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1 Faculté de Médecine, Centre de Resonance Magnetique Biologique et Medicale, Unité Mixte de Recherche 6612 Centre National de la Recherche Scientifique, Marseille 13005, France; and 2 Department of Musculoskeletal Science, University of Liverpool, Liverpool L69 3GA, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We used
31P-magnetic resonance spectroscopy to study proton
buffering in finger flexor muscles of eight healthy men (25-45
yr), during brief (18-s) voluntary finger flexion exercise (0.67-Hz contraction at 10% maximum voluntary contraction; 50/50 duty cycle) and 180-s recovery. Phosphocreatine (PCr) concentration fell
19 ± 2% during exercise and then recovered with half time = 0.24 ± 0.01 min. Cell pH rose by 0.058 ± 0.003 units during
exercise as a result of H+ consumption by PCr splitting,
which (assuming no lactate production or H+ efflux) implies
a plausible non-Pi buffer capacity of 20 ± 3 mmol · l intracellular
water
1 · pH unit1.
There was thus no evidence of significant glycogenolysis to lactate
during exercise. Analysis of PCr kinetics as a classic linear response
suggests that oxidative ATP synthesis reached 48 ± 2% of ATP
demand by the end of exercise; the rest was met by PCr splitting.
Postexercise pH recovery was faster than predicted, suggesting
"excess proton" production, with a peak value of 0.6 ± 0.2 mmol/l intracellular water at 0.45 min of recovery, which might be due
to, e.g., proton influx driven by cellular alkalinization, or a small
glycolytic contribution to PCr resynthesis in recovery.
bioenergetics; buffer capacity; glycogenolysis; phosphorus-31 magnetic resonance spectroscopy; skeletal muscle
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ALTHOUGH THE NONINVASIVE
TECHNIQUE of 31P-magnetic resonance spectroscopy
(MRS) of muscle can measure far fewer metabolites than biopsy-based
methods, time-resolved 31P-MRS measurements of exercise and
recovery changes in phosphocreatine (PCr), Pi, and
cytosolic pH offer a window into important aspects of ATP turnover and
cellular acid-base physiology ("H+ handling")
(15). There are two basic approaches: assume cytosolic buffer capacity (
) and so estimate lactate synthesis
(4); or assume a constant contractile efficiency and so
estimate, for example, glycolytic ATP synthesis in ischemic
exercise (13) and oxidative ATP synthesis in pure
"aerobic" exercise (24). The (13) is
difficult to measure in vivo, except indirectly by using
31P-MRS (1). We earlier used an analysis of
ischemic exercise (13) to estimate in human
muscle, which was complicated by its pH dependence. Here we set out to
minimize such complications by studying the early phase of the
rest-exercise and exercise-rest transitions by using
31P-MRS. Because of their bearing on the analysis of ATP
turnover, we also consider some quantitative implications of recent
proposals that rapid cycles of PCr splitting and resynthesis
(3), fueled by anaerobic glycogenolysis (29),
operate during muscle contraction, unobservable by conventional
31P-MRS or biopsy methods. Part of this work has been
presented in preliminary form (12).
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. The study was conducted on the dominant forearm of eight male volunteers, aged 25 to 45 yr. Subjects were not involved in any arm training and had no physical limitation to exercise. Their written, informed consent was obtained for the study, which was approved by the local ethics committee.
Exercise protocol. During training sessions performed several days before MRS studies, maximum isometric finger flexion force was measured until three reproducible values were sustained for 3 s. 31P-MRS investigations were carried out as previously described (13) by using a Bruker 47/30 Biospec spectrometer interfaced to a 30-cm bore, 4.7-T superconducting magnet. Subjects sat on a chair with the dominant arm, restrained with Velcro straps, resting in the magnet bore at shoulder height (to ensure good venous return). Magnetic field homogeneity was optimized by monitoring the signal from water and lipid protons at 200.14 MHz. Pulsing conditions (1.5-s interpulse delay, 120-µs pulse length) were chosen to optimize the 31P signal obtained with a 50-mm-diameter surface coil (double-tuned for 31P and 1H) positioned over the belly of the flexor digitorum superficialis muscle at the maximum diameter of the forearm. Spectra were time-averaged over 6 s (4 scans). After 10 spectra were recorded at rest (60 s), subjects performed finger flexion at 1.5-s intervals for 18 s (3 spectra), followed by 180-s recovery (30 spectra). This sequence was repeated three times consecutively. Exercise consisted of lifting a weight adjusted to 10% maximum voluntary contraction in a 50/50 duty cycle (i.e., 0.75-s contraction, 0.75-s relaxation). Contraction-relaxation cycles were gated to magnetic resonance spectra acquisition by using a home-built trigger, with spectra being recorded from the start of contraction. The sliding amplitude and frequency of the weight were recorded by using a displacement transducer connected to a personal computer running ATS software (SYSMA-FRANCE). Calculated power output was averaged over each 6 s of exercise (i.e., one spectral accumulation).
