1 Department of Human Biology & Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1; and 2 Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
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ABSTRACT |
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This study investigated whether
hyperoxic breathing (100% O2) or increasing oxidative
substrate supply [dichloroacetate (DCA) infusion] would increase
oxidative phosphorylation and reduce the reliance on substrate
phosphorylation at the onset of high-intensity aerobic exercise. Eight
male subjects cycled at 90% maximal O2 uptake
(O2 max) for 90 s in three
randomized conditions: 1) normoxic breathing and saline
infusion over 1 h immediately before exercise (CON), 2)
normoxic breathing and saline infusion with DCA (100 mg/kg body wt),
and 3) hyperoxic breathing for 20 min at rest and during
exercise and saline infusion (HYP). Muscle biopsies from the vastus
lateralis were sampled at rest and after 30 and 90 s of exercise.
DCA infusion increased pyruvate dehydrogenase (PDH) activation above
CON and HYP (3.10 ± 0.23, 0.56 ± 0.08, 0.69 ± 0.05 mmol · kg wet
muscle
1 · min
1,
respectively) and significantly increased both acetyl-CoA and acetylcarnitine (11.0 ± 0.7, 2.0 ± 0.5, 2.2 ± 0.5 mmol/kg dry muscle, respectively) at rest. However, DCA and HYP did not
alter phosphocreatine degradation and lactate accumulation and,
therefore, the reliance on substrate phosphorylation during 30 s
(CON, 51.2 ± 5.4; DCA, 56.5 ± 7.1; HYP, 69.5 ± 6.3 mmol ATP/kg dry muscle) and 90 s of exercise (CON, 90.6 ± 9.5; DCA, 107.2 ± 13.0; HYP, 101.2 ± 15.2 mmol ATP/kg dry
muscle). These data suggest that the rate of oxidative phosphorylation
at the onset of exercise at 90%
O2 max
is not limited by oxygen availability to the active muscle or by
substrate availability (metabolic inertia) at the level of PDH in
aerobically trained subjects.
pyruvate dehydrogenase activity; oxidative phosphorylation; substrate phosphorylation; 100% oxygen; dichloroacetate; acetylcarnitine
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INTRODUCTION |
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THERE IS STILL CONSIDERABLE DEBATE over what limits the rate of oxidative phosphorylation during the transition from rest to exercise. The initial rate of ATP hydrolysis exceeds the rate of ATP production from oxidative phosphorylation (2, 20, 33). This transient shortfall in oxidative ATP supply, often termed the O2 deficit, is provided by substrate phosphorylation. Glycolytic ATP production with lactate formation and the breakdown of phosphocreatine (PCr) are the major sources of substrate phosphorylation. Two explanations for the apparent lag in aerobic energy production at the onset of exercise have been proposed (for review, see Ref. 37). The first suggests that a "metabolic inertia," including lags in enzyme activation or substrate availability, requires a certain amount of time to produce the reducing equivalents needed to drive the electron transport chain. The second theory suggests that a suboptimal oxygen supply limits the production of ATP in the mitochondria of some muscle fibers.
The possibility that metabolic inertia may exist at the level of pyruvate dehydrogenase (PDH) has been investigated by examining the effects of dichloroacetate (DCA) infusion on skeletal muscle metabolism during exercise (12, 18, 19, 26, 35, 36). DCA infusion at rest causes an inhibition of PDH kinase and increased transformation of PDH to its nonphosphorylated, active form (PDHa) (39). This elevated PDH activation increases the provision of acetyl-CoA during the onset of low- and moderate-intensity exercise and decreases the reliance on substrate level ATP production, implying an increased rate of oxidative phosphorylation (18, 26, 35, 36). Therefore, these studies concluded that metabolic inertia limits the rate of oxidative phosphorylation during the onset of light- and moderate-intensity exercise (19, 35).
