JAP-01261-2003.R1
Metabolic effects of induced alkalosis during progressive
forearm exercise to fatigue
GRAYDON H. RAYMER1,2, GREG D. MARSH1,2,3, JOHN M.
KOWALCHUK3,4,5, AND R. TERRY THOMPSON1,2
1
Department of Medical Biophysics, The University of Western
Ontario, London, Ontario, Canada, N6A 5C1
2
Imaging Division, The Lawson Health Research Institute, and
Department of Radiology, St. Joseph’s Health Care, London, Ontario,
Canada, N6A 4V2
School of Kinesiology, The University of Western Ontario, London,
Ontario, Canada, N6A 3K7
4
Canadian Centre for Activity and Aging, London, Ontario, Canada,
N6G 2M3
5
Department of Physiology and Pharmacology, The University of
Western Ontario, London, Ontario, Canada, N6A 5C1
Contact:
Graydon H. Raymer
Room G450, The Lawson Health Research Institute
St. Joseph’s Health Care Centre,
268 Grosvenor Street,
London, Ontario, Canada
N6A 4V2
Phone: (519) 646-6000 x64346
Fax: (519) 646-6135
Email: [email protected]
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3
JAP-01261-2003.R1
Abstract
Metabolic alkalosis induced by sodium bicarbonate (NaHCO3) ingestion has been shown
to enhance performance during brief high-intensity exercise. The mechanisms associated
with this increase in performance may include increased muscle phosphocreatine (PCr)
breakdown, muscle glycogen utilization, and plasma lactate (Lac-pl) accumulation.
Together, these changes would imply a shift towards a greater contribution of anaerobic
energy production, but this statement has been subject to debate. In the present study,
Hz, 14 – 21 min) in a control condition (CON) and after an oral dose of NaHCO3 (ALK:
0.3 g · kg; 1.5 hrs prior to testing) to evaluate muscle metabolism over a complete range
of exercise intensities.
31
Phosphorus magnetic resonance spectroscopy was used to
continuously monitor intracellular pH, [PCr], [Pi], and [ATP]. Blood samples drawn from
a deep arm vein were analyzed with a blood gas-electrolyte analyzer to measure plasma
pH, PCO2, and [Lac-]pl, and plasma [HCO3-] was calculated from pH and PCO2. NaHCO3
ingestion resulted in an increased (P < 0.05) plasma pH and [HCO3-] throughout rest and
exercise. Time to fatigue and peak power output were increased (P < 0.05) by ~ 12 % in
ALK. During exercise, a delayed (P < 0.05) onset of intracellular acidosis (1.17 ± 0.26
vs. 1.28 ± 0.22 W, CON vs. ALK) and a delayed (P < 0.05) onset of rapid increases in
the [Pi]/[PCr] ratio (1.21 ± 0.30 vs. 1.30 ± 0.30 W) were observed in ALK. No
differences in total [H+], [Pi], or [Lac-]pl accumulation was detected. In conclusion,
NaHCO3 ingestion was shown to increase plasma pH at rest, which resulted in a delayed
onset of intracellular acidification during incremental exercise. Conversely, NaHCO3 was
not associated with increased [Lac-]pl accumulation or PCr breakdown.
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subjects (N = 6) performed a progressive wrist flexion exercise to volitional fatigue (0.5
JAP-01261-2003.R1
Keywords
Sodium bicarbonate; intracellular pH; lactate; 31-phosphorus magnetic resonance
spectroscopy; skeletal muscle; ergogenic aid
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JAP-01261-2003.R1
Introduction
Metabolic alkalosis induced by sodium bicarbonate (NaHCO3) ingestion has been shown
to enhance intense exercise lasting ~ 1 – 7 min (1; 3; 22; 25; 32). Several explanations for
this effect have been proposed, but the mechanism has not yet been clearly elucidated. A
common explanation is that induced alkalosis leads to an enhanced muscle glycolytic
ATP production, and consequently a greater capacity for high-intensity exercise. Studies
that have reported NaHCO3 ingestion increases the blood plasma lactate concentration
Furthermore, it has been reported by Hollidge-Horvat et al. (9) that induced alkalosis
may increase muscle glycogen utilization, phosphocreatine breakdown, and inorganic
phosphate (Pi) accumulation during 15 min cycling at 75% VO2max. In summary, these
findings would tend to suggest that NaHCO3 ingestion results in a shift towards a greater
contribution of anaerobic energy production during exercise.
During single and repeated bout sprint exercise, it is plausible that an increase in
non-oxidative ATP production would be beneficial to performance. However, NaHCO3
ingestion has also been shown to improve endurance activity lasting 30 – 60 min (5; 23;
26). Fatigue in exercise lasting longer than 15 min has been associated with glycogen
depletion and lactate accumulation, in which case a shift towards anaerobic energy
production is expected to inhibit, rather than improve, muscle function. Recently,
Stephens et al. (30) examined the effects of NaHCO3 ingestion on ~ 60 min exhaustive
endurance exercise and reported a decrease in muscle [H+], but no changes in
phosphocreatine or glycogen utilization. These findings appear to contradict those of
Hollidge-Horvat et al. (9) for 15 min of cycling at a similar intensity. While differences
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([Lac-]pl) during exercise, would be consistent with this explanation (2; 11; 25; 29).
JAP-01261-2003.R1
in the amount of exercise time may account for the conflicting results, a possible
explanation for these differences was the use of only a small number (< 5) of muscle
biopsies for in vivo monitoring of intracellular metabolism during continuous exercise.
