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Symposium Reports |
1 Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK
Abstract
During moderate exercise (below the lactate threshold, 
L), muscle CO2 production (
) kinetics are monoexponential, with a time constant (
) similar to that of O2 consumption. Following a delay incorporating the muscle–lung vascular transit time, 
is expressed at the lungs (
) with an appreciably longer , reflecting the influence of intervening high-capacitance CO2 stores. Above L, 
kinetics become complex, resulting from the conflation of the differing rates of HCO3– breakdown and degrees of compensatory hyperventilation with that of the underlying aerobic component. During incremental exercise, the increased rate of 
relative to pulmonary O2 uptake (
) can be used to quantify L validly if aerobic and hyperventilatory sources can be ruled out, i.e. L is then attributable to the decrease in muscle and blood [HCO3–]. In many cases, however, very rapid incrementation of work rate and/or prior depletion of CO2 stores (by volitional or anticipatory hyperventilation) can yield a ‘false positive’ non-invasive estimation of L (‘pseudo-threshold’) resulting from a slowing of the rate of wash-in of transient CO2 stores.
(Received 28 November 2006;
accepted after revision 13 December 2006; first published online 21 December 2006)
Corresponding author B. J. Whipp: Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK. Email: b.whipp{at}leeds.ac.uk
During the non-steady state of muscular exercise, the tissue capacitance of the blood and skeletal muscle (i.e. the change in the amount of gas loaded into or released from the tissue of interest per unit change in its partial pressure) dissociates the pulmonary gas exchange transients from those of the muscle metabolic changes. Since the tissue capacitance for CO2 is appreciably greater than for O2 (Farhi & Rahn, 1955), this means that the respiratory exchange ratio (R), i.e. the ratio of the volumes of CO2 and O2 exchanged across the tissue of interest per unit time, will differ from that of the respiratory quotient (RQ), i.e. the ratio of the amounts of metabolic CO2 and O2 produced and consumed, respectively, by the tissue per unit time not only across the lung, where it is most typically determined and from which inferences are most typically drawn, but also across the muscle vascular bed itself. For example, the normal CO2 capacitance of blood, evidenced by the slope of its dissociation curve over the region of interest, is severalfold greater than that for O2 (Piiper, 1965). But, in addition, skeletal muscle contraction results in a transient metabolic alkalosis in the force-generating units (Steinhagen et al. 1976; Kemp, 2005) and in the venous effluent of the exercising muscle (Wasserman et al. 1997) as a result of the net proton (H+) trapping associated with the high-energy phosphate utilization, i.e. H+ release as ATP is split, and H+ uptake consequent to phosphocreatine (PCr) splitting (Kushmerick, 1997). The proton trapping during the PCr-related regeneration of ATP is given by:
|
| (1) |
, the proton-trapping quantifier based on the charge difference between PCr and inorganic phosphate (Pi), having a value slightly less than 0.5 at muscle pH (Kemp, 2005). This transient alkalosis therefore results in a component of the metabolically produced CO2 being retained within the muscle. Constant work-rate exercise
Moderate intensity.
Below the lactate threshold (L), the time course of pulmonary CO2 output (
) relative to that of O2 uptake (
) during the non-steady-state phase of a constant work-rate (WR) test is consequently slow, in that 
normally increases in healthy young subjects with a time constant () of 
30–40 s while 
is 50–60 s (Fig. 1). Ventilation (
) changes marginally more slowly (
55–65 s; Fig. 1). Consequently, since 
is appreciably longer than 
, the alveolar and arterial partial pressures of O2 (
and 
, respectively) fall transiently (Fig. 1). But, owing to the relatively small kinetic dissociation between 
and 
, the transient arterial 
(
) increase is only a millimetre of mercury or so (see Whipp & Ward, 1981, for discussion).
