performed for V E, heart rate, and oxygen-pulse.
Blood sampling and assay. Details are provided in the online supplement.
Statistical Analysis
Results are expressed as median and range or geometric mean and range. Nonparametric statistics were used except for the blood results, which were log-transformed (except pH) before using analysis of variance. Further details are provided in the online supplement.
RESULTS
There were no adverse events during any of the tests. All subjects performed all three tests with the exception of F.K., who did not perform a low constant work-rate test.
Maximal Test
Data for the maximal test are tabulated in Table 1. All subjects cited leg fatigue as the primary cause of stopping exercise. The patients achieved a much lower peak V O^sub 2^ and maximum workrate than the control subjects. A lactic acidosis threshold was identified in all of the control subjects, but we were unable to identify a lactic acidosis threshold in any of the patients.
Low-Intensity Constant Work-rate Test
The work-rates performed during the low-intensity test were lower in patients than in control subjects (Table 2). V O^sub 2^ and V E were significantly lower in the patients than in the control subjects at the end of exercise. However, heart rate was similar in patients and control subjects. The respiratory exchange ratio did not rise from baseline in patients, but there was a small rise in control subjects. In both groups, V O^sub 2^ rose quickly to a plateau by 3 minutes with no significant change thereafter until the end of exercise (Table 2 and Figure 1). Similarly, V E, heart rate and oxygen-pulse reached plateau values before 3 minutes.
Lactate, pyruvate, and the lactate/pyruvate ratio did not rise in patients. In control subjects, lactate rose slightly, but there was no significant rise in pyruvate or the lactate/pyruvate ratio. Venous pH did not change in either group. Plasma levels of ammonia did not rise significantly in either group. Both patients and control subjects had similar maximum levels of norepinephrine and epinephrine (Table 3).
High-intensity Constant Work-rate Test
Again, patients exercised at lower work-rates than control subjects (Table 2). All subjects completed 6 minutes of exercise with the exception of patient A.M., who achieved only 4 minutes and 54 seconds. She cited severe leg fatigue as the reason for limitation of exercise. She achieved a maximum heart rate of 177 beats/minute, close to the predicted maximum of 186 beats/ min, suggesting a near-maximal effort.
Despite much lower V O^sub 2^ at the end of exercise, patients reached a similar maximum heart rate to control subjects. The respiratory exchange ratio rose markedly in control subjects but not in patients (Table 2). V O^sub 2^ continued to rise after 3 minutes until the end of exercise in both patients and control subjects and this is reflected in the positive values for [Delta]V O^sub 2^(6 - 3) (Table 2, Figure 1, and Figure 2). V E rose significantly between the third and sixth minutes of exercise in control subjects, but not in patients. Heart rate rose significantly in both groups over the same period, but there was no significant change in oxygen-pulse in either group.
Lactate, pyruvate, and the lactate/pyruvate ratio did not rise with exercise in the patients, but all three measurements rose significantly in the control subjects. Venous pH fell in the control subjects, but, if anything, rose slightly in the patients. Plasma levels of ammonia were markedly elevated in patients. Both patients and control subjects had similar maximum levels of norepinephrine and epinephrine (Table 4). Figure 2 illustrates the range of values in [Delta]V O^sub 2^(6 - 3) plotted as a function of [Delta]lactate(6 - 3) in patients and control subjects in both low and high constant work-rate tests.
DISCUSSION
We have demonstrated the presence of a slow V O^sub 2^ component during high-intensity constant work-rate exercise in subjects who cannot generate a lactic acidosis. This suggests that the slow V O^sub 2^ component is not caused by lactic acidosis. In contrast, previous studies in normal subjects and patients with heart failure have shown a close relationship between the slow V O^sub 2^ component and lactic acidosis (8-10, 26). Moreover, after endurance training, the slow V O^sub 2^ component is reduced and the reduction closely correlates with the attenuation of the lactate response (27, 28). However, doubt has previously been cast on the possibility of a causal relationship between lactate and the slow V O^sub 2^ component. While lactate infusion may increase V O^sub 2^ in humans (29), its infusion into isolated working dog gastrocnemius muscle failed to result in an increase in V O^sub 2^ (30). In another study, epinephrine was infused into normal human subjects performing heavy exercise. Despite causing a secondary increase in lactate, no augmentation of the slow component was seen (31). Lactate may increase V O^sub 2^ by gluconeogenesis and/or synthesis of glycogen. However, only 3-4% of lactate is thought to be cleared in this way during exercise (11), and this is unlikely to be sufficient to account for more than a minor proportion of the slow V O^sub 2^ component.
A number of other factors have been hypothesized as causing the slow V O^sub 2^ component (32):
1. Ventilation. V E fails to plateau and continues to rise during heavy exercise in a fashion similar to V O^sub 2^. This suggests that increased work of breathing could give rise to the slow V O^sub 2^ component. However, precise quantification of the excess ventilation suggests that no more than 15-20% could be from this source (4). This agrees with invasive studies (3) demonstrating that about 86% of the slow V O^sub 2^ component originates in the exercising limbs. Using magnetic resonance spectroscopy, the slow component has been found to follow a similar lime-course to muscle phosphocreatine depletion, again suggesting that the slow component originates within the exercising muscle (33). Dissociation of the slow components for V E and V O^sub 2^ has been found under hypoxic conditions (34). In the current study, we also demonstrated dissociation of V and V O^sub 2^. There was no significant increase in V E after 3 minutes in our patient group during the high intensity work-rate protocol (Table 2). Our findings support the contention that work of breathing is not the principal cause of the rise in V O^sub 2^.
