Pyruvate dehydrogenase activation in inactive muscle during and after maximal exercise in men

C. T. Putman1, M. P. Matsos1, E. Hultman2, N. L. Jones1, and G. J. F. Heigenhauser1

1 Department of Medicine, McMaster University Medical Centre, Hamilton, Ontario, Canada L8N 3Z5; and 2 Department of Clinical Chemistry, Huddinge University Hospital, Karolinska Institute, S-141 86 Huddinge, Sweden


    ABSTRACT
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Abstract
Introduction
METHODS
RESULTS
DISCUSSION
References

Pyruvate dehydrogenase activity (PDHa) and acetyl-group accumulation were examined in the inactive deltoid muscle in response to maximal leg exercise in men. Seven subjects completed three consecutive 30-s bouts of maximal isokinetic cycling, with 4-min rest intervals between bouts. Biopsies of the deltoid were obtained before exercise, after bouts 1 and 3, and after 15 min of rest recovery. Inactive muscle lactate (LA) and pyruvate (PYR) contents increased more than twofold (P < 0.05) after exercise (bout 3) and remained elevated after 15 min of recovery (P < 0.05). Increased PYR accumulation secondary to LA uptake by the inactive deltoid was associated with greater PDHa, which progressively increased from 0.71 ± 0.23 mmol · min-1 · kg wet wt-1 at rest to a maximum of 1.83 ± 0.30 mmol · min-1 · kg wet wt-1 after bout 3 (P < 0.05) and remained elevated after 15 min of recovery (1.63 ± 0.24 mmol · min-1 · kg wet wt-1; P < 0.05). Acetyl-CoA and acetylcarnitine accumulations were unaltered. Increased PDHa allowed and did not limit the oxidation of LA and PYR in inactive human skeletal muscle after maximal exercise.

acetylcarnitine; acetyl-coenzyme A; lactate metabolism


    INTRODUCTION
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Abstract
Introduction
METHODS
RESULTS
DISCUSSION
References

DURING HEAVY EXERCISE, the active muscles produce large amounts of lactate (28). Some of the lactate produced remains in the active muscle mass, where it is eventually metabolized, and as much as 800 mmol of lactate is transported to the extracellular fluid space (21), redistributed, and metabolized by other tissues, including adipose tissue, liver, kidney, heart, and the inactive muscle mass (14). An important contributor in the rapid metabolic disposal of excess lactate is the inactive skeletal muscle mass (1, 2, 4), indicating an important role for this tissue in relieving the acid-base and osmotic disturbances associated with a large lactate load (19, 21).

The potential routes of lactate metabolism in inactive muscle include glyconeogenesis, oxidation, lipogenesis, conversion to amino acids, and incorporation into the protein pool (14). The two quantitatively important metabolic routes are glyconeogenesis (7, 16, 27) and oxidation (1, 7, 22, 25), but considerable controversy still exists regarding their relative importance in the removal of lactate by inactive skeletal muscle (14). Although increases in glycogen synthesis have been reported in muscle recovering from exercise (3, 7, 27), during lactate infusion (24), and with incorporation of labeled lactate into glycogen (7), recent studies have shown that the major fate of lactate taken up by inactive muscles is oxidation (19, 21). Furthermore, tracer studies have consistently reported that the primary fate of infused lactate is oxidation (7, 22, 25).

In inactive muscle, the pyruvate dehydrogenase (PDH)-catalyzed conversion of pyruvate to acetyl-CoA is a potential rate-limiting step in lactate oxidation (28). In addition, the temporary conversion of acetyl-CoA to acetylcarnitine represents a further means of metabolic lactate disposal that becomes increasingly important when the rate of acetyl-CoA production is greater than its rate of oxidation by the tricarboxylic acid (TCA) cycle (11, 13, 28). To date, PDH complex (PDHc) transformation to PDH activity (PDHa) and changes in acetyl-group accumulation in response to lactate uptake by inactive skeletal muscle have not been studied. In the present study, we used an established model of repeated maximal isokinetic cycling that is known to induce large and prolonged increases in blood lactate and to result in the uptake of lactate by the inactive arm muscles (19, 21) to examine PDHc transformation to PDHa and acetyl-group accumulation in inactive muscle, during and after repeated bouts of maximal leg exercise.


    METHODS
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Abstract
Introduction
METHODS
RESULTS
DISCUSSION
References

Subjects

Seven male subjects [age 23.4 ± 1.5 (SE) yr; height 183 ± 2 cm; weight 76.4 ± 2.3 kg] participated in this study. Approval was obtained from the ethics committees of McMaster University and the McMaster University Medical Centre. Written informed consent was obtained from all subjects after an explanation of the attendant risks associated with the study protocol.