|
and 
is evident for the first of the two-step, constant-WR challenge shown in Fig. 2 (Brittain et al. 2001), and accounts for R being reduced below the RQ during the on-transient non-steady state and also for R being ‘out of phase’ with 
and 
during moderate-intensity sinusoidal exercise (Casaburi et al. 1977). At the off-transient of such a test, the stored CO2 is released, leading to R being increased above the RQ until the new steady state is attained. Note, however, that the degree of dissociation between 
and 
during the on-transient of the higher, but equal WR increment, step is appreciably less (Hughson & Morrissey, 1982; Whipp & Ward, 1991; Fig. 2). The 
time course is slowed slightly, despite the WR still being within the moderate-intensity domain, as originally demonstrated by Hughson & Morrissey (1982); this is thought to reflect the recruitment of an altered fibre-type pool (Brittain et al. 2001). In contrast, the 
time course is appreciably speeded both in absolute terms and relative to that of 
, presumably because the muscle CO2 capacitance is already partly charged at the onset of the higher WR bout; this accounts for the markedly reduced decrease of R during the higher transient (see Whipp & Ward, 1991, for discussion).
|
L, the components of the 
kinetics are more complex, reflecting in addition: (a) the translation of the non-linear 
‘slow component’ into a corresponding 
response; (b) production of supplemental CO2 from the rate (rather than the amount) at which muscle and blood [bicarbonate] ([HCO3–]) decrease consequent to buffering of the H+ associated with the [lactate] ([L–]) increase; and (c) the time course of the compensatory hyperventilation for the metabolic acidosis. At WRs during which 
and arterial [L–] ([L–]a) and [H+] ([H+]a) increase continuously to the limit of tolerance (i.e. very heavy intensity), 
kinetics often have a monoexponential-like appearance (Casaburi et al. 1989; Stringer et al. 1995; Özyener et al. 2002; Fig. 3A). Interestingly, no 
‘slow phase’ is evident, despite this being clearly discernible in 
. This apparent steady-state-like behaviour of 
, however, should not be considered reflective of simple-compartment dynamics. Rather, the 
profile conflates the offsetting influences of the slowing of the rate of [HCO3–] decrease and the delayed onset of the progressive hyperventilatory decline in 
(Sun et al. 2001) with that of the underlying aerobic component (Fig. 3B).
|
, [L–]a and [H+]a can be stabilized at constant, although elevated, levels (i.e. heavy-intensity exercise), the 
profile often evidences an overshoot before subsequently stabilizing (Özyener et al. 2002). This reflects the influence of the rapidly falling phase of [HCO3–] (Stringer et al. 1995), but with little or no early recruitment of compensatory hyperventilation (Özyener et al. 2002). The 
is typically slightly elevated (e.g. 3–4 mmHg) during the initial on-transient phase at this intensity, as a result of the kinetics of respiratory compensation for the acidosis being long (Rausch et al. 1991), presumably owing to the relatively slow carotid-body chemoreceptor responsiveness to [H+]a compared to that of 
(Buckler et al. 1991). Incremental exercise
The changes in the blood and muscle CO2 stores wrought by the increase in L–-associated protons during the heavy- and very heavy-intensity phases of ramp-type incremental exercise provide the basis for the non-invasive estimation of L. The protons are exposed to a pool of buffers, including protein-linked histidine residues, Pi and HCO3– (predominantly as potassium bicarbonate in cytoplasm and sodium bicarbonate in plasma), that constrain the acidaemia resulting from the acidosis. All the buffers are involved, but to varying degrees. In fact, the initial 0.3–0.5 mM of the [L–] increase is dominated by buffers other than HCO3– (Visser et al. 1964; Wasserman, 1994). Bicarbonate, however, is ‘special’ in this context, because it is part of an ‘open system’ subserving more than 90% of the buffering (Visser et al. 1964; Wasserman, 1994):
|
| (2) |
22.26 ml of additional CO2 is produced from each milliequivalent decrease of [HCO3–]. As [H+] increases, [HCO3–] falls, with an increase in CO2 production rate in, and from, the contracting muscle units as a necessary consequence. This results in an obligatory increase in CO2 output from the muscle and, subsequently, from the lung. The temporal dissociation between these variables is also manifest in the delay between muscle O2 consumption and 
at the lung. This is the basis for characterizing the onset of the metabolic acidosis, as estimated from pulmonary gas exchange, as a metabolic rate (
) rather than a work rate. That is, the WR continues to increase during this delay in an incremental test, by an amount that is incrementation-rate dependent.
