Download What does glycolysis make and why is it important?

J Appl Physiol 108: 1450 –1451, 2010;
doi:10.1152/japplphysiol.00308.2010.
Invited Editorial
What does glycolysis make and why is it important?
George A. Brooks
Department of Integrative Biology, University of California, Berkeley, California
derstated, but, if the stoichiometry varies, then uncertainty
arises and problems arise in determining muscle energetics.
It is clear that resting and working muscles release both
lactate and protons, and contemporary knowledge is that the
mediators of exchange include not only the monocarboxylate
transporters (i.e., MCT1 and MCT4) that are symporters facilitating the movement of protons and monocarboxylate anions
(1), but also a variety of other transporters, such as the Na⫹/H⫹
(4) and Na⫹/K⫹ (2) exchangers, as well as the Na⫹/HCO⫺
3
symport (5) and carbonic anhydrase (11), also play roles in
cellular hydrogen ion exchanges. Thus there are many factors that
affect pH in muscle, its venous drainage, and the systemic circulation (7).
Now, using a combination of contemporary 31P-magnetic
resonance spectroscopy (MRS) and biochemical assays, Marcinek and colleagues (8) provide novel data on an ischemic
mouse model system and show a tight 1:1 H⫹/L⫺ over a
significant range of ischemia durations, yielding La⫺ concentrations up to 25 mM and decrements in pH from 7.0 to 6.7.
From chemical analyses, there were no significant changes in
ATP content, so H⫹ production from net ATP degradation
could be discounted from the analysis, thus allowing ATP use
to be determined from decrements in PCr and corresponding
increments in Pi, as measured by 31P-MRS. The use of ischemia ensured that neither protons nor lactate anions could
escape detection, and that neither cell H⫹ nor CO2 production
from oxidative phosphorylation could affect H⫹ or La⫺ accounting. In this way, the authors concluded that glycolysis
produces lactic acid and that the acidosis from contraction is a
lactic acidosis in vivo. For them, this result is important, as
they use the phosphate peak separation seen in 31P-MRS to
calculate glycolytic ATP production, a key factor in determining muscle energetics.
As important as the results are, Marcinek and colleagues (8)
are encouraged to continue their efforts, moving beyond correlational analysis to show that the protons accumulated during
muscle ischemia stimulation are indeed from glycolysis and
not some other process. Perhaps prelabeling with [3H]glucose
and using 1H-MRS could be helpful in this regard? Additionally, perfusing with 13C-labeled substrates in conjunction with
13
C-MRS might prove to be useful in identifying the pathways
of intramuscular glucose disposal during repeated contractions
of graded intensities and durations. Also, perhaps more importantly, the investigators are encouraged to move from studying
stopped-flow to free-flow conditions, with gradations in hypoxemia that are more typical of both normal and pathological
conditions. In this way, we can know if glycolysis makes lactic
acid or lactate, the extent to which the acidosis of exercise is
attributable to lactic acidosis, and if lactate and proton accumulations can be used interchangeably in determining the
contribution of nonoxidative (“anaerobic”) glycolysis to muscle energetics.
Address for reprint requests and other correspondence: G. A. Brooks,
Integrative Biology, 5101 VLSB, Univ. of California, Berkeley, CA 947203140 (e-mail: [email protected]).
DISCLOSURES
1450
No conflicts of interest, financial or otherwise, are declared by the author.
8750-7587/10 Copyright © 2010 the American Physiological Society
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(e.g., Ref. 6) and Wikipedia (http://en.wikipedia.
org/wiki/Glycolysis) are alike in confusing readers on the process,
regulation, and physiological roles of glycolysis. The reference
sources assert that glycolysis produces pyruvic acid (i.e., pyruvate and
protons), and that under anaerobic conditions, glycolysis produces
lactic acid. In their thorough review of the stoichiometry of glycolysis, Robergs et al. (10), among others, including authors of papers in
the Journal of Applied Physiology, have forced us to reconsider the
matters involved. In this issue of the journal, Marcinek et al. (8) take
a major, important step on a renewed journey to understanding.
Why does it matter what glycolysis makes? Minimally, it
matters from the standpoint of understanding a fundamental process in biology: it matters because it is essential to know how
oxygenation and metabolism affect acid/base chemistry in muscle
and blood, and it matters because it is important to understand the
energetics of working muscles and other tissues.
Neglecting glycolytic flux from glycogen, consider the classical presentation of glycolysis, asserting that glucose degradation makes pyruvic acid. Then, classic resources go on to
state that under anaerobic conditions, glycolysis progresses to
make lactic acid. However, while all sources agree that the
reduction of pyruvate to lactate by lactate dehydrogenase
utilizes NADH and a proton as substrates, not all authors have
appreciated that lactate production from pyruvic acid is an
alkalinizing reaction that, in effect, buffers acid production
from glycolysis. Nonetheless, even if it is understood that the
pK of lactic acid is 3.8, and hence almost completely dissociated at physiological pH, it has often been stated that rapid
glycolysis in muscle and other tissues results in the accumulation of “lactic acid.”
Diverse observations cause contemporary physiologists to
have problems with long-standing beliefs that “anaerobic glycolysis” makes “lactic acid.” For instance, the lactate-to-pyruvate ratio (L⫺/P⫺) in resting muscle and its venous drainage is
typically 10 at rest and can rise an order of magnitude during
submaximal exercise (3); all the while, ample oxygen exists to
fully support cell respiration (9). Hence, the assumption of classic
authors that lactate production means oxygen lack proves to be
inconsistent with observations that lactate production occurs continuously and under fully aerobic conditions (1). As well, contemporary physiologists have observed that while working human
muscles release both lactate and protons, the H⫹/L⫺ stoichiometry of release can range from 1 to 2 in vivo (4).
To reiterate from above, for those interested in muscle
energetics, there is more than esoteric interest in knowing the
H⫹/L⫺ stoichiometry in muscle and other tissues. In short, if
one can relate H⫹ to L⫺, and if one can measure H⫹, then one
can relate H⫹ to a glycolytically produced ATP with certainty.
The importance of knowing the stoichiometry cannot be unCLASSIC REFERENCES
Invited Editorial
1451
REFERENCES
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