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J Appl Physiol 100:1410-1412, 2006. doi:10.1152/japplphysiol.00023.2006

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Point:Counterpoint
Point:Counterpoint: Lactic acid accumulation is an advantage/disadvantage
during muscle activity
PURPOSE AND SCOPE OF THE
POINT:COUNTERPOINT DEBATES
This series of debates was initiated for the Journal of
Applied Physiology because we believe an important means of
searching for truth is through debate where contradictory
viewpoints are put forward. This dialectic process whereby a
thesis is advanced, then opposed by an antithesis, with a
synthesis subsequently arrived at, is a powerful and often
entertaining method for gaining knowledge and for understand-
ing the source of a controversy.
Before reading these Point:Counterpoint manuscripts or pre-
paring a brief commentary on their content (see below for
instructions), the reader should understand that authors on each
side of the debate are expected to advance a polarized view-
point and to select the most convincing data to support their
position. This approach differs markedly from the review
article where the reader expects the author to present balanced
coverage of the topic. Each of the authors has been strictly
limited in the lengths of both the manuscript (1,200 words) and
the rebuttal (400). The number of references to publications is also
limited to 30, and citation of unpublished findings is prohibited.
POINT: LACTIC ACID ACCUMULATION IS AN ADVANTAGE
DURING MUSCLE ACTIVITY
Lactic acid accumulation inside muscle fibers is not respon-
sible for decreased muscle performance (“muscle fatigue”).
Muscle fatigue occurs because of disturbance to any of the
steps in excitation-contraction (EC) coupling. There are several
broad types of muscle fatigue, and the contribution of each to
the overall decline in performance depends on the muscle fiber
type and the intensity and duration of the activity (1, 27). One
type is caused by the buildup of K⫹ in the transverse-tubular
(T-) system and in the immediate vicinity of the muscle fibers.
This K⫹ buildup depolarizes the fiber, slowing or preventing
Na⫹ channels from recovering from inactivation, with conse-
quent reduced amplitude or failure of action potentials and
reduction in force production. This type of fatigue is poten-
tially of major importance because [K⫹] has been shown to
reach very high levels (⬎10 mM) outside muscle fibers during
vigorous activity (23). The other major type of fatigue, often
termed “metabolic fatigue,” arises because of direct or indirect
effects of the accumulation of metabolites (Pi, ADP, Mg2⫹,
reactive oxygen species) and decrease in substrates (ATP,
creatine phosphate, glycogen) within muscle fibers. Force pro-
duction can decrease because of reduction in Ca2⫹ release from
the sarcoplasmic reticulum (SR), decline in maximum Ca2⫹-
activated force, or decrease in Ca2⫹ sensitivity of the contrac-
tile apparatus (1). In the fastest type of twitch fibers, cellular ATP
can drop to critically low levels (⬍1 mM) (11), reducing Ca2⫹
release (8). Metabolic fatigue can also occur due to effects of Pi
(7, 29), Mg2⫹ (27), and direct and indirect effects of glycogen
depletion (6, 28).
Lactate ions in the cytoplasm, even at high concentration, do
not impair EC coupling (20). High intracellular [H⫹] also has
1410 8750-7587/06 $8.00 Copyright © 2006 the American Physiological Society
J Appl Physiol 100: 1410 –1414, 2006;
doi:10.1152/japplphysiol.00023.2006.
few, if any, deleterious effects on EC coupling because normal
voltage-sensor controlled Ca2⫹ release is little, if at all, inhib-
ited by very low pH (2, 13, 19) and at 30°C, maximum force
production by the contractile apparatus is only reduced to a
small extent (17). Furthermore, in single intact muscle fibers,
decreasing pH from 7.1 to ⬍6.7 does not cause or accelerate
the onset of fatigue, but instead seemingly slows its onset (5).
An increase in intracellular acidity in fact can help increase
cytoplasmic [Ca2⫹] and consequent activation of the contrac-
tile apparatus, because the SR Ca2⫹ pump binds and reseques-
ters less Ca2⫹ at acid pH (2, 13, 30), which can leave more of
the released Ca2⫹ available to bind to troponin C (21), more than
compensating for the small decrease in the Ca2⫹ sensitivity of the
contractile apparatus occurring at acid pH. Also, elevated muscle
acidity does not reduce muscle glycogenolysis/glycolysis (3) or
Downloaded from jap.physiology.org on August 7, 2010
otherwise inhibit energy metabolism in functioning fibers (5).