However, the effects of DCA infusion on human muscle metabolism during
high-intensity aerobic exercise have not been investigated and may be
of interest for two reasons. First, the requirement for substrate
phosphorylation is greater after the onset of exercise at higher
intensities [i.e., 90 vs. 65% maximal O2 uptake
(O2 max)] (20),
suggesting that DCA may have a greater effect at intense power ouputs.
Second, DCA caused only a 35% reduction in substrate phosphorylation
after the onset of exercise at 65%
O2 max, suggesting that other factors,
such as oxygen availability, may be limiting the rate of oxidative
phosphorylation in some muscle fibers. This effect may be exacerbated
at high power outputs, as hyperoxia has been shown to accelerate
O2 kinetics at the onset of exercise
above the ventilatory threshold (~78-82%
O2 max) while having no effect at
moderate (below ventilatory threshold) power outputs (24,
25). Most investigations examining the existence of an
O2 limitation at the onset of intense exercise have relied
on estimations of energy demand and whole body
O2 kinetics measured at the mouth, an
indirect estimation of muscle O2 phosphorylation. By use of
another approach that directly measured muscle substrate
phosphorylation, hyperoxia decreased PCr use and lactate accumulation
after 4-5 min of exercise (22, 23). However, similar
measurments were not made during the onset of intense aerobic exercise
in these studies.
This study was designed to investigate whether activating PDH before
exercise (DCA infusion) or breathing 100% oxygen would increase
oxidative phosphorylation more rapidly during the onset of exercise at
90% O2 max, as indicated by a decrease in skeletal muscle substrate phosphorylation. We hypothesized that both
DCA infusion and hyperoxia would reduce substrate phosphorylation (O2 deficit) at the onset of intense aerobic exercise. In
both cases, we directly measured muscle substrate phosphorylation (PCr degradation and lactate accumulation) and assumed a reciprocal relationship with oxidative phosphorylation.
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METHODS |
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Subjects.
Eight healthy, aerobically trained males, who regularly engaged in at
least three aerobic training sessions per week (mainly running and
cycling exercise), volunteered to participate in this study. Their mean
(±SE) age, height, weight, and O2 max were 23.6 ± 0.3 yr, 179.8 ± 0.7 cm, 75.7 ± 0.9 kg,
and 54.2 ± 0.9 ml · kg
1 · min
1,
respectively. Before participating, subjects completed health histories, the experimental procedures and potential risks of the study
were explained, and written informed consent was received. The study
was approved by the human ethics committees of the University of Guelph
and McMaster University.
DCA. DCA (monosodium salt) was obtained from TCI America (Portland, OR). It was prepared under sterile conditions at a concentration of 1 mg/ml (pH 7.0), and the concentration and purity were verified by HPLC. It was delivered intravenously to subjects in the dose of 100 mg/kg body wt using ~500 ml of normal saline solution over the course of 1 h immediately before exercise.
Preexperimental protocol.
Subjects underwent a continuous incremental exercise test on an
electonically braked cycle ergometer (Excalibur, manufactured by Lode
and distributed by Quinton Instruments, Seattle, WA) to determine their
O2 max using a metabolic cart
(SensorMedics model 2900, Yorba Linda, CA). From these values, the
power output required to elicit 90%
O2 max was calculated (273 ± 5 W). To familiarize the subjects with the experimental protocol, they
reported to the laboratory on a separate day, rested for 20 min while
breathing through a headgear-supported mouthpiece, and cycled with the
headgear for 5 min to confirm the 90%
O2 max power output. Subjects were
instructed to refrain from strenuous physical activity on the day
before and the day of the experiments and to consume the same diet (no
alcohol) before each trial.
Experimental protocol.