Calculation of pH and metabolite concentrations.
As described elsewhere (13, 23), MRS signals were
processed by using NMR1 software (New Methods Research) by 15-Hz line broadening, baseline correction, Lorentzian peak-fitting, and correction for differential magnetic saturation. Absolute
concentrations were calculated assuming [ATP] = 8.2 mmol/l
intracellular water (brackets denote concentration). Free [ADP] was
calculated from the creatine kinase equilibrium, assuming 42.5 mmol/l
intracellular water of total creatine (13).
Signal-to-noise ratio at rest was 400 for PCr and 60 for
Pi. [Mg2+] is relevant to the
stoichiometric calculations, which are described below. To test the
possibility that this changes during the rest-exercise and
exercise-rest transitions, we monitored the chemical shift of the
central resonance of -ATP (relative to PCr at 
2.45 parts/million).
Kinetic analysis. To obtain the half time of PCr recovery, we fitted the time-dependent [PCr] changes during the exercise-rest transition to a monoexponential equation (24) and assumed that the PCr resynthesis rate approximates that of oxidative ATP synthesis at the end of exercise (10). The same approach is used to estimate the initial rate of PCr depletion in exercise (a measure of total ATP turnover) (9). Due to uncertainty about steady-state [PCr] in such short exercise, a free fit is unreliable, and we constrained the half time to be the same as in recovery, in accordance with a standard model of aerobic exercise (24). In both cases, we corrected for the bias involved in sampling an exponential time course with finite time resolution (30). Because we will argue that glycolytic ATP production is negligible during exercise, we estimated oxidative ATP synthesis rates as the difference between the instantaneous and initial rates of PCr depletion (24).
"Proton balance" calculations.
The Lohmann reaction (PCr splitting to maintain constant [ATP],
despite mismatch between ATP supply and demand) can be written as
PCr 
Pi + creatine + 
H+,
where the coefficient (negative, representing net H+
consumption) is the difference between the net charges on
Pi and PCr (13), given empirically by a cubic
function of pH (4, 19). Conversely, in the reverse
Lohmann reaction (net PCr resynthesis during recovery),
Pi + creatine + H+ PCr,
representing net H+ generation. During exercise, the net
H+ load that results in pH change is the difference between
glycolytic H+ production (= change in lactate) and
H+ consumption by PCr splitting. We will argue that lactate
production is negligible, so that H+ load = 
d[PCr], which is negative and results in
alkalinization. During recovery from acidifying exercise, pH returns to
basal, despite net H+ generation by PCr resynthesis,
because of net H+ (acid) efflux from the cell by various
means (18). Here, where muscle alkalinizes during
exercise, we will argue that H+ efflux during recovery is
negligible, so that H+ load = d[PCr], which
is positive and results in acidification (8). In general,
the total (T) is estimated by T = d[H+ load]/dpH. If there is no lactate production in
exercise, this becomes T = 
[PCr]/pH. A
component of this is due to Pi (13), which is
subtracted from T to yield the true .
pH)] (15). If this is taken into account, then,
in exercise, the revised (negative) net H+ load resulting
from PCr splitting is H+ load = mQ
dt d[PCr], where Q is ATP synthesis rate and
is estimated as above, and t is time. Similarly, in
recovery, the (positive) H+ load resulting from PCr
resynthesis is H+ load = (m )d[PCr]. This correction tends to make the H+ load
more positive and increases estimated . However, we argue later that
only a small fraction of this potential H+ load remains in
the cell during recovery.
To compare recovery and exercise, we calculate, for all intervals of
recovery, the amount of H+ generated by PCr resynthesis.
Comparing this with the amount of H+ buffered, assuming the
established during exercise, we will find an excess H+
load (i.e., required to account for the pH being more acid than expected), whose cumulative expression is excess H+
load = (pH + [PCr]). We also make this point
by calculating the predicted pH change from the H+ load
from PCr resynthesis and the established in exercise: pH = ([PCr]/).
Statistical analysis. Values are reported as means ± SE and are compared by two-tailed t-tests, paired and unpaired as appropriate. Curves are fitted by least squares.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Kinetics of pH and PCr.
