BrinA Mttbcai BulUm (1992) Vol. 48, No. 3, pp. 569-591 © The Britijh Counal 1992

Aerobic exercise, anaerobic exercise and the lactate threshold N C Spurway Department of Physiology, University of Glasgow, Glasgow, UK

All exercise draws first on intramuscular stores of ATP and creatine phosphate; initially these are replenished by anaerobic glycolysis. The lactic acid produced contributes to the rapid development of fatigue in high intensity exercise. Aerobic metabolism (at first mainly of glycogen, later increasingly of fat) is the principal route of ATP resynthesis in activities lasting longer than 2 min, but can only maintain work-rates about 1/4 of those possible in very brief bursts. Blood lactate rises at the higher aerobic work rates. 'Lactate threshold' (LT: ~ 2 mmol/l) is almost exactly the speed at which endurance races are won, and close to those apparently providing optimal aerobic training. This training, predominantly of muscle aerobic capacity, elevates LT more than maximum oxygen consumption. LT is not now thought to indicate oxygen-deprivation, but intracellular adjustments driving oxidative phosphorylation faster. Ventilatory breakpoints, formerly considered to indicate LT, correlate more closely with the accumulation of potassium than lactate.

This article is in 3 sections. The first summarizes current understanding of the different stages and intensities of physical work. The second outlines some tests of work capacity. The final section attempts the controversial topic of the anaerobic threshold. Note: For simplicity, the forms of physical exercise directly discussed in this review are all ones in which external work is done by the muscles: intensity of effort is therefore expressible in terms

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of 'work-rate' or 'power'. In isometric or eccentric exercise different units of intensity would be appropriate, but the metabolic ideas presented would be essentially unchanged. STAGES AND INTENSITIES OF WORK The needs of working muscles 1 " 3 Muscles are 'chemical machines'—they do mechanical work only on the basis of chemical energy supply. The immediate currency, both for the ionic pumps which underly the excitation mechanisms and for the force-generation process itself, is of course adenosine triphosphate (ATP). We are concerned here with the different routes by which that ATP can be provided. Supply is termed 'aerobic' when it is in balance with oxygen intake, 'anaerobic' when it is not. Nevertheless, within these categories, subdivisions must be recognised. Which supply-route will predominate at a given moment is determined partly by the intensity of the work and partly by how long it has gone on. For the first few seconds of any new effort, or a marked increase of effort, muscles draw on their internal stores of high-energy phosphates: ATP and creatine phosphate (CP). When the effort is maximal these stores are probably depleted in 3-5 seconds, but they suffice for any single jump or throw on the athletics field, for diving saves and kicks for touch ... and so on. Margaria14 termed this the 'alactic' phase of anaerobic energy supply. The subsequent recovery processes are small-scale and so hard to study, but we can be sure that, like all other recovery processes, they are ultimately oxidative. A track race, even of 100 let alone 400 metres, cannot be principally fueled this way. (Nor can the 'sprints' in other sports, like cycling and swimming, where times are of the same order as those of 400 m on the track). Within 5 seconds of the start, the athlete is having to make new ATP as fast as it is used. The first pathway to become available (and the one able to supply ATP at the highest rate in the majority of any sprinter's muscle fibres) is the anaerobic pathway. This is the route which begins with the detachment of individual hexose phosphate units from stored glycogen molecules (glycogenolysis), divides each of them into 3-carbon units with the synthesis of 3 ATP molecules per hexose unit (glycolysis), and ends in the reduction of pyruvate to lactic acid. The lactic acid has two main effects. One is that, after diffusing out of the source

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muscle fibres, it is carried by tissue fluids and blood to more aerobic tissues—liver, heart, and perhaps mostly just to nearby muscle fibres with aerobic capacity to spare—where it is either further metabolised aerobically or resynthesised to carbohydrate units ('gluconeogenesis'). The balance between these latter two processes is debated, 45 but neither will have progressed significantly before the end of the sprint event we are considering. Lactic acid which has not yet left the source fibres will, however, have a different effect: when sufficient has accumulated to lower the intrafibre pH to ~6.5 (resting value being close to 7.2), enzymes both of force-generation and of further glycolysis are inhibited. The athlete is fatigued and must slow down greatly if he/she does not stop. (Whether pH-change is the sole mechanism of shortterm muscle fatigue is another subject of debate,4-6'7 but it must make a powerful contribution.) Even in the best-trained people fatigue becomes severe after some 30-60 s at the work-rates being considered. Before moving on, it is appropriate to note that recovery from strenuous anaerobic exercise is less well understood than it was once thought to be. Stores of ATP and CP are replenished, with time constants of ~2-6min. Excess lactate is substantially removed during that period also, and the rest in the following hour. The oxygen necessary for these two processes (the 'oxygen debt', of AV Hill) has turned out, however, to be considerably less than the total of the excess post-exercise oxygen consumption (EPOC)2. The extra elevation of metabolism during recovery is usually attributed to elevated temperature and hormonal effects; however, when the strenuous effort has been experimentally confined to a small muscle group these effects seem insufficient to account for the EPOC measured.8 Returning to the exercise period itself, suppose that our runner did not set off at a 400 m pace, but at that of the marathon. Then the initial lactic acid would accumulate much more slowly, and long before muscle contraction became inhibited another metabolic pathway would take over the main burden of ATP synthesis. This is the aerobic pathway, operating in mitochondria. Pyruvate molecules and hydrogen atoms, instead of producing further lactic acid, are taken up by these organelles; there they are oxidised via the Krebs cycle and the electron transport chain, producing a total of 36 ATP's per original hexose unit. Alternatively fatty acids can fuel this same mechanism (oxidative phoshorylation). The overall process is termed 'aerobic glycolysis' or '... lypolysis' according