On 3 experimental days, each separated by 1 wk, subjects arrived at
the laboratory having consumed the same meal 2-4 h before the the
start of the study. The three experimental conditions were
1) breathing room air with a saline infusion (control trial, CON), 2) breathing room air with a DCA infusion (DCA), and
3) breathing 100% oxygen with a saline infusion (hyperoxia
trial, HYP). The order of the trials was randomized, and the subjects were blind to the treatments. On each experimental day, a catheter was
inserted into the antecubital vein 1 h before exercise, and a
500-ml infusion of saline or DCA with saline was started while the
subjects rested on a bed (Fig. 1). During
this hour, subjects had one leg prepared for needle biopsies, with
three incisions made through the skin superficial to the vastus
lateralis muscle under local anesthesia (2% lidocaine without
epinephrine) as previously described (4). Beginning 20 min
before the start of exercise and lasting until the end of exercise,
subjects inspired either room air or hyperoxic (100% O2)
gas. Immediately before exercise, the infusion was stopped, the venous
catheter was removed, and a resting muscle biopsy was taken. The
subject then moved to the cycle ergometer and began pedaling at 90%
O2 max, leading with the biopsied leg
from an initial 90° angle to the ground. Exercise biopsies were taken
at 30 and 90 s while the subject remained on the cycle ergometer.
The stop time to take the 30-s biopsy was fixed at 30 s in all
trials. Muscle biopsies were immediately frozen in the needle in liquid
N2, removed, and stored in liquid N2 until
analysis.
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Analyses.
A small piece of frozen muscle (8-15 mg) was removed under liquid
N2 for the determination of PDH activity in its active form (PDHa), as described by Putman et al. (29). Total creatine
(Cr) contents were measured for each muscle homogenate, and PDHa values were corrected to the highest total Cr value in the nine biopsies from
a given subject. The remainder of the biopsy sample was freeze-dried, dissected of all visible blood, connective tissue, and fat, powdered, and stored at 80°C for subsequent analysis.
Calculations.
Free ADP and AMP concentrations were calculated assuming equilibrium of
the creatine kinase and adenylate kinase reactions (8).
Free ADP was calculated using the measured ATP, PCr, and Cr contents, a
H+ concentration estimated from the muscle lactate content
(31), and the creatine kinase equilibrium constant of
1.66 × 109. Free AMP was calculated from the measured
ATP, the estimated free ADP, and the adenylate kinase equilibrium of
1.05. Free inorganic phosphate (Pi) was calculated by
adding the estimated resting Pi of 10.8 mmol/kg dry muscle
(8) to the difference in PCr (PCr) minus the
accumulation of glycolytic intermediates G-6-P (
G-6-P) and G-3-P (
G-3-P)
between rest and each exercise time point. Substrate phosphorylation
(mmol ATP/kg dry muscle) was determined for each treatment during
0-30 and 30-90 s by adding the PCr degradation and 1.5 times
the lactate accumulation (34).
Statistics. All data are presented as means ± SE. For metabolite contents, a 2-way ANOVA (time × trial) with repeated measures was used to test for significance. For glycogen content and substrate phosphorylation, a one-way ANOVA with repeated measures was used. Significance was set at P < 0.05, and Tukey's post hoc test identified where significant differences occurred.
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RESULTS |
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PDH activation.
In the CON trial, PDHa increased dramatically from rest during the
initial 30 s of exercise at 90%
O2 max and to a lesser extent during
the 30- to 90-s period (Fig. 2). Resting and exercise PDHa values were unaffected by breathing 100% oxygen. However, DCA infusion markedly increased resting PDHa activity in the
hour preceding exercise compared with the CON and HYP trials, as
expected (Fig. 2). In the DCA trial, PDHa remained higher than the CON
and HYP trials at 30 s. In the final 60 s of exercise, PDHa
decreased significantly from the resting value in the DCA trial, such
that it was not different from CON and HYP at 90 s (Fig. 2).
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Muscle metabolites.
There were no significant differences in ATP content among the trials
or during exercise (Table 1). PCr
decreased significantly from ~85-90 mmol/kg dry muscle at rest
to ~50-60 mmol/kg dry muscle at 30 s and ~40 mmol/kg dry
muscle at 90 s of cycling at 90%
O2 max in all three trials (Fig.