Experimental Protocol

To familiarize subjects with the experimental procedure, each subject completed a trial run on an isokinetic cycle ergometer (23, 28). The run consisted of three consecutive 30-s bouts of maximal isokinetic cycling (100 rpm), with 4-min rest intervals between bouts, while the nondominant arm was immobilized in a sling. One week later, the subjects returned to the laboratory, and two biopsy sites were prepared superficial to each deltoid muscle after local anesthesia (2% xylocaine without epinephrine). A preexercise resting biopsy was obtained from the dominant arm. Subjects then completed three successive 30-s bouts of maximal cycling on the isokinetic cycle, with 4-min rest intervals between bouts, followed by a 15-min recovery period. Throughout the exercise protocol, the nondominant arm remained inactive and immobilized in a sling and the dominant arm was used only to maintain balance. Immediately after bouts 1 and 3, biopsies were obtained from the deltoid of the nondominant arm. After 15 min of recovery, a resting biopsy was obtained from the deltoid of the dominant arm. Biopsies were immediately frozen in liquid nitrogen and stored in liquid nitrogen until analyzed. All subjects consumed a high-carbohydrate diet and abstained from alcohol and caffeine consumption for 2 days before the experiments. Subjects consumed a high-carbohydrate meal on the morning of each experiment. Total work was calculated as previously described (28).

Muscle Analysis

PDHa and total PDH activity (PDHt) were analyzed as previously described (12, 28). Neutralized perchloric acid extracts of freeze-dried, dissected, and powdered muscle samples were analyzed for total coenzyme A (CoA), free CoA (CoASH), acetyl-CoA, and acetylcarnitine (9). Muscle lactate (LA) and pyruvate (PYR) concentrations were determined as previously described (28).

Summary of Data and Statistical Analyses

Data are summarized as means ± SE. Data were analyzed using a one-way analysis of variance (ANOVA) with repeated measures over time, unless otherwise stated. When a significant F ratio was found, the Newman-Kuels post hoc analysis was used to compare means. Correlation and linear regression analyses were completed to determine the relative importance of the lactate-plus-pyruvate load ([LA]+[PYR]) in determining PDHa. Differences were considered significant at P < 0.05.


    RESULTS
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Abstract
Introduction
METHODS
RESULTS
DISCUSSION
References

Total Work

The total work completed in bout 1 was 19.8 ± 1.02 kJ; it significantly decreased with each successive bout to 18.3 ± 0.81 kJ in bout 2 and to 16.2 ± 0.32 kJ in bout 3 (P < 0.05).

Muscle LA and PYR

Repeated maximal isokinetic cycling exercise resulted in a 2.6-fold increase in the concentration of lactate ([LA]) in the inactive deltoid muscle (Fig. 1), increasing from an initial resting value of 9.2 ± 0.8 to 24.2 ± 4.8 mmol/kg dry wt after bout 3 (P < 0.05). After the 15-min recovery period, muscle [LA] remained 2.3-fold elevated over rest at 20.9 ± 2.2 mmol/kg dry wt (P < 0.05). Repeated maximal isokinetic cycling also resulted in a similar increase (2.3-fold) in pyruvate ([PYR]) concentration (Fig. 2), from an initial resting level of 0.47 ± 0.12 to 1.08 ± 0.27 mmol/kg dry wt after bout 1 (P < 0.05). [PYR] remained elevated thereafter, being 0.96 ± 0.24 mmol/kg dry wt after bout 3 and 1.33 ± 0.31 mmol/kg dry wt after 15 min of recovery (P < 0.05).


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Fig. 1.   Lactate accumulation in the inactive deltoid during maximal isokinetic cycling. Shaded boxes, isokinetic cycling at 100 rpm; open boxes, rest recovery. * Different from before bout 1; + different from after bout 1.


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Fig. 2.   Pyruvate accumulation in the inactive deltoid during maximal isokinetic cycling. Shaded boxes, isokinetic cycling at 100 rpm; open boxes, rest recovery. * Different from before bout 1.

PDHa

PDHa in the inactive deltoid muscle was 0.71 ± 0.21 and 1.30 ± 0.28 mmol · min-1 · kg wet wt-1 at rest and after bout 1, respectively (not significant) (Fig. 3). PDHa increased by 2.6-fold after bout 3, reaching 1.83 ± 0.28 mmol · min-1 · kg wet wt-1 (P < 0.05), and remained 2.3-fold elevated (1.63 ± 0.24 mmol · min-1 · kg wet wt-1) after recovery (P < 0.05).