2. Temperature. An increase in temperature increases V O^sub 2^ and reduces the coupling of adenosine diphosphate to oxygen in isolated rat mitochondria (35). However, artificially increasing muscle temperature throughout an exercise bout was not found to lead to an increase in V O^sub 2^ generally nor to an increase in the slow component (36).
3. Catecholamines. Plasma catecholamines, such as epinephrine and norepinephrine, may increase metabolism. We have previously shown that infusion of the catecholamine arbutamine at rest causes an increase in heart rate, V E, and lactate, along with a small increase in V O^sub 2^, ranging from 110 to 230 ml/minute (37). However, infusion of epinephrine into human subjects performing heavy constant work-rate exercise did not augment the V O^sub 2^ slow component (31).
4. Recruitment of type II muscle fibers. It has been suggested (38-43) that recruitment of type II skeletal muscle fibers to supplement type I fibers may be responsible for the slow V O^sub 2^ component during heavy exercise. Type II fibers may be less efficient than type I fibers in the force generated for a given V O^sub 2^ (35). The magnitude of the slow V O^sub 2^ component is inversely correlated with the percentage of type I slow twitch muscle fibers on muscle biopsy (39) and is augmented under conditions of increased type II fiber activation (41, 44). Recruitment of type II fibers could also be responsible for the observed slow component in our patient group, although we are not aware of any reports examining the types of muscle fiber present in patients with glycolytic enzyme defects.
Lactic acidosis may facilitate the supply of oxygen to working skeletal muscle by causing a rightward shift of the oxyhemoglobin dissociation curve. This Bohr effect is likely to be particularly important during heavy exercise once the partial pressure of O2 reaches a 'floor' level of about 20 mm Hg (45, 46). The Bohr effect cannot explain the excess demand for oxygen by muscle during heavy exercise. Nonetheless, it is possible that dependence of oxygen supply on lactic acidosis might account for the association between lactate and the slow V O^sub 2^ component. However, the current study strongly supports the conclusion that lactic acidosis, whether by facilitating oxygen supply or stimulating demand, is not a prerequisite for the presence of a slow V O^sub 2^ component.
Assuming a normal V O^sub 2^-work-rate relationship of about 10-12 ml/minute/W, we found the V O^sub 2^ in our patient group to be greater than expected, particularly in the high-intensity test (Table 2). Part of the excess at the high work-rate is likely to be related to the presence of a slow V O^sub 2^ component in addition to the V O^sub 2^ expected for the work-rate. However, we have also demonstrated a generally elevated V O^sub 2^-work-rate relationship during incremental exercise in McArdle's disease (47). It is possible that this elevated V O^sub 2^-work-rate relationship is caused, at least in part, by markedly elevated circulatory responses (48) for a given absolute work-rate (see also Table 2). Another contributing factor may be the reliance on lipid oxidation in the patient group (20). Lipid utilization consumes more oxygen than carbohydrate utilization for a given production of high-energy phosphate compounds.
A limitation of our study is the measurement of peripheral venous lactate rather than arterial lactate. Peripheral venous lactate levels may differ from arterial levels (13). However, we measured venous lactate primarily to show that lactate did not rise in our patient group. The absence of rise in lactate is supported further by the mild alkalosis observed during the high-intensity constant work-rate.
The slow V ^sub O2^ component imposes an additional demand for oxygen delivery on the cardiopulmonary system. Patients with cardiac and pulmonary disease often have impaired exercise capacity, and reduction of the slow component could potentially result in a clinical benefit. Identification of the origin of the slow V ^sub O2^ component is clearly desirable. We have shown that the slow V ^sub O2^ component can occur during heavy exercise in the absence of changes in either plasma lactate or pH. We conclude that the slow V ^sub O2^ component at high work-rates is not dependent on a rise in plasma lactate and that another mechanism must be responsible.
Conflict of Interest Statement: H.-Y.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.S.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; V.H.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.P.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.S.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Acknowledgment: The authors are indebted to Prof. I. S. Young, Department of Clinical Chemistry, Royal Victoria Hospital, and to Dr. S. Griffiths, Harbor-University of California at Los Angeles General Clinic Research Center (GCRC) for analyzing the blood samples. The GCRC was supported by Grant M01-RR00425 from the National Institutes of Health-National Center for Research Resources. The authors thank Dr. C. Patterson, Department of Medical Statistics, Queen's University of Belfast, for his expert statistical advice, as well as E. Crawford, B. Martin, D. Wasson, and J. Megarry for their assistance with the exercise tests.
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Hean-Yee Ong, Conor S. O'Dochartaigh, Sharon Lovell, Victor H. Patterson, Karlman Wasserman, D. Paul Nicholls, and Marshall S. Riley
Department of Medicine, Royal Victoria Hospital; Department of Neurology, Royal Victoria Hospital; Department of Respiratory Medicine, Belfast City Hospital, Belfast, Northern Ireland; and Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, Torrance, California
(Received in original form July 17, 2003; accepted in final form March 31, 2004)
Correspondence and requests for reprints should be addressed to Marshall S. Riley, M.D., F.R.C.P., Department of Respiratory Medicine, Belfast City Hospital, Lisburn Rd., Belfast, BT9 7AB, Northern Ireland. E-mail: marshall.riley@bch.n-i.nhs.uk
C.S.O. was in receipt of a Royal Victoria Hospital Research Fellowship.
This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org
Am J Respir Crit Care Med Vol 169. pp 1238-1244, 2004
Originally Published in Press as DOI: 10.1164/rccm.200307-974OC on April 7, 2004
Internet address: www.atsjournals.org
Copyright American Thoracic Society Jun 1, 2004
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