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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 4 1733-1738
Copyright © 2004 by The Endocrine Society

Dichloroacetate Therapy Attenuates the Blood Lactate Response to Submaximal Exercise in Patients with Defects in Mitochondrial Energy Metabolism

G. E. Duncan, L. A. Perkins, D. W. Theriaque, R. E. Neiberger and P. W. Stacpoole

Department of Epidemiology, Nutritional Sciences Program, University of Washington (G.E.D.), Seattle, Washington 98195; and Departments of Medicine (L.A.P., P.W.S.), Pediatrics (R.E.N.), and Biochemistry and Molecular Biology (P.W.S.), and General Clinical Research Center (D.W.T.), University of Florida, Gainesville, Florida 32610

Address all correspondence and requests for reprints to: Dr. G. E. Duncan, 305 Raitt Hall, Box 353410, University of Washington, Seattle, Washington 98195. E-mail: duncag{at}u.washington.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We determined acute and chronic effects of dichloroacetate (DCA) on maximal (MAX) and submaximal (SUB) exercise responses in patients with abnormal mitochondrial energetics. Subjects (n = 9) completed a MAX treadmill bout 1 h after ingesting 25 mg/kg DCA or placebo (PL). A 15-min SUB bout was completed the next day while receiving the same treatment. After a 1-d washout, MAX and SUB were repeated while receiving the alternate treatment (acute). Gas exchange and heart rate were measured throughout all tests. Blood lactate (Bla) was measured 0, 3, and 10 min after MAX, and 5, 10, and 15 min during SUB. MAX and SUB were repeated after 3 months of daily DCA or PL. After a 2-wk washout, a final MAX and SUB were completed after 3 months of alternate treatment (chronic). Average Bla during SUB was lower (P < 0.05) during both acute (1.99 ± 1.10 vs. 2.49 ± 1.52 mmol/liter) and chronic (1.71 ± 1.37 vs. 2.39 ± 1.32 mmol/liter) DCA vs. PL despite similar exercise intensities between conditions (~75 and 70% maximal exercise capacity during acute and chronic treatment). Thus, although DCA does not alter MAX responses, acute and chronic DCA attenuate the Bla response to moderate exercise in patients with abnormal mitochondrial energetics.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PATIENTS WITH INBORN errors of mitochondrial energetics are characterized by progressive neuromuscular deterioration and accumulation of lactate and hydrogen ions in body tissues and fluids (1). Inherited or spontaneous mutations that occur in the pyruvate dehydrogenase complex (PDC) or in one or more enzymes of the respiratory chain ultimately result in diminished cellular oxidative metabolism. Consequently, exercise intolerance is a major clinical feature in these patients (1, 2, 3, 4, 5, 6, 7).

Treatment of patients with abnormal mitochondrial energetics has generally centered on providing alternate dietary substrate fuels, vitamins, or other cofactors that might stimulate residual enzyme activity or circumvent the primary enzyme defect (8). Dichloroacetate (DCA) has also been used experimentally because it stimulates PDC and accelerates the oxidation of glucose, lactate, and pyruvate to acetyl-coenzyme A (8, 9). Previous studies in patients with acquired or congenital lactic acidosis have shown significant reductions in circulating blood lactate levels (Bla) within a few hours of the initial dose (8, 9). Because DCA exerts multiple effects on pathways of intermediary metabolism (10), it may be a rational therapy for improving the exercise intolerance common in patients with defects in mitochondrial energetics.

Studies in healthy volunteers demonstrate that DCA significantly reduces Bla during exercise (11) and the rest to work transition (12), and significantly increases oxygen uptake at the individual anaerobic threshold and at maximal exercise capacity (VO2peak) (13). However, the effect of DCA treatment on exercise intolerance in patients with defects in mitochondrial energetics has not been systematically investigated. Short-term oral DCA administration to patients with mitochondrial disorders reduced Bla during (7, 14) and after (7, 15) exercise, but did not affect maximal workload or VO2peak responses (7). In an open-label study of a patient with cytochrome oxidase deficiency (2), a combination of aerobic training and DCA led to marked improvements in Bla at rest and after exercise and in estimated VO2peak. Furthermore, exercise training alone in 10 patients with various mitochondrial DNA mutations increased peak work, oxidative capacities, and markers of muscle oxidative phosphorylation (3). Together, these findings suggest that exercise intolerance in patients with mitochondrial disorders may arise because of the combined effects of the primary mitochondrial disorder and chronic deconditioning.