Importantly, decreasing intracellular pH to ⬃6.7 actually
counters the inhibitory effect of raised extracellular [K⫹] (15,
22). This is because intracellular acidity blocks the Cl⫺ chan-
nels in the surface and T-system membranes and hence reduces
the normal high leakiness to Cl⫺, thereby making it possible
for action potentials to still propagate into the T-system despite
the raised [K⫹] having caused substantial inactivation of the
Na⫹ channels (18, 19). Extracellular [K⫹] does rise to critical
levels during normal exercise (23), so it seems very likely that
the decrease in intracellular pH has substantial beneficial ef-
fects in exercising humans by delaying the onset of fatigue due
to action potential failure. This is further supported by findings
in humans deficient in myophosphorylase activity (McArdle’s
disease) who are unable to break down glycogen or accumulate
lactic acid. These subjects display faster onset of fatigue, which
is associated with failure of muscle excitation (14). These
findings are fully consistent with muscle acidity normally
playing a crucial role in helping keep action potentials propa-
gating despite the large rise in extracellular [K⫹] occurring
with strenuous activity.
The argument put forward by Kristensen and colleagues (12)
that this effect does not occur in active muscle, is not valid
because it is based on observations made with isolated whole
soleus muscles that were stimulated at such a high rate that
⬎60% of the preparation would have rapidly become com-
pletely anoxic (4). Stimulating a highly aerobic muscle under
anaerobic conditions inevitably would have generated a large
amount of reactive oxygen species and disrupted mitochondrial
function, which is known to cause muscle depolarization and
reduced force (16). Furthermore, there is no reason to expect
that adding more H⫹ to that already being generated by the
muscle activity should in any way be advantageous. It is a bit
like opening up the carburetor on a car to let in too much air or
throwing gasoline over the engine and then concluding that air
and gasoline are deleterious to engine performance.
Experiments in which manipulation of body pH affects
muscle performance should not be taken as evidence of a
deleterious effect of intracellular muscle acidity. Altering body
pH can have effects on blood oxygen saturation and unloading,
http://www. jap.org

and on central drive and other factors. Experiments with
perfused hindlimb preparations, where such variables were
under some control, showed that a decrease in blood pH
adversely affected muscle performance but that this was due to
an effect of extramuscular pH, not the pH inside the muscle
fibers (26). The accompanying perfusion pressure data indicate
that the effect was quite possibly due entirely to the acidity
disrupting the normal control of local blood flow in the
vascular beds. Similarly, alkalosis in humans can delay the
onset of fatigue (24), but alkalosis actually causes a de-
crease in extracellular [K⫹], which alone may account for
the beneficial effects, particularly given that when this effect
of alkalosis is avoided, no improvement in muscle perfor-
mance is seen (25).
Further support for the proposition that lactic acid accumulation
is advantageous during muscle activity is provided by the prop-
erties of the two major monocarboxylate transporters (MCTs),
which play a major role in the regulation of intracellular pH and
lactate concentration during intense muscle activity. The MCT4
isoform that is predominantly and abundantly expressed in fast-
twitch glycolytic fibers, the major producer of lactic acid, has a
relatively high dissociation constant (low affinity) Km of 20 –35
mM, whereas the MCT1 isoform, which is predominantly ex-
pressed in slow-twitch oxidative fibers, has a Km of 3–5 mM (9,
10). The high Km of MCT4 for lactate explains why lactic acid is
allowed to accumulate in the fast-twitch glycolytic muscle during
exercise, causing acidification of the myoplasm. This must be
beneficial for the muscle because otherwise the muscle would
have expressed the low Km MCT isoform. The lower Km value for
lactate of MCT1 isoform in the slow-twitch, oxidative muscle
fibers provides a higher affinity uptake mechanism for lactate and
protons to be used in these fibers as a respiratory fuel.
Finally, we note that a rise in blood lactate (the “lactate
threshold”) can indeed be used as an indicator of exhaustion.
However, although lactate may well increase when muscle
performance declines, lactate is not the cause of the decline.
Lactate rises in the blood when the muscle cells are using ATP
faster than they resynthesize it aerobically in the mitochondria.