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to the substrate. An important aspect of physiological economy should also be noted here: the trained endurance performer's substrate utilization shifts, as the effort continues, in the direction of more lypolysis and the relative 'sparing' of remaining glycogen. (Incidentally, we see from this why exercise undertaken for weight reduction is actually more effective—quite apart from being safer—if it is long and slow.) So far the sporting activities cited have been such that one or another route of ATP supply clearly predominates. It is estimated 13 that a uniformly-paced race lasting about 2-3 min on average invokes anaerobic and aerobic energy yields equally—the anaerobic yield predominating early on and the aerobic towards the end. There is, however, large individual variation around this mean. Nor are races necessarily uniform-paced; in sports where they are not, or in instances where a particular individual's makeup deviates from the 'norm', coaches may rightly place emphasis on training the anaerobic systems, even for events several times longer than 2 min. In many other sports, such as ball games, the pattern presumably alternates between largely-alactic bursts and aerobic repositioning runs. Specificity of training therefore requires that both kinds of work are included in the regime. Note also that, whenever lactate has been accumulated, 'active recovery' (e.g. jogging) eliminates it quicker than total rest.9 Fibre types and metabolic controls Three factors contribute to the contrasts of metabolic balance described above: the existence of different types of skeletal muscle fibre, a shift in the route of glucose metabolism, and a shift from the consumption of glucose towards the consumption of fat. Different types of skeletal muscle fibre (Fig. 1) are recruited for work of different intensities.10 Elsewhere in this issue, Jones has referred to the existence of slow and fast fibres. Slow (type 1) fibres have high aerobic but low anaerobic capacities (though in man their anaerobic short-fall seems to be less extreme than in most animals).11 It is these which are used during endurance exercise. Fast (type 2) fibres are recruited (not in lieu but in addition to the type 1 's) for higher-intensity exercise. Type 2B— the fastest of all and, in trained power athletes, the largest—have high anaerobic but (at least in their extreme form) very low aerobic capacities; these are recruited only for the most intense efforts, and fatigue fast. Between these fibre types in recruitment-

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Human Motor Units (Large Limb & Trunk Muscles)

SMALL MOTOR NEURONElow recruitment threshold

MEDIUM-SIZED MOTOR NEURONE - Intermediate recruitment threshold LARGE MOTOR NEURONE high recruitment threshold

Large no. TYPE 2B MUSCLE FIBRES fFast. glycorytlcT Pale creamy colour Highly anaerobic metabolism Fast myosln Least fatigue resistance

Strong red colour Highly aerobic metabolism Slowmyostn Great fatigue resistance

TYPE 2A MUSCLE FIBRES - Tfwrihmi no. (Tast mddaflve* glycolytlcl Red colour Both aerobic & anaerobic metabolisms well developed Fairly fast myosln Moderate faUguereslstance

Fig. 1 The three stable types of motor unit, and hence of muscle fibre, found in mature, undamaged human muscle. Units having the lowest recruitment threshold are necessarily used most often and therefore require the highest endurance within the particular muscle, individual and training state. As endurance depends upon aerobic metabolism, it follows that exercise in the lower ranges of intensity can be entirely aerobic. Conversely, as the ATP needs of 2B fibres cannot be met aerobically, exercise sufficiently intense to require their recruitment must be at least partly anaerobic.

threshold and endurance are type 2A fibres, which have high anaerobic and aerobic capacities. The pattern of recruitment is itself sufficient to ensure that high-intensity work has a large anaerobic component for as long as the work-rate can be main-