The extra-aerobic CO2 formed in these ‘anaerobic’ reactions is quantitatively large: a 2.5-fold local increase in 
(and a 12.5-fold increase in glycogen utilization rate; Whipp & Ward, 1991). It is this that makes 
analysis, as a function of 
(Fig. 4), such a good functional index of the onset of the metabolic acidosis (Beaver et al. 1986; Whipp et al. 1986).
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) under these conditions is a function of the amount of [HCO3–] decrease in blood and muscle compartments. Any contribution from non-HCO3– buffering mechanisms, while important for [H+] regulation, does not produce extra CO2. The rate at which extra CO2 is produced from these reactions (i.e. 
) is a function of the rate at which [HCO3–] falls, not the amount of the decrease. Consequently, the more rapid the rate of [L–] increase, the greater is the increase in the pulmonary CO2 exchange rate. This accounts for both 
and R being appreciably higher at a given 
in the period of increasing [L–]a during rapid-incremental exercise, compared with tests where the WR incrementation rate is relatively slow (Whipp & Mahler, 1980; Ward & Whipp, 1992; Scheuermann & Kowalchuk, 1998). In contrast, the amount of CO2 produced during a slowly incrementing test is severalfold greater than that for a rapidly incremental test (Ward & Whipp, 1992) as a result of the CO2 unloading consequent to the progressive arterial hypocapnia that provides the respiratory compensation for the metabolic acidosis.
Consequently, after the early kinetic phase, the relationship between 
and 
during an incremental test (which is termed the V-slope) is characterized by a relatively linear relationship over the moderate-intensity range, a region termed S1 (Beaver et al. 1986). This is followed by an increased slope (S2) within the ‘isocapnic buffering’ phase that extends up to the ‘respiratory compensation point’ (i.e. a region characterized by a lack of end-tidal 
(
) decrease; Wasserman et al. 1973; Whipp et al. 1989; Fig. 4). The intersection of these two linear phases has been shown to agree closely with the onset of increase in [L–]a and the [L–]a/[pyruvate]a ratio and decrease in [HCO3–]a (Beaver et al. 1986; Fig. 4) and, in those cases in which there is no sufficiently linear S2 region, the acceleration of 
relative to 
can be used as the L estimator.
However, in order to appropriately subserve its role in L discrimination, 
must not simply increase more rapidly during the phase of increasing blood and muscle [L–] but must do so such that the discernibly additional CO2 is of HCO3– origin. That is, hyperventilation (by definition, a reduction in 
) must be ruled out as the cause. This can be convincingly justified using ventilatory and pulmonary gas exchange criteria (Whipp et al. 1986; Wasserman, 1994). This is based on mass balance considerations, in that 
can only be regulated if there is a precise proportional relationship between the ventilatory equivalent for CO2 (
) and the physiological dead space fraction of the breath (VD/VT):
|
| (3) |
The decrease in 
over the early regions of an incremental test ‘matches’ the decrease in VD/VT (except for a small kinetic dissociation between 
and 
, which leads to 
being increased by a millimetre of mercury or so during the non-steady-state phase). Also, while VD actually increases as VT increases, this increase is small compared with the change in total lung volume. However, since VD/VT has usually decreased to, or close to, its minimum value at L, hyperventilation requires 
to increase or to decrease at a slower rate. For ‘standard’ ramp-incremental exercise, i.e. exercise designed to last 10 min (see Wasserman et al. 2004, for discussion), this rarely occurs until a much higher WR; how ‘much’ depends on the WR incrementation rate. Consequently, the relatively constancy (Fig. 4), or even a small continued decrease, of 
over this range rules out hyperventilation as the cause of the increased 
slope. The stability of 
(isocapnic buffering) supports this contention. However, for more prolonged incremental tests, the extent of the isocapnic buffering region is reduced or even abolished as the slow carotid-body responsiveness to [H+] has time to be expressed (Buckler et al. 1991; Rausch et al. 1991).
Avoiding a pseudo-lactate threshold
The 
can begin to increase at a discernibly greater rate during exercise, not simply because CO2 begins to be produced at a faster rate but also because its storage rate begins to slow, or stops. For example, during the non-steady-state phase of a moderate constant-WR test, the slowing of the transient CO2 storage causes R to stop decreasing and subsequently to increase to, or towards, its steady-state value at which it again equals the metabolic RQ. Similarly, during an incremental test in which the WR increases very rapidly, the transient CO2 storage can be considerable, leading to an unusually low S1 slope (Ward & Whipp, 1992; Fig. 5). The subsequent reduction in CO2 storage rate leads to an increase in the rate of 
relative to that of 
, with a new S2 slope that, of itself, would be suggestive of the onset of a lactic acidosis (Fig. 5). But the unusually low S1 slope and falling R at the time of the transition distinguish it from the conventional gas-exchange profile indicative of the onset of a lactic acidosis (Fig. 5).