But it is the other changes occurring in the muscle, not the
lactic acid accumulation, which cause the fatigue. Acidity
associated with lactic acid accumulation actually helps delay
the onset of muscle fatigue that would otherwise ensue from
the other effects of vigorous activity.
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prolonged activity: cellular mechanisms of fatigue. Exp Physiol 80:
497–527, 1995.
2. Baker AJ, Brandes R, and Weiner MW. Effects of intracellular acidosis
on Ca2⫹ activation, contraction, and relaxation of frog skeletal muscle.
Am J Physiol Cell Physiol 268: C55–C63, 1995.
3. Bangsbo J, Madsen K, Kiens B, and Richter EA. Effect of muscle
acidity on muscle metabolism and fatigue during intense exercise in man.
J Physiol 495: 587–596, 1996.
4. Barclay CJ. Modelling diffusive O2 supply to isolated preparations of
mammalian skeletal and cardiac muscle. J Muscle Res Cell Motil 26:
225–235, 2005 [Epub 2005 Nov 9].
5. Bruton JD, Lännergren J, and Westerblad H. Effects of CO2-induced
acidification on the fatigue resistance of single mouse muscle fibers at 28
degrees C. J Appl Physiol 85: 478 – 483, 1998.
6. Chin ER and Allen DG. Effects of reduced muscle glycogen concentra-
tion on force, Ca2⫹ release and contractile protein function in intact mouse
skeletal muscle. J Physiol 498: 17–29, 1997.
J Appl Physiol • VOL 100 • APRIL 2006 •
Point:Counterpoint
1411
7. Dutka TL, Cole L, and Lamb GD. Calcium phosphate precipitation in
the sarcoplasmic reticulum reduces action potential-mediated Ca2⫹ release
in mammalian skeletal muscle. Am J Physiol Cell Physiol 289: C1502–
C1512, 2005.
8. Dutka TL and Lamb GD. Effect of low cytoplasmic [ATP] on excita-
tion-contraction coupling in fast-twitch muscle fibres of the rat. J Physiol
560: 451– 468, 2004.
9. Halestrap AP and Meredith D. The SLC16 gene family-from monocar-
boxylate transporters (MCTs) to aromatic amino acid transporters and
beyond. Pflügers Arch 447: 619 – 628, 2004.
10. Juel C and Halestrap AP. Lactate transport in skeletal muscle—role and
regulation of the monocarboxylate transporter. J Physiol 517: 633– 642, 1999.
11. Karatzaferi C, de Haan A, Ferguson RA, van Mechelen W, and
Sargeant AJ. Phosphocreatine and ATP content in human single muscle
fibres before and after maximum dynamic exercise. Pflügers Arch 42:
467– 474, 2001.
12. Kristensen M, Albertsen J, Rentsch M, and Juel C. Lactate and force
production in skeletal muscle. J Physiol 562: 521–526, 2005.
13. Lamb GD, Recupero E, and Stephenson DG. Effect of myoplasmic pH
on excitation-contraction coupling in skeletal muscle fibres of the toad.
J Physiol 448: 211–224, 1992.
14. Lewis SF and Haller RG. The pathophysiology of McArdle’s disease:
clues to regulation in exercise and fatigue. J Appl Physiol 61: 391– 401,
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1986.
15. Nielsen OB, de Paoli F, and Overgaard K. Protective effects of lactic
acid on force production in rat skeletal muscle. J Physiol 536: 161–166, 2001.
16. Ortenblad N and Stephenson DG. A novel signalling pathway originat-
ing in mitochondria modulates rat skeletal muscle membrane excitability.
J Physiol 548: 139 –145, 2003.
17. Pate E, Bhimani M, Franks-Skiba K, and Cooke R. Reduced effect of
pH on skinned rabbit psoas muscle mechanics at high temperatures:
implications for fatigue. J Physiol 486: 689 – 694, 1995.
18. Pedersen TH, de Paoli F, and Nielsen OB. Increased excitability of
acidified skeletal muscle: role of chloride conductance. J Gen Physiol 125:
237–246, 2005.
19. Pedersen TH, Nielsen OB, Lamb GD, and Stephenson DG. Intracellu-
lar acidosis enhances the excitability of working muscle. Science 305:
1144 –1147, 2004.
20. Posterino GS, Dutka TL, and Lamb GD. L(⫹)-lactate does not affect
twitch and tetanic responses in mechanically skinned mammalian muscle
fibres. Pflügers Arch 442: 197–203, 2001.
