Current Trends in Lactate Metabolism:

Introduction
L. BRUCE GLADDEN
Department of Kinesiology, Auburn University, Auburn, AL

ABSTRACT

muscles are placed in O2-rich environments, Laj disappears. Subsequently, Laj took center stage with the work of
A.V. Hill (9) and the paradigm that Laj was the immediate
energy donor for muscle contraction.
A revolution in muscle physiology (10) occurred
between 1926 and 1932 with the discoveries of both
adenosine triphosphate (ATP) and phosphocreatine (PC);
this period could be called the Phosphagen Era. Based on
his own work and that of others, Lohmann (1517)
postulated that ATP hydrolysis was the immediate source
of energy for muscle contraction and that PC was used to
resynthesize ATP in the creatine kinase reaction (1). Direct
evidence of ATP breakdown during contractions did not
become available until about 30 yr later. Credit for this
proof usually goes to Cain and Davies (5), who inhibited
creatine kinase in muscles with the poison 1,fluoro-2,4dinitrobenzene (FDNB) and then immediately froze the
muscles after a series of contractions. Under these conditions in which ATP resynthesis from PC was prevented, a
decline in ATP concentration was observed. Notably, Lange
(13) had reported similar results 7 yr earlier. The reason for
the difficulty in obtaining absolute evidence of ATP
hydrolysis in muscle contractions is the incredibly rapid
kinetics of the creatine kinase reaction (1). Lardy`s group
(12) calculated that all of the ATP in a rabbit skeletal
muscle could be resynthesized from ADP and PC in only 30
ms (1), thus preventing detection of ATP breakdown unless
the creatine kinase reaction were blocked.
Given the association between Laj, O2, and fatigue
(dating from Fletcher and Hopkins (7) and A.V. Hill (9)),
and the removal of Laj from its eminent position as the
immediate energy donor for muscle contraction, it is no

s detailed by Brooks and me (4) in an historical

review, the study of lactate (Laj) metabolism can
be divided into several important time periods or
eras. During the Pre-Lactate Era (~17801907), Scheele
discovered Laj in sour milk in 1780 (14), and in 1808
Berzelius reported an elevated concentration of Laj ([Laj])
in the muscles of hunted stags (18). Several other notable
studies were reported in the 1800s, including evidence that
activity caused muscles to become acidic and that the
amount of Laj increased with the amount of work done (4).
In 1907, the Lactate Era (19071926) was ushered in by
the classic studies of Fletcher and Hopkins (7). They (7)
developed a method to prevent significant Laj formation in
resting muscles before the extraction and analysis of the
Laj. Accordingly, they were able to demonstrate that 1)
freshly excised resting muscle contains only a small amount
of Laj, 2) [Laj] increases in excised, resting, anaerobic
muscles, 3) La j accumulates to high levels during
stimulation of muscles to fatigue, and 4) when fatigued

Editors Note: This paper is an Editor-in-Chiefinvited contribution from

ACSMs conference on Integrative Physiology of Exercise held in
Indianapolis, Indiana, September 2730, 2006.
Address for correspondence: L. Bruce Gladden, Department of Kinesiology, 2050 Memorial Coliseum, Auburn University, Auburn, AL 368495323; E-mail: gladdlb@auburn.edu.
Submitted for publication June 2007.
Accepted for publication September 2007.
0195-9131/08/4003-0475/0
MEDICINE & SCIENCE IN SPORTS & EXERCISE
Copyright 2008 by the American College of Sports Medicine
DOI: 10.1249/MSS.0b013e31816154c9

475

Copyright @ 2008 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.

BASIC SCIENCES

GLADDEN, L. B. Current Trends in Lactate Metabolism: Introduction. Med. Sci. Sports Exerc., Vol. 40, No. 3, pp. 475476, 2008. In
September 2006, at the Integrative Physiology of Exercise meeting in Indianapolis, IN, a symposium entitled Current Trends in
Lactate Metabolism was presented. This short paper introduces two papers from that symposium. The first paper by L. Bruce Gladden
briefly summarizes key pieces of evidence that support the cell-to-cell lactate shuttle, a concept that is no longer an hypothesis but that,
instead, is now an established theory that provides the context for discussions of whole body metabolism. Gladden also offers a critical
appraisal of the intracellular lactate shuttle and evaluates an ongoing controversy relative to the role of lactate in acidbase balance. In
the second paper, Hashimoto and Brooks provide their evidence in support of the intracellular lactate shuttle and a lactate oxidation
complex in the inner mitochondrial membrane. They also postulate that lactate is a cell-signaling molecule, lactormone, that can
upregulate gene and protein expression. Both papers have been updated since their original presentations and represent the current
state of knowledge. Key Words: LACTATE HISTORY, LACTATE SHUTTLE, CELL-TO-CELL LACTATE SHUTTLE,
INTRACELLULAR LACTATE SHUTTLE, LACTATE OXIDATION COMPLEX, LACTIC ACIDOSIS