Consequently, the inherent limitations of infrequent sampling and poor time resolution
associated with muscle biopsy analysis may have prevented a clear understanding of the
data.
The present study, therefore, is the first to use 31-phosphorus magnetic resonance
during continuous exercise. 31P-MRS is ideally suited for this type of experiment because
it allows for continuous, non-invasive measurement of the kinetics of high-energy
phosphate metabolites associated with muscle energy production and utilization. Unlike
muscle biopsy analysis, in which intracellular metabolism is inferred from only a small
number of discrete data points, 31P-MRS allows for rapid and continuous measurement of
intracellular parameters. Previously, it has been shown with
31
P-MRS that during
incremental exercise to fatigue, the kinetics of intracellular metabolism are not linear, but
that a power output or inflection point can be identified above which the rate of decline in
the ratio [PCr]/[Pi] and in intracellular pH (pHi) is greater relative to that seen at lower
power outputs. (19). The slope, or rate of change in these variables, can thus be a useful
parameter is describing the status of cellular metabolism. In the current study, therefore,
an incremental exercise protocol was employed to examine the metabolic response to
NaHCO3 ingestion over the entire range of power output capable by the muscle (i.e. rest
to peak power output). It is hoped that with the improved time resolution of 31P-MRS, our
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spectroscopy (31P-MRS) to study the effects of NaHCO3 ingestion on muscle metabolism
JAP-01261-2003.R1
study will help to clarify the changes occurring in intracellular metabolism with exercise
during induced alkalosis.
In summary, the purpose of the present study was to use
31
P-MRS and venous
blood sampling to study the effects of NaHCO3 ingestion on the metabolic and acid-base
responses to incremental forearm wrist flexion exercise in humans. In contrast to
previous muscle-biopsy studies that have reported either significant (9) or negligible (30)
metabolic effects of induced alkalosis, we have utilized to our advantage the continuous
have been speculated to occur with NaHCO3 ingestion. Specifically, it was hypothesized
that in our study: 1) an oral dose of 0.3 g · kg-1 body weight NaHCO3 delivered 1.5 hours
prior to exercise would significantly elevate plasma [HCO3-] and lower plasma [H+] at
rest; 2) that prior to exercise, this induced plasma alkalosis would not be associated with
a decrease in intracellular [H+]; 3) that during progressive exercise, the onset of
intracellular acidosis would be delayed following NaHCO3 ingestion; and 4) that an oral
dose of NaHCO3 would be associated with increased accumulation of [Lac-]pl and
increased breakdown of PCr.
Methods
Subjects. Six male volunteers participated in the study [age 27 ± 3 (SD) yr; height
1.80 ± 0.07 m; weight 80.2 ± 8.1 kg]. All subjects were healthy and moderately active,
but none were trained specifically in sports that involved extensive use of the forearm
musculature, such as squash or tennis. Prior to the experiment, all procedures and any
potential risks were explained to each subject, and an informed consent document was
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in-vivo measurement of intracellular metabolism to elucidate the metabolic effects which
JAP-01261-2003.R1
signed previous to participation. The study was approved by The University of Western
Ontario Review Board for Health Sciences Research Involving Human Subjects.
Experimental Protocol. Subjects were studied twice during each of two
conditions, control (CON) and after NaHCO3 ingestion (ALK). Two exercise tests were
performed during each condition to evaluate 1) muscle metabolism and acid-base status
using
31
P-MRS and 2) [Lac-]pl and acid-base status in venous blood draining the active
forearm muscle using standard blood sampling techniques (BLD).
abstaining from caffeine-containing foods and beverages; exercise tests were performed
at the same time of day for each subject, and were separated by at least 48 hours. Prior to
the ALK trial, each subject was given an oral dose of NaHCO3 (0.3 g · kg-1 body weight)
which has been demonstrated consistently to elicit a state of metabolic alkalosis (16; 20).
To achieve peak venous [HCO3-], the oral dose of NaHCO3 was administered 1.5 hours
prior to the start of the exercise (17). The oral dose of NaHCO3 was contained within gel
capsules and administered with ~ 500 ml of water, as it was found from earlier testing in
our lab that this mode of administration was easier for the subjects to ingest than when
mixed with a sports drink. In both CON and ALK, subjects rested comfortably during the
period of time prior to exercise and were permitted to drink water ad libitum to minimize
the potential gastrointestinal effects that are common with NaHCO3 ingestion.
The exercise protocol was identical for each of the four tests and consisted of
progressive wrist-flexion exercise to volitional fatigue performed on a custom built wrist
ergometer. Previous to the start of exercise, subjects lay supine on a table positioned next
to the ergometer. The dominant arm of each subject was then placed inside the ergometer
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Subjects reported to the laboratory at least 2-3 hours after a light meal and after
JAP-01261-2003.R1
by placing the arm in full extension, then abducting to 90˚. The forearm was placed in the
pronated position so that subjects were able to grasp the lever of the ergometer, which
was aligned such that the pivot of the lever centred on the axis of the wrist joint. With the
arm in this position, the contracting forearm musculature was positioned at heart level,
thus
ensuring
adequate
perfusion
during
the
relaxation
phase
of
each
contraction/relaxation cycle. The subjects remained supine throughout the protocol.
The exercise consisted of repeatedly depressing the lever at a frequency of 0.5 Hz
and lowered a water reservoir through the use of a cable and pulley system. The
resistance was increased in a ramp-like fashion by pumping water by means of a roller
pump (Cole-Parmer Instruments, Chicago, IL) into the reservoir at a constant rate (0.22 L
· min-1). A metronome set at 0.5 Hz was used to keep subjects on pace, and the
experimenters monitored the movement of the water reservoir to ensure that subjects
exercised within the full range of motion through to the completion of exercise.