21. Posterino GS and Lamb GD. Effect of sarcoplasmic reticulum Ca2⫹
content on action potential-induced Ca2⫹ release in rat skeletal muscle
fibres. J Physiol 551: 219 –237, 2003.
22. Renaud JM and Light P. Effects of K⫹ on the twitch and tetanic
contraction in the sartorius muscle of the frog, Rana pipiens. Implication
for fatigue in vivo. Can J Physiol Pharmacol 70: 1236 –1246, 1992.
23. Sejersted OM and Sjögaard G. Dynamics and consequences of potas-
sium shifts in skeletal muscle and heart during exercise. Physiol Rev 80:
1411–1481, 2000.
24. Sostaric SM, Skinner SL, Brown MJ, Sangkabutra T, Medved I,
Medley T, Selig SE, Fairweather I, Rutar D, and McKenna MJ.
Alkalosis increases muscle K⫹ release, but lowers plasma [K⫹] and
delays fatigue during dynamic forearm exercise. J Physiol 570: 185–
205, 2006.
25. Spriet LL, Lindinger MI, Heigenhauser GJ, and Jones NL. Effects of
alkalosis on skeletal muscle metabolism and performance during exercise.
Am J Physiol Regul Integr Comp Physiol 251: R833–R839, 1986.
26. Spriet LL, Matsos CG, Peters SJ, Heigenhauser GJ, and Jones NL.
Effects of acidosis on rat muscle metabolism and performance during
heavy exercise. Am J Physiol Cell Physiol Cell Physiol 248: C337–C347,
1985.
27. Stephenson DG, Lamb GD, and Stephenson GM. Events of the exci-
tation-contraction-relaxation (E-C-R) cycle in fast- and slow-twitch mam-
malian muscle fibres relevant to muscle fatigue. Acta Physiol Scand 162:
229 –245, 1998.
28. Stephenson DG, Nguyen LT, and Stephenson GM. Glycogen content
and excitation-contraction coupling in mechanically skinned muscle fibres
of the cane toad. J Physiol 519: 177–187, 1999.
29. Westerblad H, Allen DG, and Lännergren J. Muscle fatigue: lactic acid
or inorganic phosphate the major cause? News Physiol Sci 17: 17–21,
2002.
www.jap.org
Point:Counterpoint
1412
30. Wolosker H, Rocha JB, Engelender S, Panizzutti R, De Miranda J,
and de Meis L. Sarco/endoplasmic reticulum Ca2⫹-ATPase isoforms:
diverse responses to acidosis. Biochem J 321: 545–550, 1997.
Graham D. Lamb
D. George Stephenson
Department of Zoology
La Trobe University
Victoria, Australia
e-mail: g.lamb@latrobe.edu.au
COUNTERPOINT: LACTIC ACID ACCUMULATION IS A
DISADVANTAGE DURING MUSCLE ACTIVITY
In an editorial of the journal Science, lactic acid was recently
described as “the latest performance-enhancing drug” (1). The
conclusion was based on studies of isolated rat skeletal and
skinned skeletal muscle fibers (11, 13, 14), and the authors
appear to have gone too far in the interpretations of their data.
In humans, the negative consequences of lactic acid accumu-
lation far exceed any positive effects.
In a number of studies, intense arm exercise has been used
to elevate the lactate concentration in the blood and all have
observed a reduction in performance of subsequent leg exercise
(see Ref. 2). In one study, arm exercise induced 12 mM lactate
in arterial plasma. In the subsequent knee-extensor exercise
bout, the time to exhaustion was 3.5 min compared with 4.7
min in the normal condition (Fig. 1; Ref. 2). The reduced
performance was associated with a significantly lower release
of lactate from the contracting leg muscles and a significantly
lower muscle pH when the leg exercise was performed with
prior arm exercise. In addition, potassium release was greater
from leg muscles during exercise after arm exercise. Thus as
muscle pH was different at exhaustion, it is not likely that the
lowered pH per se is the crucial factor, but it may still
contribute indirectly, probably through the greater potassium
release (19) perhaps mediated by a larger opening of the
ATP-sensitive potassium channels (18). The increased potas-
sium release likely leads to a greater accumulation of potas-
sium in muscle interstitium and earlier development of fatigue
Fig. 1. Arterial lactate, muscle pH, and performance. Arterial blood lactate
(circles) and muscle pH (squares) before and during exhaustive knee-extensor
exercise without (control, C, open symbols) and with prior arm exercise (high
lactate, HL, filled symbols). Time to exhaustion (EXH) is given as an arrow.