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between the control and the prior-hyperventilation tests, the 
response as a function of 
could, in each subject, be characterized by two linear phases, but with an S1 slope during the prior-hyperventilation test that was appreciably lower than control and with a subsequent S2 slope that did not differ from control (Fig. 6). The observation that 
kinetics were slowed during the early phase of the posthyperventilatory ramp is not surprising. The surprising point is that the 
slope from the S1–S2 transition to the actual L appeared to be no different from the 
slope above L (Fig. 6); this was the case in all of the subjects. Also, in each case, the S1–S2 transition occurred before the onset of the lactic acidosis (e.g. Fig. 6) and in concert with the minimum of the decrease of R. As the ventilatory and pulmonary gas-exchange responses met the currently conventional criteria for estimating L (Wasserman, 1994; Whipp et al. 1986), we termed this a pseudo-lactate threshold. Note, however, that the ratio of the baseline-phase R (R0) to S1 slope (i.e. R0/S1) was appreciably greater than that for the pseudo-threshold test, whereas it was consistently less than that for the control test, in which the pulmonary gas-exchange criteria provided a valid estimation of L.
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L was properly estimated, since there was no unusually large CO2 wash-in to a recently, partly depleted CO2 store during the transient. In this case, therefore, R0/S1 is normal, since both R0 and S1 are low as a result of the glycogen depletion. By the same token, a low baseline-phase 
is also not, of itself, a concern in this regard. As shown in Fig. 8B, subjects who manifest chronic stable hyperventilation, i.e. with low 
but with normal arterial pH (Jack et al. 2004), can regulate 
at its low but stable value during incremental exercise rather than 
increasing to re-establish a normal arterial pH, as occurs in the period following acute hyperventilation; R0/S1 is consequently normal.
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References
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, –
·
–), CO2 output ( 
; ·
·
·
·) and ventilation ( 
; ———) in response to moderate constant-load exercise from rest (top) and unloaded pedaling (middle), with corresponding profiles of arterial 
and 
(
; –
·
·
–) (bottom). 
and CO2 output 
in response to a moderate, two-step exercise protocol (i.e. two consequtive, equal work-rate increments, from unloaded pedalling) 
and 
responses normalised to the corresponding steady-state increments, for the first step (bottom) and second step (top), with mono-exponential model fits superimposed [—; after a delay accounting for the initial ‘cardiodynamic’ phase]. Note that, relative to 
is faster on the second higher step than on the first step; see text for details. Modified from 
in response to supra-threshold constant-load exercise 
(
) and 
(•) responses; note the more rapid 
response, relative to 
. Modified from 
response (top) and arterial [bicarbonate] (bottom) to supra-threshold constant-load exercise. See text for further detail.
, [lactate]a, [HCO3–]a and arterial pH 
, R and arterialized-venous [lactate]
versus 
L) was evident, occurring at a lower 
than the directly estimated lactate threshold (
) 
with continuous line showing best-fit S1 slope and vertical dashed line the lactate threshold; arterial [lactate] ([L–]); and standard [bicarbonate] (Std [HCO3–]). A, control; B, posthyperventilation. The asterisk denotes the directly measured lactate threshold for the posthyperventilation test. From 
(•) and heart rate (HR; 
, with best-fit S1 and S2 slopes (continuous lines) (top left); respiratory exchange ratio (RER) versus time (bottom left); 
(•) and 
(
(
; •) and end-tidal 
versus
, with best-fit S1 and S2 slopes (dashed lines) and values with estimated lactate threshold (
, vertical arrow) for control (top), glycogen depletion (middle) and glycogen repletion (bottom). From 
, in a chronically hyperventilating subject. From bottom to top: 
(
(•), 
(
(•), and 
with best-fit S1 slope (dashed line) with estimated lactate threshold (