The time courses of [PCr] and cytosolic pH are shown in Fig. 1,
A and C. As the
three exercise-recovery cycles gave statistically indistinguishable
results (see right side), these were combined. As
expected, [PCr] fell during exercise and rose more slowly during recovery (Fig. 1A). In aerobic exercise, PCr changes in both
exercise and recovery are expected to obey the same monoexponential
kinetics (24), from which PCr recovery half time = 0.24 ± 0.02 min (
rate constant 3.0 ± 0.2 min1). Whereas it is impossible to assess whether the
three exercise data points obey similar kinetics, the fit is acceptable
as a first approximation (Fig. 1A) and gives a total ATP
turnover rate of 43 ± 5 mmol · l
intracellular
water1 · min1. [This
is close to that given by the method in Ref. 6,
which is based on estimating what the PCr change would be
if oxidative ATP synthesis (assumed to have the same ADP dependence in
exercise and recovery) were absent.] The initial rate of postexercise
PCr resynthesis, a measure of end-exercise oxidative ATP synthesis rate
(10), is 21 ± 2 mmol · l
intracellular
water1 · min1, which
is, therefore, 48 ± 2% of the total ATP demand.
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Analysis of proton balance.
Figure 1E shows the time course of the "proton loads"
resulting from these changes. The main actual component is due to the Lohman reaction, consuming H+ during exercise when PCr is
falling and generating H+ during recovery when PCr is
resynthesized. These two components are opposite and equal (triangles
in Fig. 1E). Comparison of the pH change and this (negative)
H+ load in exercise gives = 20 ± 3 mmol · l intracellular
water1 · pH unit1
(see Fig. 2). Using this value, we have
calculated the expected pH change in recovery resulting from PCr
resynthesis (squares in Fig. 1C). Unexpectedly, the
predicted rate of reacidification is significantly slower than
observed, suggesting that extra H+ (open triangles in Fig.
1E) are being added in recovery by H+ influx
and/or glycolytic ATP production.
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= 20 mmol · l
intracellular water1 · pH
unit1 (see above). Figure 2 also shows lines of
increasing [ADP] (a function of pH and [PCr]); the experimental
point moves in the direction of increasing [ADP] during exercise and
returns during recovery (open circles, dashed line). The difference in
the "outward" and "return" trajectories can be seen. Figure
2B pursues this by plotting the H+ load
resulting from PCr changes (a function of PCr and pH) against the pH
change (13). Also shown are lines of constant : the data are consistent with = 20 mmol · l
intracellular water1 · pH
unit1 (as shown also in Fig. 2A).
The mean ± SE chemical shift of -ATP was 18.59 ± 0.02 in the 10 spectra recorded at rest, 18.58 ± 0.02 in the 3 exercise spectra, and 18.59 ± 0.01 in the first 10 spectra in
recovery. These are essentially identical, ruling out any change in
[Mg2+].
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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.
The aim of this work was to obtain an estimate of in vivo with a
minimum number of assumptions. Cell pH increased during exercise as a
result of H+ consumption, consequent on PCr splitting, and
decreased again during recovery as a result of H+
generation accompanying PCr resynthesis (Fig. 1, A and
C). On the simplest analysis, the relationship between the
PCr fall and pH rise during this brief period of exercise is consistent
with a purely oxidative (i.e., nonglycolytic) response. This resembles the response to brief contractions in dogfish white muscle
(8), and the response to exercise in McArdle's disease,
in which lactate is not produced (16).
proportionately influences the
estimate of , one could argue that the discrepancy between observed
and predicted pH in recovery (Fig. 1C) could be due to a
calculation artifact associated with errors in the Lohmann coefficient . To explain this discrepancy, we would have to postulate that some
factor could alter the coefficient between exercise and recovery,
so that there is, in truth, no "extra proton load" (as postulated
in Fig. 1E). There are no obvious candidate causes of such a
change. No appreciable change in [Mg2+] was likely with
such small changes in pH and with no change in [ATP], and our data
confirm that no such change occurred. Also, it should be kept in mind
that [Mg2+] has a very small effect on the Lohmann
coefficient, as previously reported (19). The required
change in , which could explain such a discrepancy, is actually very
large: for the first two recovery data points, a value of 0.49 ± 0.08, i.e., at least twice as large as the value of 0.206 ± 0.004 derived from the published analysis that we use
(19), would be required to eliminate the discrepancy
between observed and "predicted" pH changes (Fig. 1C).
This hypothetical value is, for example, larger than that of 0.40, which occurs in the complete absence of K+
(19) (and, in any case, intracellular K+ would
tend not to fall but to rise after the contractions, if anything, as
Na+ entering during the action potential is pumped out in
exchange for K+). It is very unlikely that the
stoichiometry of the Lohmann reaction could be this different at
essentially the same [PCr] and [Pi] and a very similar
pH (all very little different from resting values) during exercise and recovery.