Following a 5 min period during which resting measurements were taken, subjects
accommodated to the exercise protocol with 3 min of wrist flexion against low resistance
(1.0 kg). After this initial accommodation period, subjects continued to exercise while
water was continuously added to the added to the reservoir at a rate of 0.22 kg · min-1.
Subjects exercised to volitional fatigue, which was defined as the point at which subjects
failed on repeated attempts to raise the reservoir through the full range of motion. The
work done by the subject was calculated by using the known repetition rate (0.5 Hz), the
arc distance of the lever (0.10 m), and the weight of the reservoir and water [1.08 kg +
(flow rate · exercise time)] using standard physical relationships. This produced a ramp
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(1 s contraction / 1 s relaxation) through a range of motion of ~ 70˚. This action raised
JAP-01261-2003.R1
slope of ~ 0.11 W · min-1 from an initial load of 0.53 W (accommodation period). The
actual flow rate of water into the reservoir was calculated as the total volume of water
added during the exercise test divided by the time to fatigue.
P-MRS. Forearm muscle metabolism was studied using 31P-MRS with the wrist
31
flexion ergometer positioned within the bore of the magnet. Data were obtained using a
30 cm bore 1.89 Tesla superconducting magnet interfaced with a SMIS/IMRIS console
(Surrey Medical Imaging Systems, Guilford, U.K.; Innovative Magnetic Resonance
ergometer within the bore of the magnet, the belly of the forearm was situated over a 4
cm dual tuned 1H – 31P surface coil, approximately 7-9 cm distal to the medial epicondyle
of the humerus. In this position, the NMR signal was obtained primarily from the flexor
digitorum superficialis muscle. All spectra were acquired with a 3 ms 90º adiabatic
radio-frequency (rf) pulse, a 3.3 kHz receiver bandwidth, 8 µs delay time, and 2048
complex data points with a 300 µs dwell time. Each spectrum was produced from an
average of 6 free induction decay (FID) signals with a repetition time (TR) of 6 s (total
acquisition time of 36 s).
Quantification of the
31
P-MRS metabolite data was performed in the time
(acquisition) domain by fitting each 31P FID to a sum of damped sinusoids, which could
be varied in terms of amplitude, phase, delay time, damping constant, and frequency.
This method utilized a priori knowledge and a non-linear least squares algorithm to
iteratively reduced the difference between the data and the experimental model. The
concentrations of the phosphate metabolites phosphocreatine [PCr] and inorganic
phosphate [Pi] were determined from the amplitude of the exponential model function at
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Imaging Systems, Winnipeg, Canada). When the subject’s arm was placed in the
JAP-01261-2003.R1
time equal zero. Adenine triphosphate concentration [ATP] was calculated from the
average concentration of the three phosphate resonances: α-ATP, β-ATP, and γ-ATP. For
each parameter, metabolite concentration was expressed relative to total phosphate signal
[Phos], and because only ratios of metabolites were used, correction factors were not
applied. Intracellular [H+] and pHi were determined from the chemical shift of Pi with
respect to PCr.
Blood Sampling. During BLD trials, blood was drawn from a deep arm vein at the
min accommodation period; and at 1 min intervals during the ramp protocol (including
the point of fatigue). Blood was drawn into syringes containing lithium heparin, mixed,
placed in ice water, and analyzed after a short delay. Whole blood samples (200 µL) were
analyzed at 37˚C for plasma pH, PCO2, [Na+], [Cl-], [K+] and [Lac-]pl using selective
electrodes (StatProfile 9 Plus blood gas-electrolyte analyzer, Nova Biomedical Canada,
Mississauga, ON). The electrodes were calibrated before each test and at regular intervals
during analysis. Plasma [H+] was calculated from the measured pH, and plasma [HCO3-]
was calculated from pH and PCO2.
Analyses. Since exercise time to fatigue (TTF) and peak power output (POpeak)
varied among individuals, group mean comparisons were facilitated by plotting the data
as a percentage of POpeak. To perform this normalization, metabolite data during the
exercise protocol were plotted vs. power output for each subject, and a non-linear
regression algorithm was used to fit a series of ten points (deciles) to the experimental
data. Data in their final form where thus characterized by 12 data points, which included
rest, warm-up, and 10 percentiles of POpeak. In the case of resting metabolite data, values
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following times: at 3 min and 1 min prior to the beginning of exercise; at the end of the 3
JAP-01261-2003.R1
were was taken as the average metabolite concentration recorded over the 5 min rest
period, and was plotted as 0 % POpeak. Data recorded during the accommodation period
was also averaged and plotted as the mean percentage of the mean POpeak. The remaining
10 data points comprised the relative power outputs for 10 equally spaced percentiles
during exercise.
The above normalization allowed for comparison between individuals with
varying TTF or POpeak, however to compare between trials (i.e. CON vs. ALK), the data
ergogenic benefit of NaHCO3, subjects in one trial might exercise to a greater TTF and/or
peak PO than another. To allow for this variation, the normalization algorithm during the
ALK trial was constrained to fit 10 points in the exercise data which occurred at identical
absolute power output values to the 10 percentiles in CON. Thus, ALK data are
expressed relative to % POpeak in the CON condition (noted as %
CONPOpeak).
In the
situation that a subject experienced and increased TTF and/or POpeak with ALK, an
eleventh point was included (noted as > 100 %
CONPOpeak)
to represent the point of
fatigue. Similarly, if a subject experienced a decreased TTF and/or POpeak, one (or more)
of the final deciles was excluded from the regression model until it was contained within
the experimental data.