Mean ⫾ SE are given. *HL significantly different from C (data from Ref. 2).
J Appl Physiol • VOL 100 • APRIL 2006 •
(10). The effect of changing only pH has also been investigated
in humans. In a number of studies, blood pH has been elevated
by infusion of sodium citrate or bicarbonate. It is a general
finding that the alkalosis obtained by these procedures im-
proves performance (see Refs. 16, 19). This effect may be
mediated by an improved H⫹ and lactate release, increased
extracellular buffering, lowered increase in blood potassium
(16), and a reduced interstitial potassium accumulation during
alkalosis (19). Taken together, the findings in human studies
clearly suggest that lactic acid accumulation, and the associ-
ated lowering of pH in humans, is disadvantageous.
A high number of studies have examined the effect of lactic
acid in animal models. One way to investigate the effects of
lactic acid is to incubate a muscle in lactic acid before and
during stimuli. Studies using lactic acid incubation and repet-
itive exhaustive stimulation have reported a faster fatigue
development (3, 5, 9). For example, in rat skeletal muscle
incubated with 20 mM lactic acid, force development was
reduced during repetitive stimulation when compared with a
control situation (7). However, it should be mentioned that
Downloaded from jap.physiology.org on August 7, 2010
some of the experiments using exhaustive repetitive stimula-
tion have been carried out at temperatures in the range 25–
30°C, and it has been reported that part of the negative effect
disappears when experiments were conducted at body temper-
ature (12). It has also been observed that the lactate ion per se
reduces muscle force independent of any pH changes. In
isolated dog muscle, lactate ion perfusion reduced twitch force
by 15% (6) and lactate incubation reduced force in isolated
mouse muscle (17), whereas lactate did not change force in
skinned muscle fibers (15). These differences suggest that the
effect of lactate is associated with the function of the muscle
membrane. It must be noted that, although the investigations
with intact fibers used lactate incubation without plasma pH
changes, the lactate/H⫹ cotransporter will bring H⫹ into the
cells, and thus changes in intracellular pH may occur. There-
fore, it is possible that the effect of lactate is due to pH-induced
changes in, for example, the potassium balance.
The cellular mechanisms of the negative effects of lactic
acid accumulation and lowering of muscle pH may be multi-
factorial. In addition to the effect of lactate on the membrane,
the most important effect may be the influence on the handling
of intracellular Ca2⫹ during muscle activation. It has been
reported that lactate and H⫹ induce an impairment of sarco-
plasmic reticulum Ca2⫹ release channels (8), H⫹ depresses
Ca2⫹ activation of thin filaments (9), and H⫹ induces a
reduction of the Ca2⫹ reloading into sarcoplasmic reticulum (4;
also see Refs. 3, 5).
So why this debate, when the evidence for lactic acid and pH
having a negative effect on muscle performance is so strong?
It was recently demonstrated that lactic acid incubation restores
the force in rat muscle incubated in high K⫹ concentrations
(11). The underlying mechanism has been investigated with
skinned single fibers (13, 14). The positive effect appears to be
that intracellular acidosis decreases chloride permeability in
the T tubules, which allows action potentials to be propagated
despite the K⫹-induced depolarization (13, 14) Thus it might
be that lowered pH has a positive effect on specific ion
transport systems in the contracting muscles. We do not ques-
tion the outcome of these experiments, which we in part have
reproduced (7). However, there are a number of experimental
conditions that make it difficult to extrapolate these findings to
www.jap.org

the in vivo condition, in particular, during exercise in humans.
First, in the experiments by Nielsen et al. (11), a resting muscle
was studied (stimulation took place every 10 min) and exhaus-
tive repetitive stimulation was not used. Second, in vivo, the
Na⫹-K⫹ pump is activated both by hormones and the increase
in intracellular Na⫹ associated with muscle activity and pH
regulation. An active Na⫹-K⫹ pump partly restores the mem-
brane potential, thereby maintaining membrane excitability. In
the experimental model used by Nielsen et al. (11), the
Na⫹-K⫹ pump was not activated. Thus the potassium-induced
depolarization exceeded the depolarization during normal ac-
tivity in intact muscle that has an active Na⫹-K⫹ pump.