3). Free ADP, AMP, and Pi
accumulations were not significantly different among trials at any time
(Table 1). Free ADP content increased significantly by 30 s of
exercise and continued to increase at 90 s in all trials. Free AMP
increased during exercise and was significantly higher by 90 s in
all trials. The 30-s free Pi values were markedly higher
than the arbitrary resting value in all trials and accumulated further
in the CON and DCA trials at 90 s (Table 1).
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Substrate phosphorylation.
There was no significant difference in the calculated substrate
phosphorylation during the 0- to 30-, 30- to 90-, and 0- to 90-s
exercise periods between the trials (Table
2).
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DISCUSSION |
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At the onset of submaximal exercise, a transient mismatch between
the required ATP and oxidative phosphorylation necessitates that
skeletal muscle rely on substrate phosphorylation to supplement oxidative ATP synthesis. It has been proposed that either a metabolic limitation, including lags in enzyme activation or substrate
availability, and/or an oxygen availability limitation explains why
oxidative phosphorylation does not turn on quicker at the onset of
aerobic exercise. To investigate these possibilities, this study
examined the response of human skeletal muscle metabolism to both
enhanced oxidative substrate supply (DCA infusion) and O2
delivery (hyperoxia) at the onset of exercise at 90%
O2 max. It was hypothesized that both
perturbations would increase oxidative ATP production and consequently
result in a decreased reliance on substrate phosphorylation. However,
the contribution of ATP from substrate phosphorylation at the onset of
exercise, as measured from PCr degradation and lactate accumulation,
was unaffected by DCA infusion or hyperoxia. This implies that
oxidative phosphorylation is not limited by metabolic inertia at the
level of PDH or by O2 delivery to muscle during the
transition from rest to exercise at 90%
O2 max.
DCA infusion.
DCA inhibits the activity of PDH kinase and therefore increases the
amount of PDHa (39). In the present study, DCA infusion increased resting muscle PDHa to levels previously reported during intense aerobic exercise (11, 20) and increased the muscle contents of acetyl-CoA and acetylcarnitine well above the CON condition. PDHa remained significantly higher for the initial 30 s
of exercise at 90% O2 max in the DCA
trial and decreased slightly to match the CON value at 90 s. We
also reported this finding at 65%
O2 max (19) and believe it
is a function of powerful exercise-related regulators overriding the
effect of DCA on the control of PDH activation during exercise,
resulting in PDHa levels that match the control condition. The key
finding of the DCA infusion was that, despite the potential for
increased acetyl-CoA availability early in exercise, no difference in
the reliance on substrate phosphorylation and, by inference, oxidative phosphorylation was found. In fact, acetyl-CoA remained at the elevated
preexercise level, and acetylcarnitine accumulated during the 90 s
of cycling in the DCA trial.
Hyperoxic gas breathing.
We hypothesized that the rate of increase in oxidative phosphorylation
at the onset of intense aerobic exercise may be limited in some muscle
fibers by the supply of oxygen. Breathing 100% O2 has the
potential to increase both the convective and diffusive delivery of
oxygen to the active muscle. Increased O2 provision may
increase the rate of muscle oxidative phosphorylation and subsequently
reduce the reliance on substrate phosphorylation. However, substrate
phosphorylation was not attentuated in the HYP trial, and we concluded
that O2 availability does not limit O2 uptake
during the initial 90 s of exercise at 90%
O2 max.
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ACKNOWLEDGEMENTS |
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This study was supported by the Natural Sciences and Engineering and the Medical Research Councils of Canada. I. Savasi was supported by a Natural Sciences and Engineering Research Council scholarship and a Gatorade Sport Sciences Institute student award.
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. L. Spriet, Dept. of Human Biology and Nutritional Sciences, Univ. of Guelph, Guelph, ON, N1G 2W1 Canada (lspriet{at}uoguelph.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00337.2001
Received 26 July 2001; accepted in final form 12 February 2002.
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