Jap december 87/6

Skeletal muscle energy metabolism during prolonged,
fatiguing exercise

Mark A. Febbraio and Jane Dancey
Journal of Applied Physiology 87:2341-2347, 1999.
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recruitment during exercise in humans

A St Clair Gibson and T D Noakes

Glycogen availability does not affect the TCA cycle or TAN pools during prolonged,
fatiguing exercise

J. Baldwin, R. J. Snow, M. J. Gibala, A. Garnham, K. Howarth and M. A. Febbraio
Biochemistry . Polymerase Chain Reaction Biochemistry . Glycogen Physiology . Exertion Medicine . Exercise Medicine . Fatigue Medicine . Fitness (Physical Activity) including high-resolution figures, can be found at: Journal of Applied Physiology can be found at:
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Skeletal muscle energy metabolism duringprolonged, fatiguing exercise MARK A. FEBBRAIO AND JANE DANCEYExercise Physiology and Metabolism Laboratory, Department of Physiology,The University of Melbourne, Parkville, Victoria 3052, Australia Febbraio, Mark A., and Jane Dancey. Skeletal muscle
acid cycle intermediates, in turn resulting in an impair- energy metabolism during prolonged, fatiguing exercise. J. ment in ATP provision via oxidative phosphorylation Appl. Physiol. 87(6): 2341–2347, 1999.—A depletion of phos- (32, 34). Because ATP demand during prolonged exer- phocreatine (PCr), fall in the total adenine nucleotide pool cise is maintained, such a decrease in ATP provision (TAN ϭ ATP ϩ ADP ϩ AMP), and increase in TAN degrada- leads to transient ADP formation and ATP generation tion products inosine 5Ј-monophosphate (IMP) and hypoxan- from alternative pathways, including creatine phospho- thine are observed at fatigue during prolonged exercise at70% maximal O kinase (CPK) and adenylate kinase (AK) (32). Because 2 uptake in untrained subjects [J. Baldwin, R. J. Snow, M. F. Carey, and M. A. Febbraio. Am. J. Physiol. CPK has a much higher activity in skeletal muscle 277 (Regulatory Integrative Comp. Physiol. 46): R295–R300, compared with AK (7), phosphocreatine (PCr) has been 1999]. The present study aimed to examine whether these demonstrated to be an effective buffer of ADP during metabolic changes are also prevalent when exercise is per- prolonged exercise until concentrations of PCr are formed below the blood lactate threshold (LT). Six healthy, reduced to ϳ40 mmol/kg dry wt (dw), after which time untrained humans exercised on a cycle ergometer to volun- AK becomes more active, resulting in a greater forma- tary exhaustion at an intensity equivalent to 93 Ϯ 3% of LT tion of AMP, which is rapidly deaminated to inosine (ϳ65% peak O2 uptake). Muscle biopsy samples were ob- 5Јmonophosphate (IMP) (35). Accordingly, many stud- tained at rest, at 10 min of exercise, ϳ40 min before fatigue ies have noted the accumulation of IMP at fatigue (FϪ40 ϭ143 Ϯ 13 min), and at fatigue (F ϭ 186 Ϯ 31 min).
Glycogen concentration progressively declined (P Ͻ 0.01) to during prolonged exercise in the presence of low intra- very low levels at fatigue (28 Ϯ 6 mmol glucosyl U/kg dry wt).
muscular glycogen stores (2, 5, 29, 32, 34, 35).