Therefore, it is likely that the lactic acid may have overcome
the negative effect of a large nonphysiological depolarization.
Third, in the experimental model used by Nielsen et al. (11),
lactic acid incubation lowered intracellular pH less than extra-
cellular pH, which created a reduced transmembrane pH gra-
dient. In contrast, the pH gradient is actually elevated in
contracting skeletal muscles during exercise.
In conclusion, there is ample evidence in both humans and
animals that accumulation of lactic acid during exercise con-
tributes to the development of fatigue during intense exercise.
It is also clear that lactic acid accumulation and the associated
lowering of intracellular pH are not the crucial factors and the
main effect may be that the lowered pH leads to a greater
release of potassium from the contracting muscles.
REFERENCES
1. Allen D and Westerblad H. Lactic acid—the latest performance-enhanc-
ing drug. Science 305: 1112–1113, 2004.
2. Bangsbo J, Madsen K, Kiens B, and Richter EA. Effect of muscle
acidity on muscle metabolism and fatigue during intense exercise in man.
J Physiol 495: 587–596, 1996.
3. Fitts RH. Cellular, molecular, and metabolic basis of muscle fatigue. In:
Handbook of Physiology. Exercise: Regulation and Integration of Multiple
Systems. Bethesda, MD: Am Physiol Soc, 1996, sect. 12, chapt. 26, p.
1151–1183.
4. Fabiato A and Fabiato F. Effects of pH on the myofilaments and the
sarcoplasmatic reticulum of skinned cells from cardiac and skeletal mus-
cle. J Physiol 276: 233–255, 1978.
5. Gladden LB. Lactate metabolism: a new paradigm for the third millen-
nium. J Physiol 558: 5–30, 2004.
6. Hogan MC, Gladden LB, Kurdak SS, and Poole DC. Increased [lactate]
in working dog muscle reduces tension development independent of pH.
Med Sci Sports Exerc 27: 371–377, 1995.
7. Kristensen M, Albertsen J, Rentsch M, and Juel C. Lactate and force
production in skeletal muscle. J Physiol 562: 521–526, 2005.
8. Ma J, Fill M, Knudson CM, Campbell KP, and Coronado R. Ryano-
dine receptor of skeletal muscle is a gap junction-type channel. Science
242: 99 –102, 1988.
9. Metzger JM and Fitts RH. Fatigue from high- and low-frequency
stimulation: contractile and biochemical alterations. J Appl Physiol 62:
2075–2082, 1987.
10. Nielsen JJ, Mohr M, Klarskov C, Kristensen M, Krustrup P, Juel C,
and Bangsbo J. Effects of high-intensity intermittent training on potas-
sium kinetics and performance in human skeletal muscle. J Physiol 554:
857– 870, 2004.
11. Nielsen OB, de Paoli F, and Overgaard K. Protective effects of lactic
acid on force production in rat skeletal muscle. J Physiol 536: 161–166,
2001.
12. Pate E, Bhimani M, Franks-Skiba K, and Cooke R. Reduced effect of
pH on skinned rabbit psoas muscle mechanics at high temperatures:
implications for fatigue. J Physiol 486: 689 – 694, 1995.
13. Pedersen TH, de Paoli F, and Nielsen OB. Increased excitability of
acidified skeletal muscle: role of chloride conductance. J Gen Physiol 125:
237–246, 2005.
J Appl Physiol • VOL
Point:Counterpoint
1413
14. Pedersen TH, Nielsen OB, Lamb GD, and Stephenson DG. Intracellu-
lar acidosis enhances the excitability of working muscle. Science 305:
1144 –1147, 2004.
15. Posterino GS, Dukta TL, and Lamb GD. L(⫹)-lactate does not affect
twitch and tetanic responses in mechanically skinned mammalian fibers.
Pflugers Arch 442: 197–203, 2001.
16. Sostaric SM, Skinner SL, Brown MJ, Sangkabutra T, Medved I,
Medley T, Selig SE, Fairweather I, Rutar D, and McKenna MJ.
Alkalosis increases muscle K⫹ release, but lowers plasma [K⫹] and delays
fatigue during dynamic forearm exercise. J Physiol [Epub October 20,
2005].
