Download Point:Counterpoint Comments The following letters are in response

J Appl Physiol 100: 2100 –2102, 2006;
doi:10.1152/japplphysiol.00213.2006.
Point:Counterpoint Comments
The following letters are in response to the Point:Counterpoint
series “Lactic acid accumulation is an advantage/disadvantage
during muscle activity” that appeared in the April issue (J Appl
Physiol 100: 1410 –1414, 2006; http://jap.physiol.org/content/
vol100/issue4/2006).
REFERENCES
1. Allen DG. Skeletal muscle function: role of ionic changes in fatigue,
damage and disease. Clin Exp Pharmacol Physiol 31: 485– 493, 2004.
2. Fitts RH. Cellular mechanisms of muscle fatigue. Physiol Rev 74: 49 –94,
1994.
3. Lamb GD and Stephenson DG; Bangsbo J and Juel C. Lactic acid
accumulation is an advantage/disadvantage during muscle activity. J Appl
Physiol 100: 1410 –1414, 2006.
4. Lindinger MI and Heigenhauser GJF. The roles of ion fluxes in skeletal
muscle fatigue. Can J Physiol Pharmacol 69: 246 –253, 1991.
5. Spriet LL, Lindinger MI, McKelvie RS, Heigenhauser GJF, and Jones
NL. Muscle glycogenolysis and H⫹ concentration during maximal intermittent cycling. J Appl Physiol 66: 8 –13, 1989.
Michael Ivan Lindinger
Human Health and Nutritional Sciences
University of Guelph
Guelph, Ontario, Canada
To the Editor: The Point:Counterpoint discussion (4) is burdened by the 1900’s “lactate is bad” tradition, causing both
sides to ignore the lactate shuttle. Because glycolysis is the
result of contraction, and lactate production is intrinsic to
glycolysis, lactate turnover (production and disposal) is key to
the continuance of muscle function during hard exercise.
Glycogenolysis and glycolysis leading to lactate production
is attributable to the kinetics of lactate dehydrogenase (LDH).
2100
REFERENCES
1. Brooks GA. Lactate shuttles in nature. Bioch Soc Trans 30: 258 –264,
2002.
2. Hashimoto T, Hussien R, and Brooks GA. Co-localization of MCT1,
CD147 and LDH: evidence of a mitochondrial lactate oxidation (LX)
complex. Am J Physiol Endocrinol Metab (January 24, 2006).
doi:10.1152/ajpendo.00594.2005.
3. Henderson GC, Horning MA, Lehman SL, Wolfel EE, Bergman BC,
and Brooks GA. Pyruvate shuttling during rest and exercise in men before
and after endurance training. J Appl Physiol 97: 317–325, 2004.
4. Lamb GD and Stephenson DG; Bangsbo and Juel C J. Lactic acid
accumulation is an advantage/disadvantage during muscle activity. J Appl
Physiol 100: 1410 –1414, 2006.
5. Richardson RS, Noyszewski EA, Leigh JS, and Wagner PD. Lactate
efflux from exercising human skeletal muscle: role of intracellular PO2.
J Appl Physiol 85: 627– 634, 1998.
George A. Brooks
Gregory C. Henderson
Takeshi Hashimoto
Tamara Mau
Jill A. Fattor
Michael A. Horning
Raja Hussien
Hyung-Sook Cho
Nastaran Faghihnia
Zinta Zarins
Department of Integrative Biology
Exercise Physiology Laboratory
University of California at Berkeley
Berkeley, California
e-mail: [email protected]
To the Editor: We ask and answer a slightly different question:
is lactate accumulation an advantage or a disadvantage during
exercise in humans? It depends. During exercise intensities up
to maximal lactate steady state, the modest concentration of
lactate (⬃4 mM in whole blood) is likely an advantage in the
context of distributing substrate and coordinating intermediary
metabolism in different tissues, i.e., the cell-to-cell lactate
shuttle (1, 2). However, it is incautious to infer that lactate is a
performance-enhancing drug, as we are unaware of any studies
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To the Editor: Lamb and Stephenson (3) argue, based on
reductionist approaches in isolated and skinned muscle fibers at
rest, that lactate and proton accumulation during periods of
contraction may augment force production by relieving inhibition of excitation-contraction coupling processes at the sarcolemma, SR and contractile apparatus. The reductionist approaches give insight to mechanisms that may be involved in
the regulation of cellular processes, but the results are initially
valid only for the experimental conditions used. Even with
consideration of temperature effects (1), there are in vivo and
in situ metabolic, biochemical and molecular evidence that
lactate and proton accumulation within contracting muscle,
directly and indirectly, contribute to fatigue and that this is
effected by a number of factors including downregulation of
pH-sensitive enzyme systems (2, 5). Although there may be
simultaneous beneficial effects of increased lactate or protons
on some E-C coupling processes at the sarcolemma, these are
over-ridden by other, simultaneous, inhibitory effects on the
contractile machinery (1) and energy production (5) that occur
as a result of lactate and proton accumulation. The suggestion
that fast glycotic fibers benefit from lactate accumulation on
the basis of the high Km for MCT4 (3) is illogical. Fast
glycolytic fibers, during high intensity exercise, are tolerant of
large excursions of metabolite and electrolyte concentrations,
some of which are relatively slowly restored (4). However,
retention of produced lactate by fast glycolytic fibers provides
a preferred energy source for resynthesizing glycogen after
cessation of contraction. Why get rid of a most important,
readily usable postcontraction energy source?