Despite this, PCr content was not different when FϪ40 was Although these findings suggest an imbalance be- compared with F and was only reduced by 40% when F was tween ATP synthesis and degradation rates in the compared with rest (52.8 Ϯ 3.7 vs. 87.8 Ϯ 2.0 mmol/kg dry wt; presence of low glycogen stores, it is important to note P Ͻ 0.01). In addition, TAN concentration was not reduced, that these studies have been conducted in untrained IMP did not increase significantly throughout exercise, and individuals exercising at an intensity of ϳ70% maximal hypoxanthine was not detected in any muscle samples. A significant correlation (r ϭ 0.95; P Ͻ 0.05) was observed ˙ O2max). In contrast, recently we (2) and others (33) have demonstrated that neither the total between exercise time and glycogen use, indicating that adenine nucleotide pool (TAN ϭ ATP ϩ ADP ϩ AMP) glycogen availability is a limiting factor during prolongedexercise below LT. However, because TAN was not reduced, nor IMP concentrations are significantly changed from PCr was not depleted, and no correlation was observed resting values when endurance-trained men exercised between glycogen content and IMP when glycogen stores to exhaustion at a similar relative workload despite the were compromised, fatigue may be related to processes other presence of low intramuscular glycogen stores. Further- than those involved in muscle high-energy phosphagen me- more, Green et al. (23) have observed an elevation in IMP in the muscles of untrained men during prolonged total adenine nucleotides; phosphocreatine; lactate thresh- exercise at a workload corresponding to 70% V after 30 min of exercise when glycogen stores were notlimited. Importantly, the elevated IMP was not presentat the same time during exercise at the same absoluteworkload after 4 and 8 wk of endurance training. In IT IS WELL ESTABLISHED that fatigue during prolonged addition, in our recent study (2) hypoxanthine, an IMP exercise coincides with low intramuscular glycogen degradation product that can diffuse from the cell, was stores (2, 3, 9, 12, 13, 25, 32, 34, 38). Although there are markedly elevated in plasma after 5 min of exercise, several possible reasons as to the requirement for when glycogen stores were unlikely to be compromised, carbohydrate in the maintenance of contractile force (for review, see Ref. 18), it is widely accepted that possible, therefore, that the elevated IMP observed at metabolic processes are limited by carbohydrate avail- fatigue in untrained, but not endurance-trained, men ability. It has been suggested that as muscle glycogen (2) may occur in the presence of, but may not be caused stores are progressively compromised during exercise, by, low intramuscular glycogen stores. In addition, flux through glycolysis is reduced, leading to a fall in endurance exercise training also results in attenuated pyruvate formation and a reduction in tricarboxylic lactate and ammonia accumulation and PCr degrada-tion (11, 22–24). These findings demonstrate that train-ing improves the match between ATP synthesis and The costs of publication of this article were defrayed in part by the degradation during exercise at submaximal work rates.
payment of page charges. The article must therefore be hereby It is possible, therefore, that the workload of marked ‘ advertisement’ in accordance with 18 U.S.C. Section 1734 ˙ O2max, frequently chosen to examine the relationship 8750-7587/99 $5.00 Copyright ௠ 1999 the American Physiological Society between glycogen availability and muscle energy me- ˙ O2 to verify exercise intensity. Heart tabolism during fatiguing steady-state exercise, re- rate was also monitored during this trial via telemetry quires an ATP turnover rate that cannot be sufficiently (Sports Tester, Polar). An electric fan was used to circulate air, met by oxidative metabolism in untrained individuals.
and water was provided ad libitum. Subjects were instructed The increase in PCr degradation and accumulation of to cycle at the predetermined work rate, maintaining a pedal IMP observed in the presence of low glycogen concentra- frequency of 80–90 rpm until fatigue. Fatigue was defined as tion may, therefore, be unrelated to glycogen availabil- the inability to complete one pedal revolution because the ity but may be due to increased energy provision from work rate on the electrically braked cycle ergometer wasnon-pedal-frequency dependent. All subjects were given strong the CPK and AK reactions throughout exercise. Thus verbal encouragement from the investigators to continue the purpose of the present study was to examine muscle energy metabolism in untrained subjects throughout The experimental trial was conducted at least 7 days after prolonged, fatiguing exercise at a workload where the the familiarization trial. The protocol was identical to the ATP demand was met via oxidative sources. We hypoth- familiarization trial but included venous blood and muscle esized that although glycogen would be depleted at sampling at various stages throughout exercise. In addition fatigue, there would be little, if any, disruption to the ˙ O2 measurements, pulmonary gases were analyzed for the respiratory exchange ratio during this trial.