To determine the onset of intracellular [H+] accumulation, the onset of [Lac-]pl
accumulation, and the onset of rapid increases in the phosphorylation potential
([Pi]/[PCr]), these parameters were plotted as a function of power output for each subject.
Intracellular [H+] data were expressed in pH units, and the [Pi]/[PCr] data were expressed
as the logarithm (log[Pi]/[PCr]) to facilitate detection of a biphasic response. Piecewise
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also required an additional control. It was expected that due to a training effect or an
JAP-01261-2003.R1
linear regression analysis was applied to these plots by use of an algorithm which
estimated the slope and intercept parameters of two regression functions and determined
an inflection at which the slope of the two lines diverged. An F test (P < 0.05) was used
to evaluate whether a single or multiple regression provided the optimal fit of the data.
Statistical Analysis. Statistical analyses were performed using SPSS v10.0.7
statistical program for the PC (SPSS Inc., Chicago, IL). Muscle and plasma metabolic
data were analyzed for main CON, ALK, time, and interaction effects using two-way
Newman-Keuls post-hoc analysis. In addition, metabolite inflections, TTF, and POpeak
values were analyzed using a dependent samples paired Student’s t-test. In all cases,
statistical significance was considered at P < 0.05. Data presented in the text and tables
are given as mean ± SD, and figures are represented by mean ± SEM.
Results
Exercise performance. Two series of exercise tests were performed to allow
separate collection of muscle and blood metabolite data. The protocol for each series was
identical in every respect except for the use of 31P-MRS to collect muscle metabolic and
acid base data, and venous catheterization for blood sampling and collection of blood
metabolite and acid-base data. Resistance increased in a ramp-like fashion, with no
difference in the rate of ramp increase (~ 0.11 W · min-1; ~ 0.225 L · min-1 H2O) between
31
P-MRS and BLD, or CON and ALK. However, TTF and POpeak were ~ 12 % greater (P
< 0.05) during the ramp tests performed after NaHCO3 ingestion (Table 1). There was no
difference between 31P-MRS and BLD in either instance.
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repeated measures ANOVA. A significant F ratio was further analyzed using Student-
JAP-01261-2003.R1
Intramuscular metabolic and acid-base status. The effect of NaHCO3 ingestion
on intracellular pH during the forearm exercise protocol is presented in Fig. 1. In both
CON and ALK, intracellular pH/[H+] decreased/increased (P < 0.05) with increasing
power output reaching similar values at the end of exercise (CON: 6.35 ± 0.05 pH, 447 ±
50 nmol · L-1 [H+]; ALK: 6.41 ± 0.08 pH, 382 ± 75 nmol · L-1 [H+]). In both conditions,
the rate of intracellular [H+] accumulation was biphasic (P < 0.05), displaying an initial
slow and later fast component separated by a distinct point of inflection (pHT). The slope
neither instance was there any difference between conditions (Table 2). However, the
onset of intracellular acidosis was delayed (P < 0.05) in ALK (Table 3). Compared to
CON, the pHT in ALK was right-shifted and occurred at a higher power output during
exercise (CON: 1.17 ± 0.26 W; ALK: 1.28 ± 0.22 W). These changes corresponded to a
higher (P < 0.05) intracellular pH in ALK than CON at any relative power output beyond
the pHT (Fig. 1).
The effect of NaHCO3 ingestion on the high-energy phosphates: PCr, Pi, and ATP
are presented in Fig. 2. With increasing power output, [PCr] decreased (P < 0.05), [Pi]
increased (P < 0.05), and [ATP] remained similar to resting levels. No differences were
observed between CON and ALK in either case. From these data, log[Pi]/[PCr] was also
calculated, and the rate of change of log[Pi]/[PCr] was found to be biphasic (P < 0.05),
displaying an initial slow and later fast component separated by a distinct point of
inflection (PT) (Table 2). The slope of the log[Pi]/[PCr]-power output relationship was
less (P < 0.05) below the PT than above, but in neither instance was there any difference
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of the pH-power output relationship was less (P < 0.05) below the pHT than above, but in
JAP-01261-2003.R1
between conditions. However, the onset of rapid changes in log[Pi]/[PCr] (Table 3) was
delayed (P < 0.05) in ALK (CON: 1.21 ± 0.30 W; ALK: 1.30 ± 0.30 W).
Plasma lactate and acid-base status. The effect of NaHCO3 ingestion on the
equilibrated forearm venous [Lac-]pl during progressive forearm exercise is presented in
Fig. 3. Venous [Lac-]pl increased (P < 0.05) with increasing power output, reaching
similar end-exercise values in CON and ALK (CON: 7.1 ± 2.5 mmol · L-1; ALK: 7.5 ±
2.4 mmol · L-1). In both conditions, the rate plasma lactate accumulation was biphasic (P
of inflection (LT). The slope of the [Lac-]pl-power output relationship was less (P < 0.05)
below the LT than above, but in neither instance was there any difference between
conditions (Table 2). The onset of [Lac-]pl accumulation (Table 3) was similar (P =
0.241) between conditions (CON: 1.17 ± 0.19 W; ALK: 1.30 ± 0.21 W).