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tained, while low-intensity work which has been under way for some time is totally aerobic. Nevertheless, there are also shifts with time. All physical work, at the outset, has an anaerobic component; even if it is of an intensity which can ultimately be maintained entirely aerobically, this condition will not be fully established for perhaps 3-4 min. (The adjustments probably contribute substantially to the experience of 'second wind'.) The mechanisms which effect these adjustments are partly cardiovascular, partly intracellular. Those within the muscle cell may be summarized as follows.1~3'12'13 Calcium ions, acting synergistically with any adrenaline that is flowing, activate the enzyme phosphorylase, at a lower threshold concentration than that at which they activate the cross-bridges; hexose units therefore become available to the glycolytic pathway at least as soon as the muscle starts to generate force. The ATPases, both of membrane pumps and of cross-bridges, hydrolyse ATP to produce inorganic phosphate (Pj) and adenosine diphoshate (ADP); catalysed by myokinase, the latter also quickly produces some of the monophosphate (AMP). Immediate replenishment of ATP is from CP. Nevertheless, all three of the 'lower energy' phosphates, ADP, AMP and P,, allosterically stimulate the activity of the rate-controlling glycolytic enzymes, notably phosphofructokinase (PFK), so ATP synthesis via this pathway attains a significant rate a few seconds after the start of muscle work. NADH is a byproduct of glycolysis, which must be reoxidised for the process to continue; initially this can only be done by reducing pyruvate, the end-product of the glycolytic chain proper, to lactate. Other pyruvate molecules and reducing equivalents cross the mitochondrial outer membrane and become available to the Krebs cycle and the electron transport chain: however, these movements take a little time. In any case, the intramitochondrial pathways will not become productive until ADP and P,, which activate them as they do PFK, have also crossed the membrane in significant quantities. Then ATP has to be resynthesised, and pass out of the mitochondria again, before its inhibitory action upon glycolysis can begin to take effect. When the steady state is finally attained, glycolysis only needs to proceed at l/12th its initial rate to meet the same ATP requirement. Furthermore, lactate production in this steady state is likely to be at an even smaller fraction of its early peak, because the reducing equivalents of such glycolytic NADH as is still produced are substantially reoxidised within the mitochondria.

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Amongst the practical implications is that there is a large glycogen cost, and consequently a sacrifice of endurance, if one starts any aerobic activity too fast. This is amplified if the last two paragraphs are interrelated: it is probable that slow fibres, with their limited anaerobic capacity, cannot even work at their maximum rate—let alone their maximum efficiency—until the main adjustments to aerobic metabolism have occurred. 'Warm-up', in addition to reducing the risk of injury, is thus essential for fuel economy, and an event of marathon duration which allows no prerace warm-up should ideally be started slower than the mean speed at which it will be run. Conversely, type 2B fibres can never supply themselves with sufficient ATP to maintain maximum work-rate aerobically, because their mitochondrial capacity is insufficient. In fact, the account of the preceding paragraph probably applies unmodified only to type 2A fibres! Adjustment over the order of 30-90, rather than 0-3 minutes, occurs at two levels. There is an increase in fat mobilization from adipocytes, elicited principally hormonally (insulin level falls, all other hormones rise as exercise continues).1'3 Fatty acids thus enter the active muscle fibres and, via the P-oxidation spiral, feed acetyl units into the Krebs cycle (citric-acid cycle). This elevates the intra-mitochondrial citrate concentration, and initiates the second stage of adjustment, for some citrate now enters the cytoplasm where it exerts an inhibitory action on PFK; the further improved ATP/ADP ratio (mitochondrial, then cytoplasmic) acts the same way. So enhanced lipolysis leads to curtailed glycolysis. Finally, if this significantly reduces blood lactate concentration, the sequence is reinforced because lactate inhibits lipolysis. TESTS OF POWER AND FITNESS Sports scientists have developed a massive variety of performance tests, most of them designed to isolate, as far as possible, one of the metabolic phases discussed above. To illustrate what can be done, 4 of the most widely used tests are outlined below. Two preliminary comments ... Firstly: the tests, as described, measure only leg performance in some specific exercise. Old concepts of 'general fitness' being of extremely limited validity, it is essential, in connection with sports where other body actions are predominant, to substitute tests specific to those actions. Secondly: all laboratory tests are better guides to changes in individual capability than to competition-differences between individuals.

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Biomechanical factors in particular (whether arising from differences of anatomy or of skill) may make the correlations between different people's performances in the tests and in their sports rather poor. (A) Margaria-Kalamen stair run 1 * 15 This tests alactic anaerobic power. After a short run-in, stairs are taken 2 or 3 per stride in an all-out sprint and the time to climb a metre or so is measured with switch-mats. Work done against gravity can be calculated with fair accuracy provided body posture is maintained during the measured climb. (Even briefer alactic tests, based upon single impulsive actions, such as vertical jumps, are less satisfactory in this respect.) Adult male power athletes may produce 15-19 W/kg* in a stair test.16 *Note: In this paper, power outputs and oxygen consumptions are expressed per unit body mass, as a rudimentary scaling factor. More sophisticated methods, such as allometric scaling6 or regression standards (recommended originally by Tanner and recently revived)62 should, however, be considered for critical work. (B) Wingate Institute 30 s cycling test17"19 This test is used world-wide for the assessment of overall anaerobic power, glycolytic ATP resynthesis being the predominant contributor. A computerized cycle ergometer continuously records power output during the half minute's maximum effort. Peak output is typically achieved after 2-5 s, this being the time taken to accelerate the wheel. (A recent modification20 allows for the wheel's inertia and gives earlier, rather higher peaks.) Standardsystem figures collected at the British Olympic Medical Centre (BOMC) range from 12-16 W/kg for the peak powers of highcalibre explosive athletes and 9-13 W/kg for middle and long distance runners (see also 16 ). Mean powers, over 30 s, are only a little higher than those of obtained by method (C) below]. (C) Maximum aerobic power (V O2IMX ) 11618 Oxygen consumption is measured during treadmill or cycle ergometer exercise. Work-rate is gradually increased, usually in