Muscle (L/P) is minimally 10 at rest and rises one order of
magnitude under fully aerobic conditions (3, 5). Some energy
is provided by substrate-level phosphorylation in glycolysis,
and the products (lactate and pyruvate) are main substrates for
oxidative phosphorylation and ATP homeostasis. In the cytosol, the reduction of pyruvate to lactate is necessary to
regenerate NAD⫹, thus balancing cytosolic redox, permitting
carbon flux through glyceraldehyde 3-phosphate dehydrogenase. Glycogenosis XI, a gene defect causing muscle LDH
deficiency, is rare and debilitating, causing exercise intolerance.
Myocyte lactate disposal is, in part, managed by efflux via
monocarboxylate (MCT; lactate/pyruvate) transporters (3).
However, most (⬇70%) lactate formed in muscle is either
removed immediately via oxidation or on uptake after reperfusion (1, 2). In this, mitochondrial LDH and MCT1 are part of
the mitochondrial lactate oxidation complex, allowing oxidation of lactate to pyruvate and pyruvate to CO2 and acetyl-CoA
(2). Of the lactate released from working muscle, some
(⬇10%) becomes the main myocardial substrate and some
(⬇20%) serves as the major gluconeogenic precursor (1).
Point:Counterpoint Comments
2101
REFERENCES
1. Brooks GA. Lactate: glycolytic product and oxidative substrate during
sustained exercise in mammals—the ’lactate shuttle.’ In: Comparative
Physiology and Biochemistry: Current Topics and Trends, vol. A, Respiration-Metabolism-Circulation, edited by Gilles R. Berlin: Springer, 1985,
p. 208 –218.
2. Gladden LB. Lactate metabolism: a new paradigm for the third millennium. J Physiol 558: 5–30, 2004.
3. Lamb GD and Stephenson DG; Bangsbo J and Juel C. Lactic acid
accumulation is an advantage/disadvantage during muscle activity. J Appl
Physiol 100: 1410 –1414, 2006.
4. Nielsen HB. Arterial desaturation during exercise in man: implication for
O2 uptake and work capacity. Scand J Med Sci Sports 13: 339 –358, 2003.
5. Samaja M, Allibardi S, Milano G, Neri G, Grassi B, Gladden LB, and
Hogan MC. Differential depression of myocardial function and metabolism
by lactate and H⫹. Am J Physiol Heart Circ Physiol 276: H3–H8, 1999.
L. Bruce Gladden1
Michael C. Hogan2
1
Department of Health and Human Performance
Auburn University
Auburn, Alabama
e-mail: [email protected]
2
Department of Medicine
Physiology Division
University of California, San Diego
La Jolla, California
To the Editor: The long-held view that lactate accumulation
has a detrimental effect on exercise performance is challenged
by newer findings, indicating that lactate is more likely a
surrogate marker for muscle fatigue, not the direct cause of it.
Lactate is an important fuel for contracting skeletal muscle and
not, as previously believed, merely a metabolic byproduct
destined for the Cori’s cycle. Inborn errors of metabolism
resulting in blocked [McArdle’s disease (MD)] or exaggerated
[mitochondrial myopathy (MM)] production of lactate during
exercise may hint at the role of lactate in muscle fatigue.
J Appl Physiol • VOL
Premature muscle fatigue in MD, however, has little to do with
the lack of muscle acidification, as argued by Lamb and
Stephenson (1). In this setting, no muscle acidification and low
Na⫹-K⫹ pump number, as mentioned by Bangsbo and Juel (1),
are probably epiphenomena, which are outmatched by the
patients’ inability to breakdown muscle glycogen, a fuel that is
crucial for muscle energy balance during early and highintensity exercise. It has also been argued that muscle acidification is a prerequisite for sympathoactivation and thus avoidance of fatigue during exercise (2). However, abolished or
exaggerated muscle acidification in patients with MD and MM
do not alter sympathetic responses to exercise (3, 4). Maximal
levels of plasma lactate during low-intensity exercise in patients with MM were believed to impair exercise performance,
but lowering of lactate to normal by treatment with DCA had
no effect on fatigue or maximal exercise performance in the
patients (5). Thus experimental models of nature suggest that
lactate is a marker, but not the cause, of fatigue.