The primary objective of this study was to determine the acute and chronic effects of DCA treatment on maximal (MAX) and submaximal (SUB) exercise responses in patients with abnormal mitochondrial energetics. Specifically, we tested the hypothesis that DCA, compared with placebo (PL), significantly increases VO2peak and maximal power output during graded exercise in patients with mitochondrial disorders. We also tested the hypothesis that DCA, compared with PL, significantly reduces the average Bla and increases the average power output during submaximal exercise in these patients.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Human subjects

Patients with abnormal mitochondrial energetics due to congenital defects in PDC or respiratory chain complexes were recruited to take part in this study. Recruitment was accomplished primarily through the CLA-DCA web site (http://cla-dca.gcrc.ufl.edu/) maintained by the General Clinical Research Center (GCRC) at University of Florida. Eligibility criteria included 1) biochemical or molecular genetic confirmation of a defect in PDC or one or more Krebs cycle or respiratory chain enzymes, based on results of standard diagnostic studies conducted in freshly isolated peripheral blood leukocytes, cultured skin fibroblasts, or biopsied skeletal muscle; and 2) sufficient neurological and neuromuscular development to perform symptom-limited treadmill exercise. Each patient was admitted to the GCRC for an initial 6- to 7-d period and was screened on the first day of admission for contraindications to study participation and graded exercise testing through a health history questionnaire, physical examination, and standard blood chemistry panels (i.e. hematological, renal, hepatic, and endocrine function tests) (16). Before testing, each patient (and accompanying parent or guardian, if applicable) gave informed consent/assent to participate in the study, which was approved by the institutional review board at University of Florida’s Health Science Center.

Study protocol

On the first day of admission, all patients underwent an orientation trial in which they were familiarized with the exercise testing apparatus and completed a series of short treadmill bouts that consisted of walking at three graded levels for 2 min each. They were also familiarized with Borg’s rating of perceived exertion scale (RPE) (16) and completed a battery of questionnaires [demographic, physical activity recall (17), and SF-36 Health Survey (18)].

On the day of each exercise session (excluding the orientation trial) participants were fed breakfast, which was standardized for each subsequent test, at approximately 0900 h. At about 1120 h, venous blood was sampled through a cannula for measurement of Bla. The cannula was kept patent by frequent flushing with a heparinized saline solution. At approximately 1130 h, a second sample for Bla determination was drawn, and the average of the two measurements was used as the pretreatment value (i.e. baseline). Additionally, blood was drawn for measurement of the basal plasma DCA level. All blood was collected with minimal or no tourniquet pressure in tubes containing sodium fluoride (for Bla) or heparin (for DCA). The tubes were inverted gently, placed on ice, and analyzed immediately by the GCRC Core Laboratory for Bla, or plasma was separated and stored at –70 C for subsequent analysis of DCA (see Measurements below). After this, each participant took the assigned study treatment (see below) and rested quietly for 1 h. At about 1230 h, blood was drawn for measurement of Bla and DCA, and exercise testing was undertaken subsequently.

Exercise testing consisted of two treadmill bouts (MAX and SUB) performed on consecutive days while subjects received either oral DCA or PL (25 mg/kg) (19), administered randomly in a double-blind fashion. To safeguard against potential DCA toxicity, each study treatment was supplemented with oral thiamine (5 mg/kg) (19). The exercise tests were paired, such that each participant completed a graded exercise test to measure VO2peak and maximal power output on 1 d (MAX) and a 15-min work bout to measure submaximal exercise responses on the next day (SUB). Each of these tests was completed while the patient was receivng the same study treatment. A 1-d washout period followed the first pair of exercise tests. After this, patients who had completed MAX and SUB crossed over to the other study treatment (acute phase).

After completing the acute phase of the study, patients continued on a daily regimen of either DCA or PL for 3 months. During a second GCRC admission, patients repeated MAX and SUB under identical conditions, as described previously, while continuing the prescribed study treatment. After a 2-wk washout, patients crossed over to the other study treatment for 3 months and returned to the GCRC for a final admission to complete MAX and SUB (chronic phase).

All MAX bouts consisted of symptom-limited, graded treadmill exercise performed to volitional fatigue. The testing protocol began with slow walking at 21.44 m/min–1, 0% grade, for 1 min. Thereafter, treadmill velocity and/or grade was increased every minute. Each stage was designed to increase metabolic rate by 0.5 metabolic equivalents (16). The absolute workload for SUB was designed to elicit 65% VO2peak, based on the value measured the previous day, estimated from a standard prediction equation (16). Absolute VO2 (liters per minute–1) was monitored closely during the initial 3 min of SUB, and treadmill velocity and/or grade were adjusted if necessary to achieve the target level. Thereafter, treadmill velocity and grade were kept constant throughout the remainder of the exercise bout.