Venous blood samples were obtained by using a 20-gauge Teflon catheter (Terumo, Tokyo, Japan) inserted into a vein inthe antecubital space. The vein was kept patent by flushing Subjects. Six healthy but untrained subjects [20.7 Ϯ 2.4 yr; with 0.5 ml sodium chloride-5 U heparin after each sample ˙ O2peak) ϭ 2.49 Ϯ 0.5 l/min] collection. Muscle samples were obtained from the vastus volunteered for the experiment. The experimental procedures lateralis by using the percutaneous needle biopsy technique and possible risks of the study were explained to all subjects with suction. Briefly, local anesthetic was injected ϳ10 cm before they gave their informed, written consent. The experi- and 13 cm proximal to the lateral epicondyle of the femur of ment was approved by the Human Research Ethics Commit- both legs. Four separate incisions (2 in each leg) were then made over the anesthetized areas, and muscle samples were ˙ O2peak and lactate threshold (LT) determination. Each obtained at rest, at 10 min of exercise (10 min), ϳ40 min subject initially performed a cycling test to volitional fatigueon an electromagnetically braked cycle ergometer (Lode before fatigue (FϪ40 ϭ 143 Ϯ 14 min), and at fatigue (F ϭ Instrument, Groningen, The Netherlands) to determine 186 Ϯ 31 min). FϪ40 was estimated from the results obtained during the familiarization trial. On sampling, the muscle was O2peak and LT. Expired air was directed into Douglas bags via a Hans Rudolf valve and plastic tubing. Oxygen and rapidly frozen in liquid nitrogen for later metabolite analysis.
carbon dioxide content of the Douglas bags were analyzed by The time from the cessation of exercise to freezing was ϳ10 s.
using Applied Electrochemistry (Ametek, Pittsburgh, PA) Tissue treatment and analysis. After each blood sample S-3A/II and CD-3A gas analyzers, calibrated before each test collection, blood was placed in fluoride heparin, mixed, and with a commercially prepared gas mixture of known composi- spun for 3 min at 8,000 rpm. The plasma supernatant was tion. The volumes of expired gases were determined by using then removed, stored on ice until completion of the trial, and a gas meter (Parkinson-Cowan, Manchester, UK). V ˙ O2peak was then frozen until later analysis of plasma glucose and lactate calculated by using standard equations (8). During this test, by using an automated method (EML-105, Electrolyte Metabo- venous blood samples were also obtained at rest and at the lite Laboratory, Radiometer, Copenhagen, Denmark). A fur- completion of every increment in the workload. Samples of ther 1.5 ml of whole blood were placed in tubes containing 30 whole blood were immediately mixed in a tube containing µl of EGTA/GSH. This tube was placed on ice until the lithium heparin. A 125-µl aliquot of whole blood was added to completion of the trial and spun as previously described. The 250 µl perchloric acid and spun in a centrifuge, and the plasma was then frozen for later analysis of free fatty acids by supernatent was frozen and stored for subsequent lactate using an enzymatic colorimetric method (Nefa-C kit, Wako determination (26). Each subject’s LT was determined accord- Pure Chemicals) according to the methods of Miles et al. (27).
ing to the methods of Coyle et al. (14). Briefly, the increase in Muscle samples were freeze-dried for 24 h, dissected free of blood lactate was plotted against O2 uptake (V ˙ O2). After any blood and connective tissue, powdered, extracted, and determination of the lactate steady state during the initial analyzed for glycogen, lactate, adenine nucleotides (ATP, incremental workloads, a value corresponding to 1 mmol/l ADP, AMP) and their degradation products (IMP and hypoxan- above this point was taken as the LT. The corresponding V ˙ O2 thine), PCr, and creatine (Cr) as previously described (17).
at this point was multiplied by 0.95 to calculate 95% LT. The The concentrations of ATP, ADP, AMP, IMP, PCr, and Cr were desired workload was then determined from the V ˙ O2 vs. adjusted to the peak total PCrϩCr concentration for each Experimental procedure. At least 1 wk after the V subject. This procedure minimized the error in measuring test, subjects returned to the laboratory to perform a familiar- nonmuscle components of the tissue not visible in the sample.