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3-4 min steps, till volitional exhaustion and plateaued O2 consumption (supported by standard criteria for heart rate, respiratory exchange ratio and blood lactate level) indicate that a maximum has been reached. Normally, the units used are ml O 2 consumed per minute. International middle-distance runners tested at BOMC have utilised 65-85 ml/kg/min, whereas figures for explosive athletes are usually in the 50's or low 60's and those of untrained subjects in the 30's or 40's (cf also ref. 21). [To translate to watts take ~ 20 J chemical energy released per ml O 2 consumed, on mixed diet, and ~ 2 3 % of this energy converted to mechanical work. We conclude that, in elite aerobic athletes, rates of about 5-6.5 W/kg may be reached; compare with 4-5 W/kg in explosive performers. These figures, set against those of (A) and (B), reflect the relative rate at which ATP can be resynthesized aerobically.] Three comments are appropriate, on this important parameter. Firstly, like (A) and (B), it measures the peak power obtainable from its particular metabolic system. Thus the highest figures are shown by high-intensity aerobic athletes, such as 5000 m runners; whereas marathoners, trained for demand which is more protracted but less intense, tend to show slightly lower figures. Secondly, as training advances—say, through a winter pre-track period after a few weeks' autumn lay-off—VO2IMI may be expected to increase at first but then virtually level out. This is taken to indicate that physiological limits of O 2 transporting capacity are reached fairly quickly, and it is the ability of muscles (including heart) to go on performing near those limits which one chiefly improves by further endurance training. Thirdly, since this is a test in which figures from varied exercises are often compared, note that the largest values are obtained when the greatest muscle mass is involved: thus most subjects will show lower values from tests recruiting the upper body alone than from leg exercise, while cycling (static arms) usually gives values 8-10% lower than running. Cross-country skiing (all four limbs working intensively) gives the highest values of all—up to 95 ml/kg/min have been reported.16 (D) Blood lactate measurements 1 1 6 1 8 This test is usually combined with (C). At the end of each incremental work period, a small drop of capillary blood is sampled and its lactate content analysed. Lactate curves obtained this way

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are illustrated (Fig. 2). Practical testers are principally concerned to identify the work-rate at which lactate becomes elevated significantly above resting level—the 'lactate threshold' (LT). The best criterion remains a matter of debate:22'23 curve-fitting procedures allow best for individual variation but fixed concentrations (2.0, or sometimes 2.2 or 2.5 mmol/1) appear to be gaining acceptance, being simple and unambiguous. In the majority of subjects a further phenomenon enters at work-rates say 15-20% above LT: blood lactate concentration now rises steadily with time even if rate of working is thereafter held constant. This point on the curve is designated the level of 'onset of blood lactate accumulation' (OBLA). For generality, though at the cost of ignoring considerable variations between individuals, OBLA is widely identified24 as the work-rate (watts, running speed, VO2 or % VOimM) at which blood lactate reaches 4 mmol/1 in an incremental test. Note, however, that terminology also varies: one laboratory25 calls 2 mmol/1 the 'aerobic' and 4 mmol/1 the 'anaerobic' threshold. The practical uses of LT and/or OBLA are three-fold: as indi10

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Fig. 2 Lactate accumulation during incremental work tests by two 20-year-old males of similar body mass (77-79 kg) but different sporting commitments: Subject 1 is a power athlete, Subject 2 an ultra-endurance performer. Subject 2's minimum lactate level is unusually low, but his plot serves to exemplify one of the shapes of curve from which it would be hard to define the lactate threshold, other than by a fixed concentration such as 2 mmol/1 (dashed intercepts). The solid intercepts indicate 4 mmol/1 ('OBLA'). From a class experiment.