Measurements

Pulmonary gas exchange was measured continuously during each exercise test, and all metabolic variables were calculated using a 30-sec data-averaging technique with a metabolic cart (TrueMax 2400, ParvoMedics, Inc., Sandy, UT). Pulmonary ventilation (VE – liters per minute–1) was measured by a pneumotach that was calibrated daily, and fractions of O2 and CO2 were determined via analyzers that were calibrated with gases of known concentration before each test. Heart rate (HR), measured by 12-lead electrocardiography, was also monitored continuously during each exercise test. During MAX, the average of the last two consecutive 30-sec values was considered the VO2peak. Power output (total treadmill work performed divided by time, expressed in watts) was calculated for each stage, and HR and RPE were recorded at the end of each stage. Blood was drawn at 0, 3, and 10 min after MAX. The highest calculated or recorded values for VO2, power, HR, RPE, and Bla were considered the peak values for data analysis purposes. During SUB, the average of the two 30-sec values measured at 5, 10, and 15 min (e.g. average of values measured at 14.5 and 15.0 min of each test) was calculated. The relative exercise intensity (i.e. %VO2peak) for the entire 15-min SUB bout was considered the average of values measured at 5, 10, and 15 min. Similarly, power, HR, RPE, Bla, and blood pressure, measured using standard auscultation, were calculated or recorded at 5, 10, and 15 min. The average of the values for these time points was used for data analysis purposes.

An automated analyzer (YSI, Inc., Yellow Springs, OH) was used to measure venous whole Bla. Each sample was measured in duplicate, and the average value for each collection time point was used for subsequent data analysis. Quality control for this instrument included a daily calibration using three standards (low, 0.5–1.0 mmol/liter; medium, 2.5–3.1 mmol/liter; high, 7.2–8.6 mmol/liter). Samples were also sent to an independent laboratory (Nova Biomedical, Waltham, MA) as part of the quality assurance program. The cumulative mean ± SD and coefficient of variation of the standards within the calibration range for this instrument between January and December 2001 were: low, 0.8 ± 0.01 and 0.00; medium, 2.6 ± 0.04 and 1.59; and high, 7.2 ± 0.06 and 0.81. Plasma DCA levels were determined by gas chromatography after derivatization to the methyl ester (19). The intra- and interday coefficients of variation of the standards within the entire calibration range were between 0.3 and 14.5%.

For all body mass index (kilograms per meter squared) measurements, height was measured using a wall-mounted stadiometer, and weight was determined on a balance beam scale with shoes removed. Skinfold thicknesses were measured as an index of total body fat. In patients over 18 yr of age, percent body fat was estimated using age- and sex-adjusted equations based on the sum of three skinfolds (sites for women included triceps, supraillium, and thigh; sites for men included chest, abdomen, and thigh) (20). In younger patients, percent body fat was estimated using equations appropriate for age, sex, and race, based on tricep and subscapular skinfold measurements (21). Each skinfold was measured three times on the right side of the body using a Lange caliper, and the average value was used for subsequent analysis.

Chronic DCA is known to cause reversible peripheral neuropathy and elevated serum transaminase levels in some patients (10), although these also occur frequently as complications of genetic mitochondrial diseases. Therefore, at each admission we also obtained routine serum tests of hepatic function and performed nerve conduction velocity (NCV) testing in all subjects.

