Progressive decrease of intramyocellular accumulation of
H+ and Pi in human skeletal muscle during repeated
isotonic exercise
J.
Rico-Sanz
Copenhagen Muscle Research Center and Nuclear Magnetic
Resonance Center, The Panum Institute, University of
Copenhagen, Copenhagen DK-2100, Denmark
 |
ABSTRACT |
The purpose of this study was to evaluate
the hypotheses that accumulation of hydrogen ions and/or inorganic
phosphate (Pi) in skeletal muscle increases with repeated bouts of
isotonic exercise. 31P-Magnetic resonance spectroscopy was
used to examine the gastrocnemius muscle of seven highly aerobically
trained females during four bouts of isotonic plantar flexion. The
exercise bouts (EX1-4) of 3 min and 18 s
were separated by 3 min and 54 s of complete rest. Muscle ATP did not
change during the four bouts. Phosphocreatine (PCr) degradation during
EX1 (13.3 ± 2.4 mmol/kg wet weight) was higher
(P < 0.01) compared with EX3-4
(9.7 ± 1.6 and 9.6 ± 1.8 mmol/kg wet weight, respectively).
The intramyocellular pH at the end of EX1 (6.87 ± 0.05) was significantly lower (P < 0.001) than those
of EX2 (6.97 ± 0.02), EX3 (7.02 ± 0.01), and EX4 (7.02 ± 0.02). Total Pi and
diprotonated Pi were significantly higher (P < 0.001)
at the end of EX1 (17.3 ± 2.7 and 7.8 ± 1.6 mmol/kg wet weight, respectively) compared with the values at the end of EX3 and EX4. The monoprotonated Pi at the end
of EX1 (9.5 ± 1.2 mmol/kg wet weight) was also
significantly higher (P < 0.001) than that after
EX4 (7.5 ± 1.1 mmol/kg wet weight). Subjects' rating
of perceived exertion increased (P < 0.001) toward
exhaustion as the number of exercises progressed (7.1 ± 0.4, EX1; 8.0 ± 0.3, EX2; 8.5 ± 0.3, EX3; and 9.0 ± 0.4, EX4; scale from 0 to
10). The present results indicate that human muscle fatigue during repeated intense isotonic exercise is not due to progressive depletion of high energy phosphates nor to intracellular accumulation of hydrogen
ions, total, mono-, or diprotonated Pi.
oxidative phosphorylation; fatigue; hydrogen ion; inorganic
phosphate; phosphocreatine
 |
INTRODUCTION |
MUSCULAR CONTRACTION
sustained for a period of time eventually leads to muscle fatigue
or failure to maintain the required power output; that is, the
inability to produce force at a determined velocity. Among the possible
contributory factors associated with fatigue are 1)
depletion of the muscular energy deposits and 2) accumulation of their product metabolites, which might negatively affect excitation-contraction-relaxation processes (15, 44, 45). At the onset of muscle contraction, phosphocreatine (PCr) breakdown is the primary energy source to resynthesize ATP, the direct
energy donor for contraction (4, 7). Glycogen is also
broken down to provide ATP to the contracting muscle fibers (18,
21). Intramyocellular accumulation of inorganic phosphate (Pi),
lactate, and H+ ions occurs as a consequence of the
elevated degradation rate of PCr and glycogen during high-intensity
muscle contraction (13, 32, 46). Thus, as intense muscle
contraction continues, a reduction in intramyocellular PCr and glycogen
levels and accumulation of Pi and H+ take place, events
that have been associated with fatigue (15, 44, 45).
As the supply of oxygen and substrates from blood augments during
prolonged exercise, the relative contribution to the total energy
demand from these anaerobic energy sources decreases, whereas mitochondrial oxidative phosphorylation from carbohydrate and fat
metabolism increases (5, 34). It is thus possible that during intense aerobic muscle contractions, the contribution of Pi and
H+ ion accumulations might play a lesser role on fatigue.
The total work performed during one prolonged bout of muscular
contractions until the point of fatigue can be partitioned into
repeated bouts of contractions at higher intensity separated by periods
of rest (14, 23, 37). In the present experiment,
31P-magnetic resonance spectroscopy (31P-MRS)
was used to evaluate the dynamic changes in muscle high-energy phosphates, Pi, and pH during four bouts of intense isotonic exercise. The number of contractions was maintained identical in all bouts while subjects progressively became fatigued, as they were unable to complete a fifth exercise bout. This protocol permits
evaluation of the metabolic changes in muscle without confounding
factors such as lower number of contractions per bout, decreased
duration of exercise bouts, or the intensity of the previous exercise
bout. It was hypothesized that there would be a progressive degradation of high-energy phosphates and a progressive accumulation of Pi and H+ with the number of bouts. On the contrary, the
results of the experiment showed that muscle fatigue during
repeated bouts of isotonic contractions can be dissociated from the
progressive degradation of high-energy phosphates and intracellular
accumulations of total, mono-, and diprotonated Pi and H+ ions.
 |
METHODS |
Subjects.
