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Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.8

Current Trends in Lactate Metabolism:

Introduction

L. BRUCE GLADDEN

Department of Kinesiology, Auburn University, Auburn, AL

ABSTRACT

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

As 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) Laj accumulates to high levels during

stimulation of muscles to fatigue, and 4) when fatigued

muscles are placed in O2-rich environments, Laj

disap-

pears. 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-2,4-

dinitrobenzene (FDNB) and then immediately froze the

muscles after a series of contractions. Under these con-

ditions 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 rapidkinetics 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

Address for correspondence: L. Bruce Gladden, Department of Kinesiol-

ogy, 2050 Memorial Coliseum, Auburn University, Auburn, AL 36849-

5323; 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 & EXERCISECopyright 2008 by the American College of Sports Medicine

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

ACSMs conference on Integrative Physiology of Exercise held inIndianapolis, Indiana, September 2730, 2006.

475

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DOI: 10.1249/MSS.0b013e31816154c9

8/14/2019 Metabolismo Del Lactato 2008 ( Cajigal)

2/2Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.8

surprise that a long period following the 1930s could be

called the Dead-End Waste Product Era from the perspec-

tive 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 inter-

est in the topic. Although contrary evidence was beginningto mount (6,11), in the minds of many, Laj was a detri-

mental 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 overwhelm-

ing 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 Brookssummarize their evidence for the intracellular lactate shuttle

in skeletal muscle, and propose that Laj is also a cell-

signaling molecule, lactormone, that can upregulate gene

and protein expression.

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