The effect of NaHCO3 on the equilibrated forearm venous plasma pH during the
forearm exercise protocol is presented in Fig. 4. Plasma pH was higher (P < 0.05) at rest
(CON: 7.43 ± 0.01 pH, 37 ± 1 nmol · L-1 [H+]; ALK: 7.48 ± 0.01 pH, 33 ± 1 nmol · L-1
[H+]). Plasma pH decreased (P < 0.05) with increasing power output, and was higher (P <
0.05) during the entire exercise protocol in ALK compared to CON. At the end of
exercise in CON (100 %
CONPOpeak)
and ALK (112 %
CONPOpeak),
plasma pH and [H+]
reached a similar values (CON: 7.26 ± 0.09 pH, 56 ± 11 nmol · L-1 [H+]; ALK: 7.29 ±
0.10 pH, 52 ± nmol · L-1 [H+]).
The equilibrated forearm venous plasma [HCO3-], [Na+], [K+], and [Cl-] are given
in Table 4. Compared to CON, ALK resulted in an increased (P < 0.05) [HCO3-] at rest
(CON: 31.9 ± 2.6 mmol · L-1; ALK: 39.0 ± 2.5 mmol · L-1). An elevated (P < 0.05)
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< 0.05), displaying an initial slow and later fast component separated by a distinct point
JAP-01261-2003.R1
[HCO3-] during ALK was also observed throughout the entire exercise protocol. Plasma
[Na+] was not different at rest between CON and ALK, however the increase (P < 0.05)
in [Na+] with increasing power output was greater (P < 0.05) in ALK compared to CON
from warm-up to ~ 70 %
CONPOpeak.
Plasma [K+] was lower at rest in (CON: 4.1 ± 0.1
mmol · L-1; ALK: 3.7 ± 0.1 mmol · L-1). [K+] increased (P < 0.05) with increasing power
output in both conditions, however [K+] was lower in ALK compared to CON throughout
exercise. Finally, plasma [Cl-] was greater (P < 0.05) at rest in CON compared to ALK
with increasing power output in both CON and ALK, however [Cl-] was lower in ALK
compared to CON through exercise.
Muscle-to-plasma [H+] gradient. The effect of NaHCO3 on the muscle-to-venous
plasma [H+] gradient are presented in Fig. 5. At rest, the [H+] gradient was similar in both
conditions (CON: 45 ± 7 nmol · L-1; ALK: 51 ± 2 nmol · L-1). The [H+] gradient remained
at resting levels until the power output reached ~ 60 %
CONPOpeak,
at which point it
abruptly rose (P < 0.05) in both CON and ALK. The [H+] gradient was higher (P < 0.05)
in CON compared to ALK at power outputs > 60 % CONPOpeak. At the end of exercise, the
[H+] gradient remained higher in CON compared to ALK (CON: 391 ± 52 nmol · L-1;
ALK: 330 ± 79 nmol · L-1).
Discussion
In the present study, we examined the effects of induced alkalosis on the metabolic and
acid-base responses to progressive forearm wrist flexion exercise to fatigue using a
combination of
31
P-MRS and blood sampling techniques. The major findings of this
study were: 1) ALK resulted in an increased TTF and POpeak; 2) the pHi-power output
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(CON: 104.1 ± 3.3 mmol · L-1; ALK: 99.4 ± 1.6 mmol · L-1). [Cl-] decreased (P < 0.05)
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relationship was shifted rightward in ALK, such that although the rate of intracellular
acidification was similar in both conditions, the onset of this acidification was delayed in
ALK; 3) the [Pi]/[PCr]-power output relationship was also shifted rightward in ALK such
that the onset of rapid increases in this ratio was delayed in ALK; and 4) no differences in
venous [Lac-]pl were found between conditions.
The NaHCO3 protocol (1.5 hours prior to exercise) and dose (0.3 g · kg-1 body
weight) used in the present study significantly elevated plasma [HCO3-] and lowered
30).
Our observation that before exercise, muscle [H+]i or pHi was unaffected by
NaHCO3 ingestion has also been reported previously (3; 9; 11), and is consistent with the
hypothesis that the muscle membrane is relatively impermeable to HCO3-.
In the present study, the effects of induced alkalosis on pHi were not evident until
~ 60 %
CONPOpeak,
which corresponded approximately to the onset of intracellular
acidosis. Examination of the time-dependent pH relationship reveals that while the onset
of intracellular acidification was delayed in ALK, the rate (or slope) of this acidification
did not differ between conditions. This would suggest that while the initial accumulation
of H+ is delayed in ALK, the metabolic processes involved in the production and removal
of H+ remain in a similar state of balance in both conditions. These processes may
include an increased glycolytic flux and/or increased lactate efflux.
Lactate efflux across the sarcolemma occurs via a monocarboxylate cotransporter
(MCT1) (21; 27; 28). The MCT1 transporter displays concentration dependence,
saturation and stereospecifity, temperature sensitivity, and is stimulated by H+ and Lacgradients (13). However, in the present study increased Lac- efflux seems unlikely
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plasma [H+] by amounts similar to those reported in previous studies (3; 6; 9; 17; 23; 24;
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because the [H+] gradient was observed to be lower in ALK during exercise above 70%
CONPOpeak.
In fact, a decrease in the muscle-to-blood [H+] gradient would be expected to
decrease [Lac-] efflux. Indeed, Stephens et al. (30) reported approximately 10% and 20%
lower [H+] and [Lac-] gradients respectively from contracting muscle to the blood during
ALK, and suggested that the increased [Lac-]pl often seen following NaHCO3 ingestion is
a consequence of decreased Lac- uptake by inactive tissue. This suggestion is supported
by the study Granier et al. (7), who observed a lower arteriovenous Lac- difference across
these findings, Hollidge-Horvat et al. (9) reported an increase in [Lac-] efflux was
associated with an increase in the muscle-to-blood [H+] gradient in ALK. However one
might naively expect these results when intramuscular [H+] for determining the [H+]gradient is estimated from muscle biopsy measures of intracellular [Lac-]. Nevertheless,
an increased muscle Lac- efflux with NaHCO3 cannot be completely ruled out, as Lackinetics were not assessed in the present study.