Seven healthy, highly trained females (five highly competitive soccer
players and two aerobically trained athletes) volunteered to
participate in this study. The study was approved by the Local Ethics
Committee. Informed written consent was obtained from all subjects
after receiving a detailed explanation of the procedures and the risks
and discomforts of the experiment.
Procedures.
Subjects came to the laboratory on at least three occasions to become
familiarized with the equipment setup (30) and the exercise protocol. Subjects assumed a sitting position, and the pedal
and chair were well secured with straps to prevent any movement during
the exercise protocol. Recruitment from other muscles was eliminated by
fixing the knee joint in a semiextended position. A computer program
was used to trigger a light every 2 s, which prompted the subjects
to start the contraction. Psychological factors were avoided by having
subjects trained to focus on the light turning on, and the experimenter
made sure there was 100% compliance with the cycle "light
on-contraction." No other visual or verbal clues were allowed during
the entire exercise protocol. Each bout consisted of 99 plantar
flexions at the same load and was completed in 3 min and 18 s. The
subjects performed the test with exquisite concentration to complete
exactly 99 contractions in each exercise period. The repeated exercise
protocol was intended to have subjects complete four identical bouts of
intense plantar flexion at a rate of 0.5 Hz with contraction duration
of ~0.5 s and displacement of the pedal of 3 cm. The load in
subsequent visits was increased or decreased depending on whether
subjects were able or not to complete the four exercise bouts, which
were separated by 3 min and 54 s of complete rest. Once the
maximal load they were able to sustain for four bouts was identified, they were asked to come to the laboratory for the final experimental visit. The magnetic resonance data acquisition was realized just before
each contraction.
31P-MRS measurements.
A two-turn inductively driven surface RF coil, 39 mm in diameter, was
located under the gastrocnemius muscle, ~10 cm distal of the fossa
poplitea. Shimming was performed by preshimming on the proton signal
from muscle water and fine-shimmed on the PCr signal. Spectra of
phosphorus containing metabolites were obtained at 49.85 MHz with a 2.9 T, 26-cm bore diameter and 80-cm bore length Magnex magnet that was
interfaced to an Otsuka VivoSpec spectrometer. For spectra acquisition,
a pulse width of 60 ms (90°) with an interpulse delay of 6 s was
employed. One free induction decay (FID) was collected 300 ms before
every fourth contraction. Three FIDs were summed for each spectrum,
providing a time resolution of 18 s. Data were collected in 2,048 data points and with a spectral width of 10 KHz. Before Fourier
transformation, the data were multiplied by 5 Hz exponential line
broadening. Integration of the peak areas was performed after baseline
correction by applying convolution difference by a least square fitting
routine, assuming Lorentzian line shape. Peak areas were corrected for
partial saturation with saturation factors of 1.24, 1.19, and 1.15 for
Pi, PCr, and ATP, respectively, obtained experimentally on four
subjects. Because saturation factors are not affected during
contractions (29), saturation factors were assumed to be
the same throughout the protocol. After correction for saturation
effects, areas for all metabolites were converted to concentrations by
assuming average integrated ATP signal at rest for all subjects to
correspond to a resting concentration of 5.0 mmol/kg wet weight
in female athletes (31). Intracellular pH was calculated
from the chemical shift difference of the Pi peak with respect to the
PCr peak (2). The diprotonated Pi concentration
([H2PO
]) was calculated as:
[H2PO
] = [Pi]/(1 + 10pH
6.75) where 6.75 is the dissociation constant for
H2PO
.
Statistics.
Values are expressed as means ± SE. Differences among repeated
exercise bouts were analyzed by repeated measures analysis of variance.