Statistical analysis

This was a double-blind, PL-controlled, cross-over study to determine the acute and chronic effects of DCA on MAX and SUB exercise responses in patients with abnormal mitochondrial energetics. Outcome measures were analyzed separately for MAX (peak values for VO2, power, Bla, HR, and RPE) and SUB (average values for Bla, power, HR, RPE, and blood pressure) by ANOVA, using the factors treatment and period. For the chronic study phase, the factors included treatment (DCA and PL) and period (baseline, 3 months, and 6 months). It was assumed that washout was complete 24 h after administration of the first study treatment. The orientation/familiarization period was performed before administration of the first study treatment to minimize the effect of learning on the outcome measures. All tests were two-sided and carried out at {alpha} = 0.05. Subjects were randomized to one of two treatment sequences: DCA/PL or PL/DCA. Statistical power calculations were carried out based on a sample size of 10, a power of 0.80, {alpha} = 0.05, and an assumed SD of 3.08 ml·min–1·kg–1 for the paired DCA/PL VO2peak differences (13) (based on 0.80 within-subject correlation), allowing us to detect a difference of approximately 3.0 ml·min–1·kg–1 between the DCA and PL treatment groups. Data are presented as the mean ± SD. SAS statistical software, version 8 (SAS Institute, Inc., Cary, NC), was used to perform the analyses.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go summarizes the clinical characteristics of the nine subjects who participated in the trial. All subjects complained of exercise intolerance, sometimes associated with vomiting, leg pain, or profound fatigue after mild exertion. Four patients (a mother, her brother, and her two sons) had a T to A substitution at nucleotide position 9997 (T9997A) in the tRNA glycine gene encoded by mitochondrial DNA. This was associated in three of the family members with enzymological evidence, obtained in cultured skin fibroblasts, of a partial deficiency in complex IV of the respiratory chain. One patient had symptoms of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes due to an A3243G mutation in the tRNA leucine gene. Two unrelated subjects had maternally inherited deficiencies of complex V (ATP synthase), one of which was localized to position 8993 in mitochondrial encoded subunit 6 of ATP synthase. One patient had a generalized decrease in respiratory chain activity, and another patient had a deficiency in PDC activity.


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  		TABLE 1. Descriptive characteristics for nine patients with abnormal mitochondrial energetics

 
Plasma DCA levels measured 1 h after administration of the study treatment (time zero) increased significantly (all P < 0.01) from the pretreatment values (–60) on each MAX and SUB test day during both acute and chronic DCA administration. There were no measurable levels of DCA in plasma at any time point during similar PL treatment. For MAX, the changes from baseline in plasma DCA were 57.2 ± 21.3 and 85.0 ± 85.9 µg/ml during acute and chronic treatment conditions, respectively. Similarly, for SUB the changes from baseline in plasma DCA were 47.4 ± 23.1 and 70.7 ± 32.2 µg/ml during acute and chronic treatment conditions, respectively.

Resting Bla levels measured 1 h after administration of the study treatment (time zero) decreased significantly (all P < 0.05) from the pretreatment values (–60) during acute and chronic DCA administration for MAX (from 1.44 ± 0.99 to 1.19 ± 0.80 mmol/liter and from 1.25 ± 1.18 to 1.05 ± 1.16 mmol/liter for acute and chronic DCA, respectively) and SUB (from 1.42 ± 1.06 to 1.13 ± 0.82 mmol/liter and from 1.12 ± 1.00 to 0.86 ± 0.92 mmol/liter for acute and chronic DCA, respectively). There were no significant changes (all P > 0.05) in resting Bla levels preceding either MAX or SUB during acute or chronic PL treatment. The change in resting Bla levels was significantly different (P < 0.05) between DCA and PL conditions preceding MAX during acute (–0.25 ± 0.36 vs. –0.05 ± 0.36 mmol/liter) but not chronic (–0.20 ± 0.33 vs. –0.17 ± 0.52 mmol/liter) treatment. There were no significant (P > 0.05) differences between DCA and PL with respect to the change in resting Bla levels preceding SUB during either acute or chronic treatment.

Table 2Go illustrates the effects of MAX and SUB on the primary outcome measures during the acute study phase. There were no acute treatment effects (P > 0.05) for DCA compared with PL for any of the MAX outcome measures. However, average Bla during SUB was lower during DCA treatment compared with PL (1.99 ± 1.10 vs. 2.49 ± 1.52 mmol/liter; P = 0.007). This difference occurred despite the fact that patients were exercising at the same relative exercise intensity during both treatment conditions (~75% VO2peak; P > 0.05).


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  		TABLE 2. Primary outcome measures during the acute study phase (n = 9)

 
Table 3Go shows the effects of MAX and SUB on the primary outcome measures during the chronic study phase. Similar to the findings from the acute phase, there were no chronic treatment effects (P > 0.05) for DCA compared with PL for any of the MAX outcome measures. Average Bla during SUB was again lower during DCA treatment compared with PL (1.71 ± 1.37 vs. 2.39 ± 1.32 mmol/liter; P = 0.02; Fig. 1Go). There was also no difference (P > 0.05) in relative exercise intensity between treatment conditions during the chronic study phase (~72 vs. 67% VO2peak for DCA vs. PL, respectively).