It is important to note that changes in [Lac-]pl detected in blood samples reflect the
balance between Lac- production and efflux from active tissues and Lac- removal by
inactive tissues. While numerous studies have reported increases in [Lac-]pl during
exercise following NaHCO3 ingestion (2; 4; 7-9; 11; 25; 26; 30; 32), our results did not
show any difference between conditions, suggesting a possible decrease in [Lac-]
production and/or efflux. Thus, the present study is in contrast with previous studies that
have reported increases in muscle Lac- production (2) and/or increased by similar or
lower [Lac-]pl during exercise following NaHCO3 ingestion (3; 10; 12; 15; 23; 31). While
the present study cannot reconcile these apparent contradictory findings, it is possible that
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the inactive forearm during repeated sprint cycling after NaHCO3 infusion. In contrast to
JAP-01261-2003.R1
differences in the types of exercise protocols and muscle groups used in these studies
may be an important and often overlooked factor.
The results of the present study do not agree with those of Hollidge-Horvat et al.
(9), who observed that increased Lac- production and efflux caused by 15 minutes of
cycling exercise at 75% VO2max with NaHCO3 lead to increased glycogen utilization,
increased PCr utilization, and increased ADP, AMP, and Pi accumulation. Furthermore,
these perturbations were associated with a greater pyruvate dehydrogenase (PDH)
rising [H+]. While glycogen and PDH activity were not assessed in the present study, we
believe that none of these effects would be present in our study since there did not appear
to be an enhanced rate of high-energy phosphate metabolism as seen in the HollidgeHorvat et al. study (9). Rather, our results indicate that for the contracting forearm, no
significant differences in ATP breakdown, PCr utilization or Pi accumulation were
detected between CON and ALK (Table 1). Furthermore, when the ratio of [PCr]/[Pi] (or
log[Pi]/[PCr]) was plotted against power output for each subject, the transition from slowto-rapid increases in this ratio was delayed (P < 0.05) with ALK. Presumably, these
intracellular concentrations of PCr and Pi reflect the metabolic activity of the muscle, and
as such have often been used as an in vivo estimate of the phosphorylation potential, or
[ATP]/[ADP]. Stable values of this ratio indicate an adequate energy status while rapid
increases in this ratio reflect an inability of the cell to meet ATP demands. Therefore, it is
our conclusion that the delay prior to the rapid increases in [Pi]/[PCr] with ALK was
associated with the delayed accumulation of intracellular [H+]. In other words, the
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activation which presumably allowed for increased glycogenolytic flux in the face of
JAP-01261-2003.R1
enhanced exercise performance with induced alkalosis is related to the ability of NaHCO3
to maintain a more optimum intracellular pH in the face of increasing metabolic demand.
In this respect, we may consider that the fatiguing effects of a declining pHi
during
exercise
include:
allosteric
inhibition
of
the
rate
limiting
enzymes
phosphofructokinase and glycogen phosphorylase; decreased release of Ca2+ from the
sarcoplasmic reticulum; and a reduction in the number and force of muscle cross-bridge
activations. Hence, it may be possible that the maintenance of a more favourable pHi
reduced muscle [H+] in ALK are unclear. In the present study, we believe that a more
prolonged maintenance of normal pHi was achieved by either increased Na+/H+ transport,
and/or an increased intracellular SID. Since blood plasma [Na+] was significantly
elevated in ALK throughout the entire exercise protocol (Table 5), a similar increase in
muscle [Na+] may also have occurred. As a result, an increased H+ efflux via the skeletal
muscle Na+/H+ transporter (14) and/or an increased intracellular SID may have occured.
While the measurement of muscle [Na+] was not possible with the techniques used in the
present study, it has been shown previously that metabolic alkalosis increased muscle
[Na+] during exercise in a perfused rat hindlimb model (18).
An intracellular alkalosis may also have resulted from disruptions in the balance
of strong cations and anions within the muscle. The increase in plasma [Na+] and
decrease in plasma [Cl-] (Table 5) in the present study would have the combined effect of
increasing the plasma SID, which has been shown to be the major contributor to plasma
alkalosis with NaHCO3 ingestion (17). If a similar increase in the SID in the intracellular
compartment was present prior to exercise, then it is expected that the elevated SID
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during exercise may enhance performance, however the mechanisms responsible for the
JAP-01261-2003.R1
would partially counteract the acidifying effect (through a fall in SID) of the rise in
muscle [Lac-], attenuating the acidification of both the intracellular and extracellular
compartments.
In summary, the metabolic effects of induced alkalosis were shown to include an
increased plasma pH at rest that led to a delayed onset of intracellular acidification during
incremental exercise. In our study, NaHCO3 was not associated with increased [Lac-]pl
accumulation or increased PCr breakdown. We have concluded therefore that the oral
small but measurable decrease in [H+] which is not evident until ~ 60 % POpeak. It is
believed that this effect may have been consequence of increased skeletal muscle Na+/H+
exchange and/or an increased intracellular SID. Furthermore, we suggest that previous
reports in the literature of increased blood [Lac-] during ALK are not due to increases in
muscle Lac- production, but instead may be due to decreased Lac- uptake by inactive
tissues.