A post hoc Scheffe's F-test was used to analyze any significant difference. Differences were considered significant at the
5% probability level.
 |
RESULTS |
Figure 1, A and
B, shows a stack and contour
plot, respectively, of a representative nuclear magnetic resonance
(NMR) spectrum from one of the subjects. Whereas muscle ATP remained
the same during the four exercise bouts, the net amount of PCr degraded in EX1 (13.3 ± 2.4 mmol/kg wet weight) was larger
(P < 0.01) compared with EX3 (9.7 ± 1.6 mmol/kg wet weight) and EX4 (9.6 ± 1.8 mmol/kg wet
weight) (Fig. 2). The PCr/ATP ratio at
the end of EX3 (2.02 ± 0.30) and EX4
(2.07 ± 0.52) was also larger (P < 0.01) than that at the end of EX1 (1.47 ± 0.30). After exercise,
the half time of PCr recovery was slightly longer after EX1
(29.6 ± 3.6) compared with those of
EX2-EX4 (19.5 ± 1.2, 17.5 ± 1.9 and 23.0 ± 2.8 s, respectively), but the difference was not
statistically significant. The PCr/ATP ratio at the end of the recovery
from the four exercise bouts was not different from the resting PCr/ATP ratio (3.95 ± 0.36).

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Fig. 1.
Representative stack (A) and contour (B)
plots from one of the subjects during rest before the exercise
protocol (3 min and 54 s), 4 exercise bouts of 3 min and
18 s, and recovery (3 min and 54 s) from each
exercise bout. PCr, Phosphocreatine; Pi, inorganic phosphate; PME,
phosphomonoesters; ppm, parts per million.
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Fig. 2.
Time course of muscle PCr changes in the gastrocnemius
muscle during the repeated exercise protocol. Values are means ± SE of 7 subjects. The net amount of PCr degraded in exercise bout 1 (EX1) tended to be larger (P = 0.14) than
that of EX2 and was significantly larger (P < 0.01) than those of EX3 and EX4.
|
|
Figure 3 shows the changes in muscle pH
during the four exercise bouts. At around 50 s and throughout the
exercise, muscle pH was higher in EX2-4
compared with EX1. The end-exercise muscle pH of
EX1 (6.87 ± 0.05) was significantly lower
(P < 0.001) than end-exercise pH of EX2
(6.97 ± 0.02), EX3 (7.02 ± 0.01), and
EX4 (7.02 ± 0.02). The total Pi at the end of
EX1 (17.3 ± 2.7 mmol/kg wet weight) was significantly
larger (P < 0.001) compared with the values at the end
of EX3 and EX4 (12.3 ± 1.7 and 11.7 ± 1.8 mmol/kg wet weight, respectively) (Fig.
4). The diprotonated Pi concentration was
also larger (P < 0.001) at the end of EX1
(7.8 ± 1.6 mmol/kg wet weight) compared with those of
EX3 and EX4 (4.4 ± 0.7 and 4.2 ± 0.7 mmol/kg wet weight, respectively) (Fig.
5). The monoprotonated Pi at the end of
EX4 (7.5 ± 1.1 mmol/kg wet weight) was significantly
lower (P < 0.01) compared with that of EX1
(9.5 ± 1.2 mmol/kg wet weight) (Fig.
6). The rating of perceived exertion
increased (P < 0.001) progressively from 7.1 ± 0.4 after EX1 to 7.9 ± 0.3 (EX2), 8.5 ± 0.3 (EX3), and 9.0 ± 0.4 (EX4) in a
scale from 0 to 10, 9 reflecting signs of exhaustion and 10 reflecting
when subjects could not continue. Subjects were unable to complete a
fifth bout.

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Fig. 3.
Time course of muscle pH changes during the repeated
exercise protocol. Values are means ± SE of 7 subjects.
Estimation of the pH before EX2-4 was not
possible due to Pi peak disappearance. At around 45 s and
throughout the exercise, muscle pH was higher in
EX2-4 (P < 0.001) compared with
EX1.
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Fig. 4.
Time course of muscle total Pi during the repeated
exercise protocol. Values are means ± SE of 7 subjects.
Estimation of the total Pi before EX2-4 was not
possible due to Pi peak disappearance. The total Pi at the end of
EX1 was larger (P < 0.001) compared with
EX3 and EX4.
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Fig. 5.
Time course of muscle diprotonated Pi during the repeated
exercise protocol. Values are means ± SE of 7 subjects.
Estimation of the diprotonated Pi before EX2-4
was not possible due to Pi peak disappearance. The diprotonated Pi at
the end of EX1 was larger (P < 0.001)
compared with EX3 and EX4.
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Fig. 6.
Time course of muscle monoprotonated Pi during the
repeated exercise protocol. Values are means ± SE of 7 subjects.