REFERENCES
1. Lamb GD and Stephenson DG; Bangsbo and Juel CJ. Lactic acid
accumulation is an advantage/disadvantage during muscle activity. J Appl
Physiol 100: 1410 –1414, 2006.
2. Victor RG, Bertocci LA, Pryor SL, and Nunnally RL. Sympathetic nerve
discharge is coupled to muscle cell pH during exercise in humans. J Clin
Invest 82: 1301–1305, 1988.
3. Vissing J, Vissing SF, MacLean DA, Saltin B, Quistorff B, and Haller
RG. Sympathetic activation in exercise is not dependent on muscle acidosis: direct evidence from studies in metabolic myopathies. J Clin Invest 101:
1654 –1660, 1998.
4. Vissing J, MacLean DA, Vissing SF, Saltin B, and Haller RG. The
exercise metaboreflex is maintained in the absence of muscle acidosis:
insights from muscle microdialysis in humans with McArdle’s disease.
J Physiol 537: 641– 649, 2001.
5. Vissing J, Gansted U, and Quistorff B. Exercise intolerance in mitochondrial myopathy is not related to lactic acidosis. Ann Neurol 49: 672– 676,
2001.
John Vissing
Department of Neurology
National University Hospital, Rigshospitalet
Copenhagen, Denmark
e-mail: [email protected]
To the Editor: All too often in physiology our discussions
about muscle fatigue are based on a model of isometric
contractions. In this context, Lamb and Stephenson (2) argue
that lactic acid does not cause fatigue but actually helps delay
the onset of fatigue in two ways: 1) by offsetting the negative
effects of raised extracellular [K⫹] on membrane excitability
and 2) by inhibiting the SR Ca2⫹ pump that would help
increase cytoplasmic [Ca2⫹] and consequent force. On the
basis of strong evidence cited by Lamb and Stephenson, I
would agree that lactic acid accumulation appears to be an
advantage during isometric contractile activity; however, it
should be pointed out that reduced Ca2⫹ uptake would increase
basal intracellular Ca2⫹, which is thought to be important in
causing low-frequency fatigue (4).
Acidosis-induced slowing of Ca2⫹ removal by the SR would
reduce muscle relaxation rate, which may be appropriate for
isometric conditions, but sluggish muscle relaxation would not
be optimal for muscle performance when viewed from a
kinesiology perspective (3). From a kinesiology perspective,
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demonstrating that ingestion or infusion of lactate improves
performance.
During intense exercise, whole blood lactate levels may be
⬃20 mM and plasma pH ⬍7.0, with even more extreme
muscle values. At a minimum, it is likely under these conditions that a low tissue pH will cause pain and the blood acidosis
will encourage arterial hemoglobin desaturation that diminishes aerobic performance (4). Furthermore, in isolated nonischemic rat hearts, we observed a depression in contractility in
response to low pH, high [lactate], and the combination of the
two (5).
Specifically regarding skeletal muscle activity, Lamb and
Stephenson (3) summarize intriguing studies suggesting that
lactate accumulation and the resulting low pH via a decrease in
the strong ion difference, may actually alleviate fatigue. However, studies of isolated, skinned muscle fibers at temperatures
of 28 –30°C and externally elevated [lactate] may not extrapolate accurately to contracting whole muscle groups in exercising humans where the muscle temperature may be as high as
42°C. Regardless of the final mechanism of action, it is
premature to eliminate lactate accumulation as a potential
cause of fatigue under at least some circumstances.
Point:Counterpoint Comments
2102
muscle activity is viewed in the context of locomotion (i.e.,
running) that requires precise temporal recruitment between
groups of agonist and antagonist muscles to coordinate rapidly
alternating movements. In this context, slowed relaxation rate
means that locomotion must also slow down to maintain
coordinated alternating movements (i.e., fatigue).
Therefore, although lactic acid enhances the excitability of
working muscle, I would agree with Bangsbo and Juel (2), that
describing lactic acid as “the latest performance-enhancing
drug” (1) is going a bit too far.
2. Lamb GD and Stephenson DG, Bangsbo and Juel CJ. Point:Counterpoint: Lactic acid accumulation is an advantage/disadvantage during muscle
activity. J Appl Physiol 100: 1410 –1414, 2006.
3. Tupling AR. The sarcoplasmic reticulum in muscle fatigue and disease:
role of the sarco(endo)plasmic reticulum Ca2⫹-ATPase. Can J Appl Physiol
29: 308 –329, 2004.
4. Westerblad H, Bruton JD, Allen DG, and Lännergren J. Functional
significance of Ca2⫹ in long-lasting fatigue of skeletal muscle. Eur J Appl
Physiol 83: 166 –174, 2000.
Russell Tupling
Department of Kinesiology
University of Waterloo
Ontario, Canada
e-mail: [email protected]
REFERENCES
1. Allen DG and Westerblad H. Lactic acid-the latest performance-enhancing drug. Science 303: 1112–1113, 2004.
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