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ingestion of NaHCO3 appears to effect intracellular metabolism primarily by inducing a
JAP-01261-2003.R1
Tables
Table 1. Time to fatigue and peak power output during ramp exercise to fatigue in the 31P-MRS and blood sampling exercise series
during control and induced alkalosis
31
P-MRS
CON
BLD
TTF, min
POpeak, W
TTF, min
POpeak, W
13.0 ± 4.1*
1.96 ± 0.49*
15.2 ± 2.9*
2.20 ± 0.30*
ALK
14.3 ± 3.5*
2.11 ± 0.40*
17.5 ± 2.1*
2.47 ± 0.21*
Values are means ± SD. BLD, blood sampling; TTF, time to fatigue; POpeak, peak power output; CON, control; ALK, alkalosis. * Significant difference (P < 0.05)
between CON and ALK.
Initial Phase (Below Threshold)
Rapid Phase (Above Threshold)
Slope (m1)
Intercept (b1)
Slope (m2)
CON
ALK
-0.14 ± 0.10
-0.11 ± 0.05
7.09 ± 0.04
7.09 ± 0.04
-0.69 ± 0.23
-0.69 ± 0.20
7.71 ± 0.27
7.82 ± 0.28
CON
ALK
0.65 ± 0.24
0.63 ± 0.13
-0.80 ± 0.16
-0.81 ± 0.12
1.43 ± 0.34
1.42 ± 0.27
-1.73 ± 0.13
-1.83 ± 0.29
CON
0.67 ± 0.41
1.62 ± 0.44*
5.01 ± 2.03
-3.65 ± 2.84
Intercept (b2)
pHT
PT
LT
ALK
0.76 ± 0.47
0.93 ± 0.46*
4.83 ± 1.97
-4.25 ± 1.93
Values are means ± SD. Slope and intercept parameters given for the piecewise linear regression function: y = m1x + b1, [x < threshold]; y = m2x + b2, [x ≥ threshold].
pHT, intracellular pH threshold; PT, log[Pi]/[PCr] threshold; LT, plasma lactate threshold. * Significant difference (P < 0.05) between CON and ALK.
Table 3. Piecewise linear regression analysis for the determination of an onset (or threshold) of a rapid decrease in intracellular pH,
and the rapid increases in log[Pi]/[PCr] and blood plasma lactate during CON and ALK
pHT
CON
PT
LT
pH
PO, W
% POpeak
log[Pi]/[PCr]
PO, W
% POpeak
[Lac-]pl, mM
PO, W
% POpeak
6.93 ± 0.13
1.17 ± 0.26*
60.4 ± 5.0
-0.049 ± 0.21
1.21 ± 0.30*
62.7 ± 7.1
2.4 ± 0.4
1.17 ± 0.19
53.1 ± 5.4
ALK
6.94 ± 0.07
1.28 ± 0.22*
61.3 ± 2.1
-0.026 ± 0.13
1.30 ± 0.30*
61.6 ± 4.1
1.9 ± 0.5
1.30 ± 0.21
52.3 ± 6.0
Values are means ± SD. pHT, intracellular pH threshold; PT, log[Pi]/[PCr] threshold; LT, plasma lactate threshold; PO, power output, POpeak, peak power output. *
Significant difference (P < 0.05) between CON and ALK.
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Table 2. Biphasic parameters of intracellular pH, log[Pi]/[PCr], and blood plasma lactate occurring during progressive exercise in
CON and ALK
JAP-01261-2003.R1
Table 4. Venous plasma concentrations of HCO3-, Na+, K+, and Cl- during progressive exercise in CON and ALK
Rest
Start
Progressive Exercise (% CONPOpeak)
0%
27%
34%
31.9 ± 2.6*
32.7 ± 2.0*
32.4 ± 1.8*
32.4 ± 2.0*
32.5 ± 2.4*
32.8 ± 2.5*
32.5 ± 2.7*
32.4 ± 3.1*
32.4 ± 2.8*
32.8 ± 3.1*
32.8 ± 3.3*
32.2 ± 3.0*
ALK
[Na+]
CON
39.0 ± 2.5*
38.7 ± 2.1*
38.5 ± 2.0*
38.8 ± 2.1*
38.8 ± 2.3*
39.0 ± 2.5*
39.0 ± 2.6*
38.7 ± 2.9*
38.4 ± 3.2*
38.6 ± 3.2*
38.2 ± 3.2*
38.0 ± 3.2*
132.2 ± 1.1
135.8 ± 3.5*†
137.5 ± 1.3*† 139.2 ± 1.3*† 139.7 ± 1.8*† 139.3 ± 0.8*† 139.7 ± 1.5*† 140.2 ± 1.2*†
140.8 ± 1.5†
141.6 ± 2.1†
141.7 ± 1.7†
141.6 ± 2.4†
ALK
[K+]
CON
133.3 ± 3.0
139.9 ± 4.5*†
141.0 ± 4.7*† 143.2 ± 3.9*† 144.2 ± 3.3*† 144.4 ± 3.4*† 144.2 ± 3.0*† 144.7 ± 1.8*†
142.9 ± 2.1†
143.1 ± 2.4†
142.1 ± 1.9†
142.1 ± 2.3†
4.1 ± 0.1*
4.7 ± 0.2*†
4.6 ± 0.2*†
4.6 ± 0.3*†
4.6 ± 0.3*†
4.7 ± 0.3*†
4.7 ± 0.3*†
4.7 ± 0.3*†
4.9 ± 0.3*†
5.0 ± 0.2*†
5.1 ± 0.2*†
5.3 ± 0.3*†
ALK
[Cl-]
CON
3.7 ± 0.1*
4.1 ± 0.2*†
4.2 ± 0.2*†
4.2 ± 0.2*†
4.2 ± 0.2*†
4.3 ± 0.2*†
4.4 ± 0.2*†
4.4 ± 0.3*†
4.5 ± 0.3*†
4.4 ± 0.3*†
4.6 ± 0.3*†
4.7 ± 0.3*†
104.1 ± 3.3*
101.2 ± 4.5*†
101.1 ± 4.1*
101.2 ± 4.8*
101.6 ± 5.4*
101.5 ± 5.5*
101.3 ± 4.7*
101.4 ± 4.8*
102.0 ± 4.7*
102.5 ± 4.2*
[HCO3-]
CON
42%
49%
56%
63%
71%
78%
85%
93%
100%
100.8 ± 4.4*† 100.8 ± 4.0*†
108%
36.9 ± 5.3*
140.1 ± 6.7†
4.7 ± 0.5*†
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99.4 ± 1.6*
94.9 ± 2.6*†
94.0 ± 1.9*† 94.2 ± 2.0*† 94.5 ± 1.9*† 94.6 ± 2.1*† 94.8 ± 2.0*† 95.5 ± 2.0*†
97.5 ± 4.3*
98.6 ± 4.1*
98.2 ± 4.3*
98.7 ± 3.3*
100.7 ± 3.1
ALK
Concentration expressed in mmol · L-1. Values are means ± SD. % CONPOpeak, percent peak power output in CON. * Significant difference (P < 0.05) between CON and
ALK. † Significant difference from rest (P < 0.05).