Estimation of the monoprotonated Pi before EX2-4
was not possible due to Pi peak disappearance. The monoprotonated Pi at
the end of EX1 and EX2 were larger
(P < 0.01) compared with EX4.
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 |
DISCUSSION |
The main purpose of this experiment was to examine the
hypothesis that intramyocellular accumulation of metabolites of the anaerobic energy delivery pathways is associated with fatigue during
repeated bouts of intense isotonic exercise in humans. The data
showed that the accumulation of intracellular total, mono-, and
diprotonated Pi and H+ decreased with repeated bouts of
intense contraction.
Clearly, the muscle pH results do not support a role for
intramyocellular H+ accumulation as the cause of fatigue
during repeated intense exercise. Previously, it had been proposed that
accumulation of H+ is associated with fatigue due to
decreased Ca2+ sensitivity of force activation, peak force,
and maximum velocity of shortening during maximal Ca2+
activation and prolonged sarcoplasmic reticulum Ca2+
reuptake and relaxation time (6, 9, 10, 25, 40). Furthermore, Metzger and Moss (25) suggested that
accumulation of H+ causes decrements in the number of
crossbridges in fast-twitch (FT) muscle fibers and reduces the force
per crossbridge in both slow- and FT muscle fibers, as differential
causes of fatigue in each fiber type. Taking into consideration that
during submaximal exercise there is an orderly recruitment of
slow-twitch (ST) and FT oxidative-glycolytic (FTa) and FT glycolytic
(FTb) as contraction time progresses (12, 18, 42), it is
unlikely that accumulation of H+ was the cause of
progressive fatigue in the present study, because during
EX4, the accumulation of H+ was basically
insignificant and similar to the resting H+ values. Also,
during the first bout when the intramyocellular pH decreased 0.2 units,
subjects exercised for an additional 2 min (total of 60 more
contractions) without decreasing the rate of isotonic contractions. The
present findings agree with some reports dissociating H+
from muscle fatigue in animals and humans (1, 3, 11, 13).
The Pi data of the present study also indicated that total Pi is
not associated with fatigue during repeated, intense, isotonic exercise. It had been suggested that accumulation of total Pi during
intense muscle contraction depresses force by reducing the crossbridge
transition from the low- to the high-force state and slowing
Ca2+ reuptake into the sarcoplasmic reticulum (20,
27, 44, 45). It has been proposed that intramyocellular
concentrations of Pi between 15 and 30 mmol cause force decline in frog
semitendinosus, skinned rabbit psoas fibers, and human muscles
(13, 20, 27, 39, 43, 46). The depressive effect of total
Pi on force production appeared larger in FT muscle fibers than in ST
muscle fibers already at a Pi concentration of 15 mmol
(39). However, in the present study, muscle total Pi
during EX1 was above 15 mmol/kg wet weight for over 2 min
while subjects maintained the rate of contraction remarkably, and Pi
concentration decreased with the number of bouts when the FT fibers are
progressively recruited. Therefore, it is unlikely that Pi is the cause
of fatigue because total Pi accumulation decreased progressively with
the number of bouts.
Increments in H+ concentration augment the diprotonated
levels of Pi, which might independently cause skeletal muscle force depression. Wilson et al. (46) indicated that fatigue in
humans correlates with diprotonated Pi and pH during maximal
contractions, but when maximal exercise is preceded by submaximal
exercise, diprotonated Pi rather than H+ was believed to be
the primary metabolic factor responsible for muscular fatigue. In their
study, 4 min of maximal wrist flexion contractions caused a ninefold
increase in diprotonated Pi and a 25% reduction in force. However, an
~eightfold increase in diprotonated Pi during EX1 did not
cause a drop in force generation in the present study. Nosek et al.
(28) suggested that perhaps total and monoprotonated Pi
cause fatigue in ST muscle fibers and total and diprotonated Pi in FT
muscle fibers. However, in the present study, coinciding with
progressive recruitment of FT fibers (12, 18, 42), the
accumulation of total, mono-, and diprotonated Pi was progressively
lower during repeated bouts. If the accumulation of total, mono-, and
diprotonated Pi and H+ is a major cause of human muscle
fatigue, a progressive rise in their concentration should have
been observed with the number of exercise bouts as progressive
increasing rates of perceived exertion were reported. The present
findings agree with those of Adams et al. (1) in cat
muscles, which indicated that force during repetitive contractions is
not directly due to pH or diprotonated phosphate, and those of Cieslar
and Dobson (11) in rat gastrocnemius, which showed that
force decline is not due to increased pH and/or diprotonated Pi.