17. Spangenburg EE, Ward CW, and Williams JH. Effects of lactate on
force production in mouse EDL muscle: implications for the development
of fatigue. Can J Physiol Pharmacol 76: 642– 648.
18. Spruce AE, Standen NB, and Stanfield PR. Voltage-dependent ATP-
sensitive potassium channels of skeletal muscle membrane. Nature 316:
736 –738.
19. Street D, Nielsen J, Bangsbo JJ, and Juel C. Metabolic alkalosis reduces
exercise-induced acidosis and potassium accumulation in human skeletal
muscle interstitium. J Physiol 566:481– 489, 2005.
Jens Bangsbo1
Carsten Juel2
Downloaded from jap.physiology.org on August 7, 2010
1
Institute of Exercise and Sport Sciences
Copenhagen Muscle Research Centre
2
Institute of Molecular Biology and Physiology
University of Copenhagen
Copenhagen, Denmark
e-mail: JBangsbo@ifi.ku.dk
REBUTTAL FROM DRS. LAMB AND STEPHENSON
The Counterpoint by Bangsbo and Juel does not provide
evidence that lactic acid accumulation in muscle is disadvan-
tageous. Instead the authors agree with us in saying that “lactic
acid accumulation and the associated lowering of intracellular
pH are not the crucial factors” in the development of fatigue.
They argue that raised extracellular [K⫹] is the main cause of
fatigue and agree that intracellular acidosis does have a posi-
tive effect by decreasing chloride permeability. Given this, we
must say we are puzzled that they further argue that the results
of Nielsen et al. (5) supporting these conclusions are somehow
incorrect and based on “nonphysiological depolarization.” It
cannot be claimed that humans are entirely different from other
mammals in this regard while agreeing that raised extracellular
[K⫹] has the same deleterious effects on membrane potential
and action potential propagation. There is also no question that
human muscle, like that of other mammals, has a high resting
chloride conductance that acts to depress membrane excitabil-
ity; this is very well known, especially as the absence of this
chloride conductance is the cause of myotonia.
The data of Bangsbo et al. (1) do not demonstrate a delete-
rious effect of lactate accumulation. As that paper itself con-
cluded, the more rapid fatigue could well have been caused by
central fatigue or other factors, as the authors did not demon-
strate that the muscle itself was fatigued. The greater intracel-
lular acidity in the prior exercise case in fact was likely keeping
the muscle excitable. Furthermore, such experiments do not
address the main issue of whether lactic acid produced in a
muscle is advantageous or disadvantageous.
When arguing that intracellular acidification is deleterious,
Bangsbo and Juel do not refer to the large body of data
published over the last 15 years showing that acidification does
not inhibit physiological Ca2⫹ release (4, 6, 9). Furthermore,
they do not appreciate that inhibition of Ca2⫹ uptake at acid pH
100 • APRIL 2006 • www.jap.org
Point:Counterpoint
1414
actually favors increased force production. They do evidently
agree with our findings (7) that intracellular lactate per se does
not reduce the force response. The cited experiments where
lactate was applied outside muscles (2, 8) do not show that
lactate is deleterious, because there was an appreciable to very
large increase in extracellular osmolality, which would have
drawn water out of the muscles and had direct inhibitory
effects by increasing intracellular ionic strength (3).
In conclusion, the case for beneficial effects of lactic acid
accumulation is clear.
REFERENCES
1. Bangsbo J, Madsen K, Kiens B, and Richter EA. Effect of muscle acidity
on muscle metabolism and fatigue during intense exercise in man. J Physiol
495: 587–596, 1996.
2. Hogan MC, Gladden LB, Kurdak SS, and Poole DC. Increased [lactate]
in working dog muscle reduces tension development independent of pH.
Med Sci Sports Exerc 27: 371–377, 1995.
3. Lamb GD, Stephenson DG, and Stienen GJ. Effects of osmolality and
ionic strength on the mechanism of Ca2⫹ release in skinned skeletal muscle
fibres of the toad. J Physiol 464: 629 – 648, 1993.
4. Lamb GD and Stephenson DG. Effects of intracellular pH and [Mg2⫹] on
excitation-contraction coupling in skeletal muscle fibres of the rat. J Physiol
478: 331–339, 1994.