ization trial. This trial served to familiarize subjects with the Lactate and glucose were not corrected because of their cycling protocol and enabled us to check the workload and determine an approximate time to fatigue. Subjects were Statistical analyses. A one-way ANOVA with repeated instructed to refrain from alcohol, caffeine, tobacco, and measures on the time factor was used to compare blood and strenuous exercise and to consume their normal diet for the muscle metabolite data throughout the trial. A Newman- preceding 24 h. Subjects arrived in the laboratory in the Keuls post hoc test was used to locate difference when the morning after an overnight fast, were weighed, and then ANOVA revealed a significant interaction. Correlation coeffi- commenced cycling on the previously mentioned cycle ergom- cients were determined by using Pearson’s product moments.
eter at the predetermined workload. Expired gases were All data are reported as means Ϯ SE unless otherwise stated.
collected via Douglas bags during this trial and analyzed at The level of significance for all tests was set at P Ͻ 0.05.
Subjects cycled for 186 Ϯ 31 min at a workload that corresponded to 93 Ϯ 8% LT. This was equivalent to1.60 Ϯ 0.1 l/min or ϳ64% V plasma lactate accumulation increased (P Ͻ 0.05) inthe initial period of exercise, but concentrations re-turned to resting levels thereafter, indicating that thecontribution to energy metabolism via anaerobic glycoly-sis was minimal (Fig. 1).
Heart rate initially increased (P Ͻ 0.05) but reached throughout exercise (data not shown). Although therespiratory exchange ratio progressively fell (P Ͻ 0.05)during the first 80 min, it was maintained thereafter(Fig. 2). In addition, plasma glucose concentration didnot alter throughout exercise, indicating that circulat-ing glucose availability was not compromised at fatigue Fig. 2. Plasma free fatty acids (FFA; A), plasma glucose (B), andrespiratory exchange ratio (RER; C) throughout cycling exercise tofatigue, at 93 Ϯ 8% of lactate threshold. Values are means Ϯ SE; n ϭ 6subjects. *Different (P Ͻ 0.05) from R. #Different (P Ͻ 0.5) from 80 min.
Fig. 1. Muscle (A) and plasma (B) lactate concentrations at rest andthroughout cycling exercise to fatigue, at 93 Ϯ 8% of lactate thresh- (Fig. 2). Plasma free fatty acid concentrations increased old. Muscle lactate measurements were taken at rest (R), 10 min of (P Ͻ 0.05) after 60 min of exercise (Fig. 2).
exercise (10), 40 min before fatigue (FϪ40), and fatigue (F). Plasma Muscle glycogen concentration decreased (P Ͻ 0.05) lactate measurements were taken at rest (0 min) and every 20 min progressively throughout exercise, and concentrations throughout exercise. Values are means Ϯ SE; n ϭ 6 subjects.
* Different (P Ͻ 0.05) from rest.
were very low (Ͻ50 mmol glucosyl U/kg dw) at F (Fig.
Fig. 3. Muscle glycogen at R, 10, FϪ40, and F during cycling exerciseat 93 Ϯ 8% of lactate threshold. Values are means Ϯ SE; n ϭ 6subjects. * Different (P Ͻ 0.05) from R. # Different (P Ͻ 0.05) from 10.