So far we have ignored the argument (15, 21) that
oxidative ATP synthesis involves a small amount of net H+
synthesis (see METHODS). The effect of assuming that this
occurs at the start of recovery is to make the estimated much
closer to that at the start of exercise, as one might wish. However, if
we assume that this process operates in later data points (albeit at a
decreasing rate as PCr synthesis slows down), we find that the
predicted acidification is significantly faster than observed, leading
to an overshoot of pH (not shown). This point can be seen more
directly: total H+ consumption due to PCr splitting during
exercise is almost exactly balanced by total H+ generation
due to PCr resynthesis during recovery. However, the hypothetical
oxidative H+ production reduces H+ consumption
during exercise but increases H+ generation during
recovery, throwing these out of balance. Given the size of the
H+ load potentially available for oxidation, only a small
fraction of this is necessary to reconcile exercise and recovery
observations (circles in Fig. 1E). It may be, therefore,
that the muscle is more or less an open system to CO2
(28) in exercise, but not fully so during recovery. This
cannot, at present, be tested.
On this basis, analysis of the changes in exercise yields an estimate
of = 20 ± 2 mmol · l1 · pH
unit1. This is close to estimates derived from
ischemic exercise using the same assumption of zero lactate
production in very early exercise (13) and consistent with
estimates derived from inferred lactate accumulation later in
ischemic exercise (13) (note that these experiments used the same subjects as the present experiments, apart
from one substitution, and the same coil and exercise rig). This can be
seen by comparing Fig. 2B with the similar Fig. 4, E and F, in Ref. 13,
where data points in ischemic exercise move at
first into the lower left quadrant (as in the present experiments),
representing pure PCr consumption of H+, and then move far
into the upper right quadrant as lactate production outweighs
H+ consumption by PCr splitting (13).
As we have discussed in detail elsewhere (13), comparison
of with published values is complicated by technical factors. The
present estimate and our earlier estimate in ischemic exercise (13) are similar to other MRS-based estimates in forearm
muscle (4) and calf muscle (25, 31). The
muscle best studied by needle biopsy is quadriceps, but this seems to
have a higher than forearm or calf muscle, ~40
mmol · l1 · pH
unit1 (see references in Ref. 13). A recent
attempt to predict from chemical composition suggests ~30
mmol · l1 · pH
unit1 (26), but other versions of this
calculation differ considerably, mainly because of the difference in
the assumed contribution by protein-bound histidine residues (see
references in Ref. 13).
Glycogenolysis during aerobic exercise?
If the assumption of zero lactate production in exercise is wrong, then
we have overestimated true ; however, any smaller estimate is
difficult to reconcile with published biopsy and in vitro data, which
are discussed in detail elsewhere (13). It is unlikely
that there is any appreciable lactate generation in this exercise,
given the match between the implied and estimates obtained in
ischemic exercise, not just before lactate production appears
to start, but also later on where lactate changes can be calculated
indirectly (13).
0.67 per PCr "turned over." This is a slight
overestimate if, as has been postulated, oxidation of some of this
lactate had met the ATP requirement for glycogen resynthesis
(29), but we calculate that this full shunt still
generates 0.625 lactate per PCr turned over, and although this might in
the end leave the cell (29), its intracellular
concentration must rise
first.1 In the whole exercise
period, the net [PCr] change of 7.0 ± 0.8 mmol/l intracellular
water consumes 1.5 ± 0.2 mmol/l intracellular water of
H+ via the Lohman reaction (see Fig. 1E). The
fact that the pH increased shows that there was net H+
consumption. Thus H+ production by glycogen shunting cannot
have exceeded 1.5 mmol/l intracellular water, corresponding to PCr
"turnover" of 1.5/0.625 = 2.4 mmol/l intracellular water, or
~30% of the net PCr depletion observed during exercise. However, if
shunting even approached this limit, the implied would be very much
lower than has ever been reported, inconsistent with in vitro data
(13). We conclude that glycogen shunting in this form, if
it occurs, cannot be quantitatively significant, unless there are
unknown routes for lactate-H+ efflux, which can operate,
despite negligible lactate accumulation and intracellular alkalosis.
Glycogenolysis in recovery?