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Fig. 3.   Pyruvate dehydrogenase activity (PDHa) in the inactive deltoid during maximal isokinetic cycling. Shaded boxes, isokinetic cycling at 100 rpm; open boxes, rest recovery. * Different from before bout 1.

Correlation Between Increases in [LA]+[PYR] and PDHa

Increases in the sum of the muscle [LA]+[PYR] were positively correlated with PDHa (rxy = 0.42; P < 0.04). Changes in the sum of muscle [LA] and [PYR] accounted for 78% of the variation in the dependent variable PDHa, as follows
PDH<SUB>a</SUB> = 0.0755 × ([LA] + [PYR]),
<IT>R</IT><SUP>2</SUP> = 0.78, <IT>P</IT><0.000001 
SE of slope = 0.0080; <IT>F</IT>(1,25) = 88.3; &bgr; = 0.88 ± 0.09.
LA and PYR are expressed as millimoles per kilogram dry weight, and PDHa is expressed as millimoles per minute per kilogram wet weight.

CoA, Acetyl-CoA, the Acetyl-CoA-to-CoASH Ratio, and Acetylcarnitine

Total and free CoA (CoASH) and acetylcarnitine concentrations were not altered in inactive muscle by maximal exercise (Table 1). In contrast, the concentration of acetyl-CoA was slightly lower after the recovery period compared with rest (P < 0.05; Table 1). Despite the small change in the concentration of acetyl-CoA, the acetyl-CoA-to-CoASH ratio (acetyl-CoA/CoASH) in the deltoid also remained unaltered by repeated maximal exercise (Table 1).

                              
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Table 1.   Changes in CoA, acetyl-CoA, CoASH, acetyl-CoA/CoASH, and acetylcarnitine in the inactive deltoid muscle during maximal isokinetic cycling


    DISCUSSION
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Abstract
Introduction
METHODS
RESULTS
DISCUSSION
References

We examined the transformation of PDHc to PDHa and acetylation of the CoA and carnitine pools in inactive muscle metabolizing a LA load. The protocol used is known to rapidly generate a large amount of LA, typically reaching peak intramuscular levels in the active leg muscles >120 mmol/kg dry wt (28) and arterial blood LA concentrations during exercise and 15 min of recovery in the ranges of 15-24 and 12-18 mmol/l (19, 21), respectively. The uptake of LA by the inactive arm, as reflected by the arteriovenous LA concentration difference, is large under these conditions, typically reaching 5 and 1-2 mmol/l during exercise and the first 15 min of recovery, respectively (19, 21). This model also has the advantage that LA is generated endogenously by the active muscle mass, causing associated increases in arterial and venous [H+] that accompany LA accumulation in vivo, unlike studies employing Na-lactate infusion, which result in decreased [H+] (14). Thus the present protocol allowed examination of some factors contributing to enhanced LA metabolism by inactive muscle under relevant and maximal physiological conditions.

LA Metabolism

Oxidation. Increases in LA uptake (1, 2, 4, 10, 19, 21) and LA turnover (7, 22, 25) in inactive muscles have been demonstrated in both human (1, 4, 8, 19, 21) and animal models (7, 10, 25) of exercise (1, 4, 8, 19, 21) and LA infusion during rest (2, 7, 10, 22, 25, 30) and exercise (1, 4, 7, 8, 22). Furthermore, muscle O2 uptake corresponded to the molar quantity expected from oxidation of the LA load (2, 4, 19, 21), suggesting that, in the inactive muscle mass, oxidation is an important route of metabolism. Thus, in light of these observations, and because LA taken up by the inactive muscles is rapidly converted to PYR via the equilibrium enzyme lactate dehydrogenase, we hypothesized that increased PDHc transformation to PDHa would occur in the inactive muscles despite the absence of significant contractile activity, thus demonstrating the potential for flux through this rate-limiting step leading to oxidation.

During the exercise period, deltoid PDHa increased by 2.6-fold (i.e., from 0.71 to 1.83 mmol · min-1 · kg wet wt-1 after bout 3), whereas LA accumulated in the deltoid throughout exercise (Fig. 1), indicating that the rate of LA uptake exceeded its rate of metabolic removal. The arteriovenous O2 and LA concentration differences during this time have been reported to be 7 and 5 mmol/l, respectively (21), a stoichiometric relationship (i.e., 1.4:1) that would suggest that only a portion of the LA taken up by the inactive muscles could have been oxidized during the non-steady-state exercise period.