surprise that a long period following the 1930s could be

called the Dead-End Waste Product Era from the perspective of Laj metabolism. Certainly, there was a great deal of
research during this period including a flurry of activity
surrounding the anaerobic threshold, a term coined by
Wasserman and McIlroy (19) in 1964. In 1973, Wasserman,
his colleague Whipp, and other coworkers refined the concept
in their classic paper (20), which generated tremendous interest in the topic. Although contrary evidence was beginning
to mount (6,11), in the minds of many, Laj was a detrimental by-product of high-intensity, O2-limited metabolism.
As recounted in the first of two papers in this symposium,
the prevailing view of Laj in metabolism underwent a sea

change following the introduction of what is now known as

the cell-to-cell lactate shuttle by George Brooks in 1984 (2).
In terms of Laj metabolism, we are presently in the midst
of what could be called the Lactate Shuttle Era (8). In the
first symposium paper, I briefly summarize the overwhelming case for the cell-to-cell lactate shuttle, offer a critical
view of the more recently proposed intracellular lactate
shuttle (3), and analyze an ongoing debate about lactic
acidosis. In the second paper, Hashimoto and Brooks
summarize their evidence for the intracellular lactate shuttle
in skeletal muscle, and propose that Laj is also a cellsignaling molecule, lactormone, that can upregulate gene
and protein expression.

BASIC SCIENCES

REFERENCES
1. Barnard RJ, Holloszy JO. The metabolic systems: aerobic
metabolism and substrate utilization in exercising skeletal
muscle. In: Tipton CM, editor. Exercise Physiology People
and Ideas. New York (NY): Oxford University Press; 2003.
p. 292321.
2. Brooks GA. Lactate: glycolytic product and oxidative
substrate during sustained exercise in mammalsthe Flactate
shuttle.` In: Gilles R, editor. Comparative Physiology and
Biochemistry: Current Topics and Trends, vol. A, Respiration
MetabolismCirculation. Berlin (Germany): Springer; 1985.
p. 20818.
3. Brooks GA, Dubouchaud H, Brown M, Sicurello JP, Butz CE.
Role of mitochondrial lactate dehydrogenase and lactate oxidation
in the intracellular lactate shuttle. Proc Natl Acad Sci USA.
1999;96:112934.
4. Brooks GA, Gladden LB. The metabolic systems: anaerobic
metabolism (glycolytic and phosphagen). In: Tipton CM, editor.
Exercise Physiology. People and Ideas. New York (NY): Oxford
University Press; 2003. p. 32260.
5. Cain DF, Davies RE. Breakdown of adenosine triphosphate
during a single contraction of working muscle. Biochem Biophys
Res Commun. 1962;8:3616.
6. Connett RJ, Gayeski TE, Honig CR. Lactate accumulation in fully
aerobic, working, dog gracilis muscle. Am J Physiol Heart Circ
Physiol. 1984;246:H1208.
7. Fletcher WM, Hopkins FG. Lactic acid in amphibian muscle. J
Physiol. 1907;35:247309.
8. Gladden LB. Lactate metabolism: a new paradigm for the third
millennium. J Physiol. 2004;558:530.
9. Hill AV. The energy degraded in the recovery processes of
stimulated muscles. J Physiol. 1913;46:2880.

476

Official Journal of the American College of Sports Medicine

10. Hill AV. The revolution in muscle physiology. Physiol Rev.

1932;12:5667.
11. Jobsis FF, Stainsby WN. Oxidation of NADH during contractions
of circulated mammalian skeletal muscle. Respir Physiol. 1968;4:
292300.
12. Kuby SA, Noda L, Lardy HA. Adenosinetriphosphate-creatine
transphosphorylase. III. Kinetic studies. J Biol Chem. 1954;210:
6582.
13. Lange G. Dephosphorylation of adenosinetriphosphate to adenosinediphosphate during contraction phase of rectus muscles in frog
[in German]. Biochem Z. 1955;326:17286.
14. Lockwood LB, Yoder DE, Zienty M. Section 1. Chemistry and
enzymology of lactate isomers. Lactic acid. Ann N Y Acad Sci.
1965;119:85465.
15. Lohmann K. Darstellung der adenylpyrophosphorsaure aus muskulatur (production of adenylpyrophosphoric acid from musculature). Biochem Z. 1931;271:4609.
ber die enzymatische aufspaltung der kreatinphos16. Lohmann K. U
phorsaure; zugleich ein beitrag zum chemismus der muskelkontraktion. Biochem Z. 1934;271:26477.
ber die pyrophosphatfraktion im muskel. Natur17. Lohmann K. U
wissenschaften. 1929;17:62425.
18. Needham J. Introduction. In: Needham J, editor. The Chemistry of
Life; Eight Lectures on the History of Biochemistry. Cambridge
(England): University Press; 1970. p. viixxx.
19. Wasserman K, McIlroy MB. Detecting the threshold of anaerobic
metabolism in cardiac patients during exercise. Am J Cardiol.
1964;14:84452.
20. Wasserman K, Whipp BJ, Koyl SN, Beaver WL. Anaerobic
threshold and respiratory gas exchange during exercise. J Appl
Physiol. 1973;35:23643.

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