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  		TABLE 3. Primary outcome measures during the chronic study phase (n = 9)

 


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  		FIG. 1. Bla before, during, and after submaximal exercise after chronic (3-month) DCA treatment. The average Bla response during submaximal exercise (average of 5, 10, and 15 min) was significantly lower (P = 0.02) during DCA compared with similar PL treatment (1.71 ± 1.37 vs. 2.39 ± 1.32 mmol/liter, respectively). The relative exercise intensities of the treatment conditions (72 vs. 67% VO2peak for DCA vs. PL, respectively) were similar (P > 0.05).

 
Overall, regardless of the testing period, the average Bla was lower during DCA compared with PL treatment during SUB (1.86 ± 1.20 vs. 2.44 ± 1.38 mmol/liter; P = 0.0001) despite the finding that relative exercise intensity was similar between conditions (~74 vs. 70% VO2peak for DCA and PL, respectively).

There were numerous reports of side-effects during the chronic phase of the study, including increased fatigue, shortness of breath, episodes of vomiting and/or gastrointestinal distress, and increased incidence of tremors. Most occurred during DCA administration and were considered mild. However, because of the small sample size, it was not possible to attribute causality unequivocally to drug administration. Serial NCV assessments were unchanged from baseline in five subjects, improved in two subjects, and decreased in two subjects.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Patients with mitochondrial disease commonly have low levels of cardiorespiratory fitness and exercise tolerance. In an early report (5), systematic evaluations of exercise tolerance were performed in 13 individuals with various forms of mitochondrial disorders (e.g. PDC deficiency, carnitine palmitoyl transferase deficiency, and ragged red fiber myopathies) using graded treadmill testing. In these patients, who had metabolic defects characteristic of our subjects, VO2peak ranged between 9.0 and 41.4 ml·min–1·kg–1, or approximately 26–84% of age- and sex-predicted normal values (5). Our results are consistent with this report in that VO2peak ranged between 9.4 and 44.2 ml·min–1·kg–1, or roughly 28–100% of age- and sex-predicted normal values, as defined as the 50th percentile of Cooper Clinic standards (22). In another report (21), 26 patients with mitochondrial myopathies had 33% lower VO2peak values during treadmill testing than healthy control subjects with similar anthropometric characteristics (27 ± 8 vs. 40 ± 7 ml·min–1·kg–1). Finally, Taivassalo and colleagues (4) recently reported significantly lower, and highly variable, VO2peak values during cycle ergometry for 40 patients with biochemically or molecularly defined mitochondrial myopathy compared with healthy, sedentary subjects [16 ± 8 (range, 6–47 ml·min–1·kg–1) vs. 32 ± 7 ml·min–1·kg–1]. Thus, the VO2peak values measured in our subjects are similar to those reported in the literature and are consistent with deficient cardiorespiratory fitness levels and a wide spectrum of exercise intolerance.

Despite an extended 3-month daily regimen of DCA, neither maximal power output nor maximal aerobic power (VO2peak) was increased above that measured for similar PL treatment. Thus, our results are consistent with the idea that chronic DCA administration does not improve MAX exercise responses in patients with genetic mitochondrial defects, as reported previously (7, 15).

It is well established that DCA administration lowers Bla levels at rest in subjects with (7, 8, 9, 10, 14, 15, 23) and without (11, 13) mitochondrial disease. Furthermore, several reports have substantiated that DCA administration attenuates the normal Bla increase during SUB exercise in animals (24, 25, 26, 27) and in human subjects with (7, 14) and without (11, 13) mitochondrial disease. In addition, Taivassalo and colleagues (2) found that Bla levels at rest and after a constant amount of work decreased by approximately 50% after 8 wk of aerobic training alone and by a further 20% with continued training and the addition of DCA, administered at a dose of 25 mg/kg twice daily for 6 wk, in a 25-yr-old woman with cytochrome oxidase deficiency. Our results extend these observations and demonstrate that both acute and chronic DCA administration significantly reduce Bla at rest and attenuate the Bla response to a continuous bout of moderate intensity exercise in patients with mitochondrial disorders. In contrast to some reports (7, 15), we did not find that Bla was significantly reduced after MAX exercise during either acute or chronic DCA administration. However, it is difficult to compare our study directly to other studies because of differences in study design, the dosage and duration of DCA administered, the exercise test modalities and protocols used, and the blood sampling time points during and after exercise.