It is generally assumed that lactate is not produced in recovery,
although strictly what has been shown is that, apart from a small
transient component after 60-s calf muscle exercise in a recent report
(7), PCr recovery requires oxygen (27) (as lactate production would not). If PCr recovery were funded by glycolysis, synthesis of one PCr would produce (2/3) 0.88 H+ and acidify the cell by ~0.04 units;
compare this with the H+ load resulting from PCr
resynthesis alone ( 0.21) and the H+ load
resulting from PCr synthesis and funded by oxidative ATP synthesis with
"fully retained" H+ (m 0.35). In fact, the required "extra" H+ load peaks at
~0.2 min and then gradually declines to zero (Fig. 1D). It
is impossible to say whether this represents the temporary retention of
60% of the H+ from oxidation (21), a small
(9%) glycolytic contribution to PCr resynthesis (7)
(although this was apparently absent during exercise, see above), or
even H+ influx, perhaps in response to cellular
alkalinization (which is opposite to what has to postulate on the
glycogen shunt hypothesis, see above).
PCr recovery kinetics. Although it is often useful to treat the PCr recovery rate constant (or, inversely, the half time) as a system property (24), it characterizes a dynamic response that does depend, to some extent, on initial conditions. The effect of pH is well recognized (2, 32), but it must also be assumed to depend somewhat on initial [PCr]. Thus the appropriate literature comparison for the PCr half time seen here (0.24 ± 0.02 min) is with studies showing, let us say, <30% PCr depletion and <0.2 pH change: among these we find PCr half times of 0.15-0.3 min in voluntary dynamic quadriceps exercise (22), ~0.3 min in two studies of isometric calf muscle exercise (11, 20) and one of calf muscle stimulation (5), and in voluntary dynamic finger flexion (17). Even without the known complication of pH change, it probably cannot be assumed that linear extrapolation of PCr resynthesis rate to "complete" PCr depletion gives a valid estimate of maximal mitochondrial ATP synthesis rate in the present experiments (32), in view of the degree of extrapolation implied from the minimal PCr perturbation.
Possible limitations of this work. The sample volume of the coil (~30 ml) might include a component of nonexercising muscle. The absence of split Pi peaks argues against this, although, in the absence of large pH changes, this would be difficult to detect. This would lead to underestimation of changes and rates of changes, but would not affect the ratios used to estimate buffer capacities and predict pH changes, for example. All MRS data are the weighted mean of changes in different fibers and thus fiber types, so possible effects of changing patterns of recruitment cannot be excluded. This could be avoided in further studies with the use of electrical stimulation.
Significance and implications.
Why does this matter? First, that these experiments can be plausibly
interpreted as a purely oxidative (nonglycolytic) exercise response,
consistent with a of 20 ± 2 mmol · l1 · pH
unit1, lends support to the buffer-based approach to
estimating glycolytic ATP synthesis by 31P-MRS (see the
introduction). However, that pH recovery is faster than expected
implies H+ generation in excess of that produced by PCr
splitting, either by H+ influx due to cellular
alkalinization, or by a small glycolytic contribution, or by some other
mechanisms not identified so far. Second, uncertainties about glycogen
shunting (29) counsel caution in calculating ATP turnover
in exercise on this timescale, quite apart from other possible
complications, such as varying recruitment patterns and the series
elastic component. It is difficult to rule out possible real changes in
contractile efficiency, in the absence of firm evidence that glycogen
shunting is either negligible, as suggested here, or constant in rate
and stoichiometry (29).
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ACKNOWLEDGEMENTS |
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We acknowledge the support of Centre National de la Recherche Scientifique, Association Francaise Contre les Myopathies, Programme Hospitalier de Recherche Clinique, and Association pour le Developpement de la Recherche Medicale.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. Bendahan, Centre de Resonance Magnetique Biologique et Medicale, UMR CNRS No. 6612, Faculté de Médecine, 27 Boulevard Jean Moulin, 13005 Marseille, France (E-mail: david.bendahan{at}medecine.univ-mrs.fr).
1
This is 0.625 = (1/3)[2 (2/16)],
where 3 is the glycogenolytic ATP yield from 1 glucosyl unit, and the
first 2 is the corresponding lactate yield; 16 is the ATP yield from
oxidation of 1 lactate, and the second 2 is the ATP required to add 1 glucosyl unit to glycogen (based on Ref. 29).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 28, 2003;10.1152/japplphysiol.00589.2002
Received 2 July 2002; accepted in final form 28 January 2003.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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). 
,
Hypothetical predicted pH change in recovery, based on the assumption
that proton handling is simply the reverse of that in exercise (see
text). * Significantly different from observed pH (P < 0.05 by paired t-test). D: power output (W)
during exercise. E: inferred cumulative proton load during
exercise and recovery. 
, Negative load resulting from
the Lohman reaction (PCr splitting) during exercise and its reversal
during recovery; 