Deltoid PDHa remained 2.3-fold elevated over rest (Fig. 3), and muscle LA concentration did not significantly change thoughout recovery (Fig. 1), indicating that the rates of LA uptake and metabolic removal were similar. The average arteriovenous O2 and LA concentration differences during the recovery period were previously reported to be 4.0 and 1.3 mmol/l, respectively (21), a stoichiometric relationship (i.e., 3:1), which is consistent with the oxidative removal of the LA load. Utilizing the values of plasma LA previously reported (21) at the beginning (25 mmol/l) and end (20 mmol) of 15 min of recovery, and assuming a fluid space of 60% of body weight (46 liters), we calculated that the rate of whole body LA disappearance was ~13.8 mmol/min. Correcting for hepatic LA metabolism (10%) (3) and anaplerotic reactions involving pyruvate (10%) (15) and intramuscular glycogen resynthesis in the active leg muscles (5%) (3), and assuming an inactive muscle mass of 20 kg (21), we estimated the average PDHa flux to be ~0.5 mmol · min-1 · kg wet wt-1. This value is only 31% of the measured PDHa at the end of recovery and indicates that oxidation was not limited by PDHc transformation to PDHa.

Thus, although the extent of PDHc transformation to PDHa may have limited LA oxidation during the non-steady-state exercise period, PDHa appears to have posed no limitation to LA oxidation during the recovery period. Physiological regulatory factors may have been responsible for downregulating the in vivo PDHa flux during this time and may explain the discrepancy between the calculated in vivo flux and in vitro determined PDHa. It is conceivable that increased cytosolic NADH, generated during the conversion of LA to PYR, was transported into the mitochondria, leading to a corresponding rise in the mitochondrial NADH/NAD ratio, resulting in end-product inhibition of PDHa flux. This phenomenon has been reported in human muscle during electrically evoked muscle contractions during ischemia (13). The availability of ADP and/or Pi may also have contributed in this regard as potential rate-limiting steps for oxidative phosphorylation and O2 consumption in inactive skeletal muscle.

Acetyl-CoA and acetylcarnitine. The absence of increases in the accumulation of acetyl-CoA (Table 1) and acetylcarnitine (Table 1) during the exercise and recovery periods indicates that LA oxidation was not limited by TCA cycle flux. If the rate at which LA-derived pyruvate was converted to acetyl-CoA via PDHa had exceeded its rate of oxidative removal by the TCA cycle, there would have been corresponding increases in acetyl-CoA and acetylcarnitine, as previously reported under a number of experimental conditions (11, 13, 28, 31, 32). It is possible that the absence of increases in acetyl-CoA and acetylcarnitine accumulation may have resulted from the conversion of some of the newly formed PYR directly to oxaloacetate (15), thereby activating citrate synthase at a lower acetyl-CoA concentration and simultaneously accelerating TCA cycle flux.

Our observation that acetylation of the CoA and carnitine pools was not altered is in contrast to recent studies on resting ischemic muscle (31, 32), in which enhanced PDHa, induced by infusion of the pyruvate analog sodium dichloroacetate (DCA), resulted in lower resting muscle LA accumulation and increased acetylcarnitine accumulation. In the present study, blood flow to the inactive muscles could be expected to increase by as much as two- to threefold (1, 2, 4), whereas those studies employing a model of peripheral muscle ischemia would have resulted in reduced blood flow (31, 32). Thus TCA cycle flux and terminal substrate oxidation probably were not limiting in our subjects but were during tissue hypoxia (31, 32). Under the conditions employed in the present study, the formation of acetylcarnitine, via the carnitine-acetyltransferase-catalyzed reaction, was not a quantitatively important route of LA disposal in inactive muscle.

Glyconeogenesis. Although it is possible that LA may have been metabolized in the deltoid via glyconeogenesis (16, 24), this seems unlikely for several reasons. First, the rate of glyconeogenesis is inversely proportional to glycogen content (5), but glycogen level remains unaltered in the inactive deltoid (21). Furthermore, we took additional precautions to ensure that glycogen content was high by completely immobilizing the deltoid during exercise and by having our subjects avoid physical activity and consume a high-carbohydrate diet for 2 days before the experiments. Second, the largest fiber population in human deltoid muscle is type I slow-twitch (20), which is known to have a very low maximal capacity for glyconeogenesis (24). Finally, glyconeogenesis only becomes thermodynamically feasible when phosphoenolpyruvate is rapidly removed (24), a condition likely to be satisfied in inactive muscle only when glycogen content is very low and glycogen synthetase activity is high (5).