5. Nielsen OB, de Paoli F, and Overgaard K. Protective effects of lactic acid
on force production in rat skeletal muscle. J Physiol 536: 161–166, 2001.
6. Pedersen TH, Nielsen OB, Lamb GD, and Stephenson DG. Intracellular
acidosis enhances the excitability of working muscle. Science 305: 1144 –
1147, 2004.
7. Posterino GS, Dutka TL, and Lamb GD. L(⫹)-lactate does not affect
twitch and tetanic responses in mechanically skinned mammalian muscle
fibres. Pflügers Arch 442: 197–203, 2001.
8. Spangenburg EE, Ward CW, and Williams JH. Effects of lactate on
force production by mouse EDL muscle: implications for the development
of fatigue. Can J Physiol Pharmacol 76: 642– 648, 1998.
9. Westerblad H, Allen DG, and Lännergren J. Muscle fatigue: lactic acid
or inorganic phosphate the major cause? News Physiol Sci 17: 17–21, 2002.
REBUTTAL FROM DRS. BANGSBO AND JUEL
We have read the contribution by Lamb and Stephenson with
great interest. It was, however, a challenge to find data sup-
porting their hypothesis. Most of the arguments seem to be
based on speculation. They refer to a few human studies, and
we agree that “extracellular K⫹ does rise to critical levels
during normal exercise.” However, the argument that “it seems
very likely that the decrease in intracellular pH has substantial
beneficial effects in exercising humans by delaying the onset of
fatigue” does not have experimental support. In contrast, a
number of studies have shown that lowered pH leads to a
greater potassium release and potassium accumulation in mus-
J Appl Physiol • VOL
cle interstitium, as we have described in our contribution.
Furthermore, that the McArdle patients display faster onset of
fatigue due to lack of lactate accumulation is hard to follow.
Fatigue in these patients is more likely related to a high K⫹
efflux and the reduced number of Na⫹-K⫹ pumps compared
with control subjects (3).
The arguments for a positive role of lactic acid are based on
studies of isolated noncontracting muscle and skinned muscle
fibers. In our review we argued that these results represented
artificial nonexercise-related conditions and it is not possible to
extrapolate to the in vivo condition.
The argument that the results we obtained with isolated rat
muscle incubated in Na-lactate are not valid because of pro-
gressive developing anoxic conditions (2) can be rejected,
because the force reduction was obtained already in the first
bout of activity (4).
It is argued by Lamb and Stephenson that the high Km for the
lactate/H⫹ cotransporter MCT4 in fast-twitch muscle is to
allow for lactic acid accumulation, and this notion is used to
support the theory that high lactate concentrations delays
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fatigue. They wrote “This must be beneficial . . . ,” which is not
a very strong argument. It could as well be that the high lactate
is protecting the muscle cell from reaching a situation of very
low ATP levels. The capacity for lactate/H⫹ transport in
human muscle is increased by training and there is a positive
correlation between transport capacity (i.e., efflux) and perfor-
mance (5); these findings further suggest that lactic acid accu-
mulation is a disadvantage.
In the 1990s, we argued that high lactate and low muscle pH
is not the primary cause of fatigue in humans (1), but it seems
to contribute during intense exercise. As it currently stands,
evidence is still lacking that this is not the case.
REFERENCES
1. Bangsbo J, Graham T, Johansen L, Strange S, Christensen C, and
Saltin B. Elevated muscle acidity and energy production during exhaustive
exercise in humans. Am J Physiol Regul Integr Comp Physiol 263: R891–
R899, 1992.
2. Barclay CJ. Modelling diffusive O2 supply to isolated preparations of
mammalian skeletal and cardiac muscle. J Muscle Res Cell Motil 26:
225–235, 2005.
3. Haller RG, Clausen T, and Vissing J. Reduced levels of skeletal muscle
Na⫹,K⫹-ATPase in McArdle disease. Neurology 50: 37– 40, 1998.
4. Kristensen M, Albertsen J, Rentsch M, and Juel C. Lactate and force
production in skeletal muscle. J Physiol 562: 521–526, 2005.
5. Pilegaard H, Bangsbo J, Richter EA, and Juel C. Lactate transport
studied in sarcolemmal giant vesicles from human muscle biopsies: relation
to training status. J Appl Physiol 77: 1858 –1862, 1994.
100 • APRIL 2006 • www.jap.org