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cators of fitness, as guides to tactics and as criteria for training. The first use arises because LT and OBLA are found 2326 ' 27 to increase rather more rapidly than V Oimai and go on increasing substantially longer, as intensive aerobic training advances. Lactate measurements are therefore now widely preferred as indicators of aerobic fitness. Their tactical use arises from observations that optimal times in marathon and similar events are achieved by performing at 97-100% LT 22 ' 27 ' 28 while events of 5-10000 m type require running speeds nearer OBLA.27'29 Finally, many coaches are satisfied, on the basis of experimental evidence22'25'26 and their own experience, that training at or slightly above OBLA is the most effective way to develop aerobic fitness. Those who have the resources therefore monitor lactates regularly, so as to increase intensity abreast of improvement. In terms of the broad tenet that one must controlledly overload the specific system one seeks to enhance, this approach makes sense, but to spell out a more detailed rationale is probably premature. It is not clear, for instance, whether the reason that working harder still is less beneficial is that, cumulatively over days, it depletes glycogen reserves too far, or that during each training session it raises the concentrations of H + and/or other fatigue-inducing products too quickly.

'ANAEROBIC THRESHOLD' CONCEPT Three linked thresholds So far this article has dealt mainly with accepted thought and practice; any controversy was remarked in the briefest way. By contrast, I shall now attempt to reach conclusions in an area of strongly divergent views. The standard texts previously cited,1"3 themselves exemplify the divergences. Many recent reviews have addressed these matters; those cited 5 ' 23 ' 27 ' 30 ' 31 represent the main range of opinion. They also supply references to early workers who will be merely named here. It was appreciated by Hill, Meyerhoff and others, early in the century, that the blood concentration of lactate was elevated by intensive work. By the 1930's, building on studies in Douglas's laboratory, Bang32 definitively established that lactate only rose at work rates elevating VOj to at least half maximum (Fig. 2). These investigators also observed that the rate of increase of ventilation with work-rate rose along with the lactate concentration; they proposed that breathing was stimulated by the CO2 released from

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plasma bicarbonate by the lactic acid. Thirty years later, in the early 1960's, independent contributions by Hollmann33 and by Wasserman and colleagues34 developed such thinking into the postulate that LT could be non-invasively detected using respiratory measurements. By analogy widi LT, the discontinuity in the ventilation/O2-uptake plot even became termed in several laboratories the 'ventilatory threshold' (VT), though of course a literal threshold of ventilation was not remotely intended. LT's importance was seen in terms of a concept enunciated more than 40 years earlier by Hill, which both Hollmann and Wasserman re-emphasized: namely that lactate accumulation indicated inadequacy of O2 supply to the active muscles. Hence a third, more fundamental threshold was considered to underlie the other two: the 'anaerobic threshold' (AT). (The later25 misappropriation of this term, noted above, need not detain us.) Conflation of the three thresholds is illustrated by this comment of Wasserman and colleagues:35 'The anaerobic threshold is defined as the level of work or of O2 consumption just below that at which metabolic acidosis and the associated changes in gas exchange occur.' Ventilatory threshold VO2 increases linearly with work-rate over almost the whole aerobic range. No other respiratory parameter does this; all the rest relate linearly to work-rate up to the threshold (or 'break') point in an incremental work test, and often linearly again above it—but on a different gradient. Thus ventilation rate (VE) and CO2 output CVco2) both rise more steeply above the breakpoint; so do many of the ratios between primary variables, such as the ventilatory equivalents for O2 and CO2 (VE/VO2, VE/Vco2). Conversely, %CO 2 in end-tidal air falls. Every one of the breakpoints could reasonably be attributed to a single underlying disturbance, such as the onset of metabolic acidosis. Appropriately, the majority of investigators have found the various breakpoints the same within experimental error, implying that any one could be used as a routine marker. VE, which is easily measured, is the most commonly selected though27 not the most sensitive indicator of VT. Accepting these procedures, we have next to ask whether VT always coincides with LT. Sadly, it does not. In healthy subjects, on a normal diet, the agreement between the two is usually27'34'35 (though not always36) found to be very close. However, glycogen