JAP-01261-2003.R1
Figure Captions
Fig. 1. The effect NaHCO3 ingestion (ALK) on forearm muscle intracellular pH during incremental wrist
flexion exercise to fatigue. In both CON and ALK, muscle pH during exercise is expressed relative to a
percentage of the peak power output in CON (% CONPOpeak). Dashed lines indicate power outputs
corresponding to the delayed (P < 0.05) onset of intracellular acidosis (pH threshold) in CON (pHTCON)
and ALK (pHTALK). Values are mean ± SEM. * ALK significantly different than CON (P < 0.05).
Fig. 2. The effect NaHCO3 ingestion (ALK) on forearm muscle phosphocreatine [PCr] (z) , inorganic
phosphate [Pi] (S), and adenosine triphosphate [ATP] („) concentrations. Solid symbols represent CON,
open symbols represent ALK. Power output during exercise is expressed relative to a percentage of the
peak power output in CON (% CONPOpeak). Values are mean ± SEM. No significant differences between
CON and ALK.
Fig. 4. The effect NaHCO3 ingestion (ALK) on forearm venous plasma pH during incremental wrist flexion
exercise to fatigue. In both CON and ALK, muscle pH during exercise is expressed relative to a percentage
of the peak power output in CON (% CONPOpeak). Values are mean ± SEM. * ALK significantly different
than CON (P < 0.05).
Fig. 5. The effect NaHCO3 ingestion (ALK) on forearm muscle-to-venous H+ gradient during incremental
wrist flexion exercise to fatigue. In both CON and ALK, the H+ gradient during exercise is expressed
relative to a percentage of the peak power output in CON (% CONPOpeak). Values are mean ± SEM. * ALK
significantly different than CON (P < 0.05).
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Fig. 3. The effect NaHCO3 ingestion (ALK) on forearm venous plasma lactate concentration [Lac-]pl during
incremental wrist flexion exercise to fatigue. In both CON and ALK, venous [Lac-]pl during exercise is
expressed relative to a percentage of the peak power output in CON (% CONPOpeak). Dashed lines indicate
power outputs corresponding to the onset of plasma lactate accumulation (lactate threshold) in CON
(LTCON) and ALK (LTALK). Values are mean ± SEM. No significant differences between CON and ALK
for [Lac-]pl or LT. (P = 0.255, 0.241)
JAP-01261-2003.R1
Figures
Fig. 1
pHTCON pHTALK
7.20
CON
7.10
*
Intracellular pH
7.00
6.90
ALK
*
*
6.80
*
6.70
*
6.60
*
6.50
6.30
6.20
0%
20%
40%
60%
80%
100% 120%
Power Output (% CONPOpeak)
Fig. 2
0.70
% Total Phosphate [Phos]
[PCr]
0.60
[Pi]
0.50
[ATP]
0.40
0.30
0.20
0.10
0.00
0%
20%
40%
60%
80%
100%
Power Output (% CONPOpeak)
Page 24 of 30
120%
Downloaded from http://jap.physiology.org/ by 10.220.33.2 on June 14, 2017
6.40
JAP-01261-2003.R1
Fig. 3
Plasma [Lac - ] (mmol/L)
LTCON LTALK
9.00
CON
8.00
ALK
7.00
6.00
5.00
4.00
3.00
2.00
1.00
0.00
0%
20%
40%
60%
80%
100%
120%
Fig. 4
7.60
Plasma pH
7.50 *
7.40
CON
ALK
* *
* *
* *
* * *
* *
7.30
7.20
7.10
7.00
0%
20%
40%
60%
80%
100% 120%
Power Output (% CON POpeak)
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Power Output (% CON POpeak)
JAP-01261-2003.R1
Fig. 5
CON
400
ALK
350
300
250
200
*
*
150
*
100
*
*
50
0
0%
20%
40%
60%
80%
100%
Power Output (% CONPOpeak)
Page 26 of 30
120%
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Muscle - Plasma [H+] (nmol/L)
450
JAP-01261-2003.R1
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