PDHa

PDHc transformation to PDHa. In the present study, it was possible to examine the coordinated changes in [PYR] and PDHa, independent of changes in other regulators of PDHc transformation. PYR is a substrate for the PDHa reaction and, like DCA, exerts its effect on PDHc transformation to PDHa by allosterically inhibiting PDH kinase (18). Although it is not possible in the present study to directly assess the effect of an associated increase in the intracellular hydrogen ion concentration ([H+]i), which occurs secondary to enhanced LA uptake, it is possible that it too may have contributed to PDHa transformation. This suggestion is supported by the observation that PDHc transformation to PDHa is increased during acidosis in the perfused rat heart (26). However, it remains to be determined whether the effect of [H+]i on PDHa was indirect, by enhanced carrier-mediated mitochondrial PYR transport, or whether it was a direct effect explained by the slightly different pH optima for the regulatory subunits PDH phosphatase and PDH kinase (17).

We have previously reported that [H+] and [PYR] were positively correlated with changes in PDHa in previously active skeletal muscle recovering from repeated 30-s bouts of maximum isokinetic cycling (28). In that study, PDHa was 0.5 mmol · min-1 · kg wet wt-1 at rest and increased to 3 mmol · min-1 · kg wet wt-1 in the active muscles during each exercise bout. At the end of the intervening 4-min rest recovery periods, PDHa remained 2.2- to 2.8-fold elevated over the initial resting level (i.e., 1.1 to 1.3). In the present study, PDHa in the inactive and immobilized deltoid muscle was 1.8 mmol · min-1 · kg wet wt-1 after bout 3 and remained elevated at 1.6 after 15 min of recovery. The slightly higher PDHa observed in the present study during recovery compared with muscles recovering from maximum activity (28) may be explained by the presence of other allosteric regulators of PDHa in the previously active muscles that were absent in the inactive muscles of the present study. In the previously active muscle, there was a progressive increase in acetyl-CoA/CoASH (28) during each rest recovery period, which would have resulted in lower PDHa (29). Thus, in previously active muscle during recovery, there were both positive (i.e., [PYR] and [H+]i) and negative (i.e., acetyl-CoA/CoASH) regulatory factors acting to determine PDHc transformation to PDHa. In contrast, the absence of changes in acetyl-CoA/CoASH (Table 1) in the inactive muscles of our subjects would have allowed the activating effects of increased [PYR], and possibly [H+]i, to prevail.

Parallel increases in [PYR] and PDHa during LA uptake by inactive muscle point to the importance of a positive feed-forward mechanism of LA oxidation. Increased LA uptake by inactive skeletal muscle would ensure its own immediate disposal by inducing PDHc transformation to PDHa, first by increases in [PYR] and second by associated increases in [H+]i. This has important implications for understanding some of the metabolic events associated with the operation of the "lactate-shuttle hypothesis," as proposed by Brooks (6). It also highlights an active metabolic role for the nonworking muscle mass in experimentally or pathologically induced states of lactic acidosis.

Summary and Conclusions

We examined PDHa and the accumulation of acetyl-CoA and acetylcarnitine in the inactive deltoid muscle during and after repeated bouts of maximum isokinetic cycling. PDHa increased by 2.6-fold in the inactive deltoid muscle during maximal leg exercise and remained 2.3-fold elevated during 15 min of recovery. Greater PDHa was attributed to increases in muscle LA uptake and associated increases in the intramuscular concentration of PYR. A comparison of previous measures of LA uptake by inactive muscles with measured PDHa of the present study indicates that PDHc transformation to PDHa during recovery was sufficiently high so as not to limit oxidation of the LA load. LA oxidation by inactive skeletal muscles was not associated with changes in the intramuscular concentrations of acetyl-CoA and acetylcarnitine, indicating that TCA cycle flux also did not limit oxidation. The nonworking muscle mass contributes to acid-base, osmotic, and energetic homeostasis by actively metabolizing LA produced by the working muscles.


    ACKNOWLEDGEMENTS

The authors thank T. Bragg, E. Wyma, and G. Obminski for excellent technical assistance.


    FOOTNOTES

This study was supported by the Canadian Medical Research Council and the Heart and Stroke Foundation of Ontario. G. J. F. Heigenhauser is a Career Investigator of the Heart and Stroke Foundation of Ontario.

Present address of C. T. Putman: Faculty of Physical Activity Studies and Department of Biological Sciences, University of Regina, Regina, Saskatchewan, Canada S4S 4L9.

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. §1734 solely to indicate this fact.

Address for reprint requests: G. J. F. Heigenhauser, Dept. of Medicine, McMaster Univ. Medical Centre, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5.

Received 8 July 1998; accepted in final form 5 November 1998.


    REFERENCES
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Abstract
Introduction
METHODS
RESULTS
DISCUSSION
References

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Am J Physiol Endocrinol Metab 276(3):E483-E488
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society




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