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depletion lowers the breakpoint in VE yet elevates LT; glycogen loading does the opposite.37 It is also reported that training dissociates LT from VT: both variables rise, but LT significantly more so, at least in early weeks.38 Finally, sufferers from McArdle's syndrome (who cannot produce lactate) have reasonably normal-looking ventilatory curves, showing break-points in VE and end-tidal gas partial pressures at workloads of 70-80% their own (very low) aerobic maxima.39 Thus it becomes appropriate to ask whether some other cause, normally but not mechanistically associated with the onset of lactate accumulation, underlies the various indications of VT. One possibility, which seems to have received less attention than it merits, is that other acidic products could be this cause—nonCO2 acid output from active dog muscles has been found to be as much as eleven times lactate output in one experimental condition.40 There are however recent, persuasive proposals that elevation of plasma potassium concentration, [K + ], is the principal influence leading to the disproportionate increase in ventilatory drive. Both in McArdle's-syndrome patients and in trained subjects with manipulated glycogen loads it is the [K + ] of the plasma, not its lactate content or pH, which correlates closely with VE;41-42 furthermore, this correlation applies not only to the work-rate at which the ventilatory break-point occurs, but to the post-exercise return towards normal respiration, the rapid part of which, following a period of work at high intensity, occurs in most normal subjects while blood lactate is still rising (Fig. 3). It appears that the stimulatory effect of K + on respiration, giving rise to VT, is mediated via the carotid bodies; these are K +-sensitive,43 and ventilatory transients are markedly depressed by their denervation or removal. (However, appropriate steady-state responses to exercise are ultimately attained after carotid body resection, so the K + effect at this site is not the crucial initiator of the main ventilatory adjustment. What is, is still debated.) As to the mechanism by which [K + ] is elevated, small quantities of the ion flow outward through muscle fibre membranes in the falling phase of every action potential; when vigorous exercise is sustained for periods of several minutes the summed effect of the barrage of electrical activity is a substantial elevation of the plasma concentration. The elevation is ~50% in representative situations. (Within the interstitial fluid of active muscle, [K + ] must rise considerably more than this; current thinking implicates such intramuscular [K + ] elevations in several aspects of fatigue and in

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Fig. 3 Mean plots of (a) blood lactate, (b) blood potassium, (c) ventilation for 5 endurance-trained subjects performing two successive incremental exercise tests with 7 minutes' recovery (working at 100 watts) between. Solid lines: normal conditions. Dotted lines: depleted muscle glycogen stores. Dashed lines: repleted (probably high) muscle glycogen stores. Plots (c) correspond substantially more closely to (b) than to (a), especially during recovery from the first test and performance of the second, but also in the comparison of low with normal glycogen results during the first test. Blood pH plots closely paralleled those for lactate. Results from Busse et al./ 2 redrawn with permission.

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exercise hyperaemia.) At high work-rates the [K + ] rise may41 be enhanced by another consequence of activity—accumulation of ADP and P, ions, which inhibit ATPases.6 Among the inhibited enzymes would be the Na/K-ATPase of the surface-membrane pump, the function of which is to transport K + back into the muscle fibres in exchange for Na + . We shall later see that ADP and Pj accumulation is also part of the process which, in fibres with normal enzyme complement and glycogen load, will promote an increase in lactate production. It should be acknowledged that, in the last 10-15 years, more sophisticated means of identifying AT from respiratory parameters have been developed by Davis and colleagues,27'44 following Wasserman & Whipp. The methods depend on rapidly-incrementing work tests (1-min stages), during which a phase of increasing VE/VO2 occurs at constant VE/Vco2 ('isocapnic buffering'). A specific intention is to evade confusing effects such as emotional hyperventilation; these, it has been suggested, are particular problems with McArdle's patients, since exercise is more likely to cause them pain. However, to most other workers the sophisticated definition appears arbitrary: the appeal of a simple cause-andeffect response to the elevation of blood lactate has been lost. Furthermore, the dependence upon rapid-increment protocols is open to two serious criticisms. Firstly, the insufficient time for lactate in the blood to equilibrate with the enhanced production by muscle runs counter to the objective of reflecting intramuscular redox state in respiratory drive. Secondly, after only 1 minute at a given work-rate muscle metabolism is still more anaerobic than it would be in the steady state (see first section on 'Stages & intensities of work'). If results for rapid-increment tests have proved at all compatible with other data, this can only be explained in terms of lactate mechanisms if the consequences of these two deficiencies have chanced to cancel each other. It is presumably for such reasons that only a few challengers38 to the belief that VT = LT have employed Davis's revised criterion. Nevertheless, until and unless VT thus defined is shown to coincide with the breakpoint in the K curve more precisely than it does with LT, the potassium hypothesis, favoured in this section, is unlikely to win acceptance in the opposing camp. Meaning of the lactate threshold This topic has recently been the subject of even more controversy than the one just discussed. There are two main questions:

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(1) Does the threshold for elevation of blood lactate represent the onset of its production in the muscles? (2) Does its production in the muscles indicate oxygen lack? Hollmann33 and Wasserman3435 of course took the answers to both questions as being affirmative. Brooks led the concerted attack on assumption A. Studies with isotopically labelled lactate suggested that substantial lactate turnover occurred within muscle at work-rates below those which released it into blood.4-45 This turnover was conceived as being between glycolysing muscle fibres which released lactate and others, with spare aerobic capacity, which took it up—a 'lactate shuttle'. Only when the uptake capacity was exceeded would lactate be released at significant rate into the blood. Even then, while other organs such as liver remained able to clear it there would be little accumulation. Significant elevation of blood lactate concentration in an incremental work test might be due to sympathetic vasoconstriction of visceral blood flow, with no nonlinearity at all in the rate of increase of release from muscle. However, it seems probable that Brooks and colleagues overestimated the extent of both the 'non-standard' mechanisms they considered. Katz & Sahlin 546 confirm earlier workers' evidence that exchange of labelled lactate with pyruvate is likely to have made the lactate shuttle appear several times more active than it is. Brooks's supporting concept of a sharp decline in visceral lactate clearance was always somewhat speculative, and a close match between the thresholds of elevation of intramuscular and blood lactates has been demonstrated in several studies. 2747 At work-rates > 80-90% V Oimai , and blood lactate concentrations > 7 mmol/1, intramuscular concentrations exceed extracellular, probably because a membrane carrier saturates; but exchange looks free and reasonably rapid (equilibrating in a few minutes) for the concentrations operative in the vicinity of threshold. Studies on partially-isolated dog gracilis muscles48 support this view. I shall therefore take it that LT represents, sufficiently for practical purposes, the start of significantly elevated intramuscular lactate production, as traditionally assumed. However, the further assumption, that lactate production indicates O2 starvation, is not acceptable. There are two reasons, both of which follow directly from the first section on 'stages and intensities of work'. The first consideration is the low aerobic capacity of the majority

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of 2B fibres: the ATP-synthesizing capacity of their sparse mitochondria falls far short of requirements. I suspect the shortfall is around 30-fold, for (taking data from Xenopus*9 in the absence of suitable mammalian information) this is the factor by which the ratio of aerobic to ATPase capacity in slow twitch, oxidative fibres exceeds that in fast, glycolytic ones—and it is improbable that the oxidative capacity of slow fibres exceeds requirements. The major pathway of ATP synthesis in 2B fibres must therefore be the pathway of anaerobic glycolysis ('anaerobic' meaning 'without involving O2', not 'when O2 isn't available'). It follows that lactate and H + ions are steadily released from fully-activated 2B fibres, irrespective of PO2. Probably the greatest surprise in the LT literature is that this point has apparently been so widely overlooked. What remains a valid research question is whether recruitment of 2B motor units, specifically those with aerobic capacities demonstrably insufficient to match their ATP consumption rates, begins at LT or only at higher work-rates still. It is suggestive but not conclusive that there are strong positive correlations between LT and the percentage of type 1 fibres.5051 Electromyographic evidence can also be interpreted as indicating the onset of 2B recruitment close to LT, 52 but more investigation of this point is desirable. The second consideration relates to highly-aerobic (red) muscle generally, and most specifically to 2A fibres. Here the question, 'Does lactate production indicate O2 starvation?' is a much more difficult one. However, the fact that blood lactate concentration is rarely less than 1 mmol/1 in resting and very lightly-exercising subjects, who cannot possibly be using any 2B fibres, should prepare us for the answer to be 'No'. One line of evidence pointing in this direction is that venous P Oj from a vigorously-exercising limb is many times the limiting value for mitochondrial function.53 However, this is not conclusive: there has to be an inward P 02 gradient from the capillaries, even at their venous ends, to the core of each active muscle fibre, and we need to know how large that gradient is. Modern work on the oxygenation of myoglobin, 31 ' 54 ' 55 supplies the answer. P Oj in the cores of the fibres of a red muscle fibre working maximally (i.e. substantially above what would, in the whole man or animal, elicit LT) is, in almost every instance, several torr. Estimates of how low it would have to be to impair mitochondrial function vary from 0.5-0.05 torr— l/10th-l/200th of the values observed. The electron transport chains are therefore still functioning at their maximum rates, and

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cannot usefully be said to be O2-deprived. Yet the individual animal muscles upon which these experiments are done (notably dog gracilis3148) show the same LT phenomenon as a human athlete: lactate efflux from them increases markedly at work-rates above about 50% of their V 02mai . It is true that POj becomes sufficiently diminished at this workrate that increased intramitochondrial levels of NADH are necessary to maintain the electron flux. Thus the difference between the viewpoints of those such as Katz & Sahlin5 who describe the metabolism in this condition as 'O2-limited' and of Connett and colleagues31 who say that it is not, might perhaps be considered semantic. The substantive point is, however, that the observed increases of [NADH] do not imply P 0 3 sufficiently low that electron transport, and therefore aerobic ATP production, is curtailed. Flux along the electron transport chain continues to increase with need, and supply all but a trivial quantity of the required ATP. What we observe are merely the adjustments necessary to maintain this flux (Fig. 4). However, if mitochondrial [NADH] rises, so will cytoplasmic— which causes the phenomenon we have been seeking to explain, production of more lactate. As part of the same adjustment, [ADP] and [P,] will have risen also, producing the side effects on ATPases previously noted. (In the language of biochemical systems theory,31 the redox and phosphorylation states within the cell must change in parallel.) One last experiment on autoperfused canine gracilis. As observed on many previous occasions, lowering the P Oj of the inspired air increases lactate production: over a considerable range below normal, however, it does so without measurably reducing VOj.56 Thus the rate of oxidative phosphorylation is maintained, and it is calculated that at least 97% of the muscle's ATP is made that way. So even in this simulated altitude situation the HillMeyerhoff assumption, that muscle metabolism is being curtailed by lack of O 2 , cannot be upheld. Returning to the whole man, there are several indications that the viewpoint just presented is correct.2223 Among the strongest is that training which lowers blood lactate at a given submaximal work-rate does not increase that work-rate's VOl.57 Limits to oxygen uptake One problem remains with the above account—what happens at the approach to V03mmi? There are strong grounds58 for believing