Rather than being a direct cause of muscle fatigue, the elevation of
intramyocellular total Pi, diprotonated Pi, and H+
concentrations during exercise might be metabolic consequences of the
duration and intensity of the contraction, metabolism of the type of
recruited muscle fibers, oxidative capacity of the fibers, and oxygen
and energy substrate supply to the active fibers. Indeed, PCr and
glycogen breakdown in human FT muscle fibers is higher than in ST
fibers (8, 19), and their net breakdown is higher as the
exercise intensity increases (21, 22, 36). High-intensity
exercise provokes the accumulation of intracellular H+ and
Pi in human muscle to levels above those during moderate-intensity exercise (22). It has also been shown that the
intracellular Pi accumulation during muscle contraction is higher in FT
compared with ST fibers (1). Moreover, when the duration
of maximal contractions increase from 1 to 2 s, the increments of
diprotonated Pi and H+ in human muscle are larger
(46). Also, the FT fibers have lower oxidative potential
than the ST fibers, as demonstrated by their lower density of
capillaries, mitochondria, and enzymes of the oxidative energy pathways
(35). Furthermore, Pi accumulation in human muscle is
lower in a highly trained state (24). Many of the results
associating hydrogen ion and Pi accumulation with fatigue have been
obtained in animal muscle with the skinned fiber model, which does not
provide circulating sources of energy to muscle (20, 26, 27, 39,
40). In addition, the experimental protocols in human
experiments employed progressive intensity to fatigue, maximal
contractions, or maximal contractions preceded by submaximal
contractions that naturally increase the H+ and Pi
accumulation in muscle as exercise intensity is elevated (13, 25,
42, 45).
In evaluating the entire data set of the present repeated exercise
protocol, a change from relatively more anaerobic metabolism to aerobic
metabolism presumably occurred from EX1 to EX2
and less progressively from EX2 to EX4. The pH
changes during the exercise periods indicate a larger glycolysis to
lactate and hydrogen ion production in EX1 compared with
EX2-4. Evidence for decreased anaerobic
glycolysis in EX2-4 compared with EX1
in the present study is further supported by the reduced accumulation
of the phosphomonoesters resonance (see Fig. 1) and the higher
pH. Decrements in anaerobic glycolysis in repeated exercise protocols
have also been previously reported (5, 23, 31, 36). It is
doubtful that accumulation of glycolytic intermediates and
H+ is the cause of the reduction of anaerobic glycolysis in
subsequent exercise bouts because PME and pH were similar to resting
levels at the initiation of each repeated contraction. Because ATP was maintained the same throughout all the exercise bouts and the net PCr
utilized during EX3-4 was lower than that used
during EX1, the data strongly suggest a net decrement in
anaerobic energy production after the first exercise bout.
Changes in blood flow, oxygen uptake, and oxidative phosphorylation may
account for the alterations in energy metabolism during repeated
exercise bouts. The glycogen breakdown rate is significantly enhanced
in ST fibers when circulation is occluded but not in FT fibers in which
the rate is kept to about the same maximal level as when the
circulation is intact (19). It is likely that oxidative
phosphorylation was not fully optimized during EX1. The
blood flow in vastus lateralis after 3 and 10 min of passive recovery
from intense exercise of similar duration as in this study was higher
compared with resting blood flow (3). Whole body oxygen
uptake is also enhanced during repeated bouts of intense exercise
(5, 32). In addition, adipose tissue lipolysis is increased during a repeated bout of aerobic exercise (38).
Thus, as a consequence of the increased blood flow and the delivery of
oxygen and circulating substrates, it is expected that oxidative phosphorylation plays a more significant role than anaerobic metabolism during the repeated exercise bouts.
In conclusion, the results of this study show that repeated isotonic
exercise does not cause a progressive accumulation of intramyocellular
total, mono-, and diprotonated Pi and hydrogen ions nor depletion of
high-energy phosphates in humans.
 |
ACKNOWLEDGEMENTS |
This research was supported by the Danish National Research
Foundation. During the completion of the present work, I was supported by the Copenhagen Muscle Research Center, Copenhagen, Denmark.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: J. Rico-Sanz, Human Genomics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808 (E-mail:
rico-sj{at}pbrc.edu).
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 5, 2003;10.1152/ajpcell.00419.2002
Received 9 September 2002; accepted in final form 29 January 2003.
 |
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