3). However, despite the fact that glycogen content was decreased by 50% in all subjects when FϪ40 wascompared with F, this decrease was not statisticallysignificant. Muscle PCr was higher (P Ͻ 0.05) whenrest was compared with 10 min, FϪ40, and F. Of note isthe fact that, although PCr declined (P Ͻ 0.05) asexercise progressed beyond 10 min, it did not decreasewhen FϪ40 was compared with F (Table 1). Conversely, the concentration of intramuscular Cr increased (P Ͻ0.05) throughout exercise and was different from rest at10 min, FϪ40, and F (Table 1). There was no change inmuscle ATP, ADP, or AMP concentrations throughoutexercise, and, therefore, the TAN pool remained un-changed throughout exercise (Table 1). Although thereappeared to be a tendency for IMP to accumulate throughout exercise, this did not reach statistical signifi-cance (P Ͼ 0.05) (Table 1). Hypoxanthine was notdetected in any sample despite an analytic detectionlimit of between 0.005 and 0.01 mmol/kg dw. Further-more, the change in IMP throughout exercise was notdifferent (Fig. 4), and there was no correlation (r ϭ Fig. 4. Change in inosine 5Ј-monophosphate (IMP) from rest to 10 0.056, P Ͼ 0.05) between IMP and glycogen content at min of exercise (10–0 min), from 10 min of exercise to ϳ40 min before either FϪ40 (r ϭ 0.083; P Ͼ 0.05) or F (r ϭ 0.73; P Ͼ fatigue (FϪ40–10), and from fatigue to ϳ40 min before fatigue(F–FϪ40) during cycling exercise at 93 Ϯ 8% of lactate threshold (A)and relationship between IMP and glycogen at FϪ40 (r) and at F (s; Table 1. Muscle metabolite concentrations before B). Values are means Ϯ SE; n ϭ 6 subjects.
exercise, at 10 min of exercise, at 40 min beforefatigue, and at fatigue during cycling exercise 0.05) (Fig. 4). In contrast, a significant correlation (r ϭ at 93 Ϯ 8% of blood lactate threshold 0.95; P Ͻ 0.05) was observed between time to exhaus-tion and glycogen use (Fig. 5).
This study is the first to measure muscle energy metabolism throughout exercise in untrained subjects at a workload below the LT, where ATP supply from oxidative metabolism is sufficient to meet the ATP demand. Unlike previous studies conducted in un- Values are means Ϯ SE in mmol/kg dry wt; n ϭ 6 subjects. Rest, trained subjects (2, 5, 32, 34), the results from this before exercise; 10 min, 10 min of exercise; F Ϫ 40, 40 min before study suggest that despite compromised intramuscular fatigue (F); PCr, phosphocreatine; Cr, creatine; TAN, total adenine glycogen stores, fatigue appears to be associated with nucleotide pool (TANϭATPϩADPϩAMP); IMP, inosine 5Ј-monophos- factors other than those related to muscle high-energy phate. * Different (P Ͻ 0.05) from rest. † Different (P Ͻ 0.05) from 10min.
phosphagen metabolism. The relationship between gly- ˙ O2max, factors such as metabolic acido- sis may have contributed to fatigue before glycogendepletion.
It is important to note, however, that although glycogen was reduced by ϳ50% in all subjects whenFϪ40 is compared with F, the fall was not statisticallysignificant. Although unlikely, because of the relation-ship between glycogen use and exercise duration (Fig.
5), the possibility cannot be ruled out that fatigue wasrelated to factors other than glycogen availability, suchas a decrease in the central drive to exercise. It hasbeen proposed for a number of years (39) that theserotoninergic system may play a crucial role in thecentral control of fatigue during prolonged exercise. Inaddition, prolactin has been proposed as a marker ofcentral serotoninergic activity, and increases in plasmaprolactin concentration have been observed as exerciseintensity increased (16). Recent evidence suggests thatmuscular contraction increases reactive oxygen speciesin skeletal muscle, which promote low-frequency fa- Fig. 5. Correlation between exercise duration and glycogen utiliza- tigue in vitro (30). Therefore, the impairment of contrac- tion during cycling exercise at 93 Ϯ 8% of lactate threshold. Values tile function may be independent of glycogen availabil- are means Ϯ SE; n ϭ 6 subjects.
ity. Further investigations into the role of the centralnervous system and reactive oxygen species production cogen use and exercise duration (Fig. 5), as well as the during prolonged exercise to fatigue are needed.