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ATPase sites

ATP'

•ADP + P, + ENERGY

G-6P

LACTATE

PYRUVATE

FA's NAD+

NADH Shuttle

NADH Mitochondrion

Fig. 4 Pathways of muscle metabolism. As the demands on a muscle fibre rise, the ATPase sites on its crossbridges and membrane pumps increase their rates of breakdown of ATP to ADP and P,. Allosterically (dashed lines and ' + ' signs) these products enhance the activities of both glycolytic pathway and Krebs cycle enzymes. More pyruvate is produced, and the great majority of it feeds into the cycle, increasing intramitochondrial production of NADH. This is predominantly re-oxidised in the electron transport chain, at a rate proportional to the product rNADH][O2][ADP][P|] and inversely proportional to [NAD+][ATP]. Therefore the ratio [NADH]/[NAD+] will vary inversely with [O2], but over a wide range the rate of rephosphorylation of ADP on the chain will remain effectively constant, so that the fibre cannot be said to be oxygen-starved. Nevertheless, any increase in the mitochondrial [NADH]/[NAD+] ratio will be reflected cytoplasmically, as NADH reducing equivalents are equilibrated by shuttling across the mitochondrial outer membrane. Lactate production from pyruvate will thus increase. However, the contribution of glycolysis-terminating-in-lactate to the overall energy output will remain almost negligible. Formation of AMP from ADP, and production of NADH by glycolysis, omitted to minimise complexity. G-6P = glucose-6-phosphate, FA's = fatty acids.

that this parameter is determined by the pumping capacity of the heart, not the metabolic capacity of the muscles. Thus, in humans, 1-legged exercise achieves a VOimtx which is typically ~ 7 5 % , not 50%, of the 2-legged figure. It seems that only ~ l / 3 the total muscle mass of a trained man, if maximally active, would require his full cardiac output (CO). Mammals like dogs, horses and particularly certain antelopes, which have higher CO's per kg than humans, have proportionately higher VO2mM values also; their

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muscle aerobic capacities are not proportionately elevated.58'59 From such considerations it appears likely that when large, though not small, muscle masses in humans are fully active, regions within them must be O2-deprived. In turn the possibility arises that with these large active masses, even at LT, some deprivation is beginning. Connett, Hogan and their respective colleagues,31'56 after all, did their experiments on single (dog!) muscles, with the rest of the body quiescent under anaesthetic. They have shown that LT need not imply hypoxia, but not that it never does. Experiments should therefore be designed in which single human muscles or small groups are worked at the same rates alone and as parts of whole-body efforts, to establish whether they produce lactate earlier in the latter case. Meantime, there are pointers that they will not do this. One was given at the end of the last subsection. Earlier we saw that, even in large-mass efforts, such as running and cycling, LT and VOimMX are not tightly coupled: LT is more susceptible to training, and seems to correlate more closely with muscle aerobic enzymes than with whole-body VO2mMI. A final indication is that, after cardiac rehabilitation, endurance running performance and LT may be normal, despite severely reduced CO and V02mai—in the extreme, VO2moi and LT (defined as lmmol/1 above baseline) become effectively coincident.23'60 The probability is, therefore, that even in humans, and even when a large muscle mass is active, O 2 deprivation does not enhance lactate production until very close to V Oimai . But one would prefer to know for sure. ACKNOWLEDGEMENTS I gratefully acknowledge contributions to this review—in terms of fact, comment or encouragement—by Martin Busse, Richard Connett, Leopold Faulmann, Richard Godfrey, Stanley Grant, Sheila Jennett, Gordon Lindsay and Edward Winter; but none of these must be held in the least responsible for my failures to be educated properly. REFERENCES 1 Astrand P-O, Rodahl K. Textbook of work physiology. New York: McGrawHill, 1986 2 Brooks GA, Fahey TD. Exercise physiology. New York: Wiley, 1984 3 Powers SK, Howley ET. Exercise physiology. Dubuque, la: WC Brown, 1990 4 Brooks GA. Lactate production during exercise: oxidisable substrate versus fatigue agent. In: Macleod D, Maughan R, Nimmo M, Reilly T, Williams C, eds. Exercise: benefits, limits and adaptations. London: Spon, 1987: pp. 144-158

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