Mechanisms accounting for exercise intolerance in patients with inborn errors of mitochondrial energy metabolism include disruptions in the normal regulation of cardiac output and ventilation, relative to muscle metabolic rate, that arise from impaired oxidative phosphorylation in the working musculature (28), chronic muscle weakness (29), and specific defects in protein-coding genes of mitochondrial DNA, including mutations in genes for respiratory chain complexes I, III, and IV (30, 31). Chronic deconditioning probably also contributes to exercise intolerance and low cardiorespiratory fitness levels in patients with mitochondrial disease, although its significance is often overlooked, as suggested by the findings of previous reports (2, 3, 32). Interestingly, the addition of DCA therapy and continued aerobic training led to further improvements in exercise tolerance in the case report presented by Taivassalo et al. (2). Improved exercise endurance by DCA administration alone was first suggested in a study (25) demonstrating that rats treated with DCA were able to swim 40% longer and maintain higher muscle glycogen levels after exhaustive exercise than controls, and that DCA-treated rats had longer run times than controls (27).

Although lactic acidosis is probably not the factor limiting MAX exercise tolerance in patients with mitochondrial disease, as suggested by our findings and a previous report (7), elevated Bla levels may contribute to diminished exercise capacity during prolonged SUB exercise. For example, increased plasma lactate levels during exercise were attributed to an enhanced breakdown of muscle glycogen, promoted by an exaggerated catecholamine response, in patients with mitochondrial disease compared with sedentary control subjects (33). Increased lactic acid production decreases the total ATP yield produced from glycogen compared with the complete aerobic breakdown of glycogen, which results in a more rapid depletion of glycogen stores and subsequent negative consequences on endurance performance (34). Chronic DCA administration profoundly lowered Bla levels during short-term, moderate intensity exercise compared with similar PL treatment in our subjects despite the fact that exercise was performed at similar relative exercise intensities during both conditions. The lower Bla levels during exercise after DCA administration could potentially help to preserve glycogen stores and thus promote sustained SUB exercise. Furthermore, the level of exercise performed by our subjects during SUB is consistent with recommendations for making improvements in cardiorespiratory fitness and other health-related measures (16). Together, these and related data (2) indicate that the combination of DCA and moderate intensity aerobic training may be a viable treatment regimen for targeting exercise intolerance in patients with mitochondrial disorders affecting energy production, although this suggestion will require additional prospective studies before definitive recommendations can be made.

The potential benefits of DCA, with or without aerobic training, must be weighed against the potential side-effects of the drug. There were numerous adverse reports during the course of the chronic phase of the study that were directly attributable to DCA, including increased fatigue, shortness of breath, episodes of vomiting and/or gastrointestinal distress, and increased incidence of tremors, although NCV assessments were decreased in only two subjects. However, contrary to the reports of increased fatigue in some subjects, others reported feeling as if they had more energy and were able to accomplish more work. Although we administered a physical activity questionnaire and the SF-36 to quantify changes in health status, the overall small sample size and number of children precluded us from directly quantifying changes in habitual physical activity and health status to corroborate these anecdotal positive reports. We further acknowledge that the heterogeneous defects presented by our subjects preclude us from generalizing our findings to all patients with mitochondrial disease. Future studies could address these limitations by examining these issues in a larger, more homogenous patient group.

In summary, our results demonstrate that acute and chronic DCA treatments, administered in a single dose of 25 mg/kg, attenuate the normal Bla increase in response to moderate to heavy intensity exercise, but has no affect on maximal aerobic power or cardiorespiratory fitness levels, in patients with inborn errors in mitochondrial energy production. Based on our results and those of previous reports, the combination of DCA therapy and regular aerobic training may prove useful in targeting exercise intolerance in this patient group.


   Acknowledgments
 
We thank the participants for their dedication, the General Clinical Research Center staff for their support, Ms. Margaret Francis, ARNP, for coordinating patient testing and reporting adverse events, and Mr. Larry Shroads, B.S., for performing the DCA analyses.


   Footnotes
 
This work was supported by American Heart Association Grant 9920174V and NIH Grants ES-07355 and RR-00082.

Abbreviations: Bla, Blood lactate; DCA, dichloroacetate; HR, heart rate; MAX, maximal; NCV, nerve conduction velocity; PDC, pyruvate dehydrogenase complex; PL, placebo; RPE, rating of perceived exertion scale; SUB, submaximal; VO2peak, maximal exercise capacity.

Received September 26, 2003.

Accepted January 20, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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