very low levels of glycogen within the muscles at In the present study, TAN did not fall, IMP did not fatigue, supports previous studies (2, 3, 9, 12, 13, 25, 32, significantly accumulate, PCr was not reduced when F 34, 38) that suggest that glycogen availability may be a was compared with FϪ40 (Table 1), and no hypoxan- limiting factor during steady-state exercise. However, thine was detected in the muscle samples. Taken together, because TAN was not reduced, PCr degradation did not these data demonstrate that the intracellular high-energy fall at fatigue, IMP did not significantly accumulate phosphagen pool was not affected to a great extent. Even (Table 1), and no correlation was observed between though there was a tendency for IMP to accumulate, glycogen content and IMP late in exercise (Fig. 4), there the important factor was that there was no correlation was little evidence that this reduced glycogen availabil- between IMP accumulation and glycogen concentration ity had a major influence on muscle high-energy phos- near the end of exercise, when glycogen levels were compromised. In fact, the subject with the lowest The workload selected in the present study was muscle glycogen content at fatigue displayed no detect- designed such that the ATP requirement was ad- able IMP accumulation, whereas the subject with the equately met by oxidative processes. Although lactate highest glycogen at fatigue had the highest IMP level at concentration increased in both muscle and plasma at this point (Fig. 4). This lack of a correlation between the onset of exercise, this rise was transient, and IMP and glycogen content when glycogen is compro- concentration fell to resting levels thereafter (Fig. 1).
mised is in contrast to the data of Sahlin et al. (33). Of Although these data only reflect a balance between note, however, is the fact that in the previous study the lactate production and removal, they suggest that ATP exercise intensity at which the subjects exercised ranged supply from oxidative metabolism was sufficient in meeting energy demand. Given this, it was not surpris- correlation was significant, three of seven subjects ing that these untrained subjects were able to exercise demonstrated no IMP accumulation at fatigue.
for ϳ3 h. In addition, the low muscle glycogen levels Another important finding in this study was that the observed at fatigue were expected because carbohy- small accumulation of IMP occurred progressively drate has been demonstrated to provide ϳ50% of the throughout exercise and did not occur late in exercise, total energy metabolized during exercise at this inten- when glycogen was compromised (Fig. 4). In fact, when sity (31). Interestingly, the concentration of glycogen at a power analysis was performed on these data, the FϪ40 was lower than that previously observed at number of subjects needed to obtain a statistical differ- fatigue in some studies (2, 32, 35). This is probably due ence was 102. Therefore, despite the facts that IMP to the important fact that this is the only study to date rose slightly over time and our subject number was low, that has normalized the exercise intensity to a marker we are confident that our data demonstrate no biologi- of metabolic stress rather than to a percentage of cal relationship between glycogen content and IMP ˙ O2max. Therefore, factors such as metabolic acidosis, formation. In addition, the fact that the TAN pool was which can disrupt contractile processes, could not have not altered at all suggests that the small and insignifi- resulted in fatigue in the present study. In contrast, in cant rise in IMP over time was physiologically unimpor- previous studies where the workload was normalized to A limitation of the present study is that analyses lar processes, which may cause a disturbance in contrac- were conducted on whole, mixed-fiber muscle samples.
It is possible that the accumulation of IMP may havebeen related to fiber-type activation. As discussed above, The authors acknowledge the technical assistance of Jo Ann Parkin, Damien Angus, and Kirsten Howlett, and the medical IMP accumulated progressively throughout exercise assistance of Dr. Andrew Garnham. The authors also acknowledge rather than at fatigue (Fig. 4). It has been demon- Dr. Michael Carey for generous use of his laboratory in the HPLC strated that type II fiber activity increases as submaxi- analyses and Dr. Rod Snow for assistance in preparing this manu- mal-intensity exercise progresses (20). Furthermore, script. We also thank the subjects for their participation in this study.
Address for reprint requests and other correspondence: M. A.
Norman et al. (28) demonstrated that glycogen-de- Febbraio, Dept. of Physiology, The Univ. of Melbourne, Parkville, pleted type II fibers accumulate more IMP compared Victoria 3052, Australia (E-mail: m.febbraio@physiology.unimelb.
with type I fibers. It would have been desirable in the present study to perform pooled single-fiber analyses.
Received 19 May 1999; accepted in final form 16 August 1999.
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