Journal of Physiology (2002), 542.2, p. 333
020974
© The Physiological Society 2002
Lactate – the forgotten fuel!
John C. Chatham
Journal of Physiology
University of Alabama at Birmingham,
CNIR Building, 828 Eighth Court South,
Birmingham, AL 35294-4470, USA
Email: jchatham@uab.edu
A balance between energy supply and demand
is essential for the viability of all cells but is
particularly critical in the heart where energy
demand is high and continuous. The
maintenance of energy homeostasis is dependent
on a continual supply of ADP, inorganic
phosphate, oxygen and reducing equivalents in
the form of NAD(P)H. The importance of
sufficient oxygen delivery for maintenance of
cardiac energy production is well established;
however, the fact that this must be matched to
NAD(P)H production is frequently overlooked.
The principal source of NAD(P)H is from the
metabolism of blood-borne carbon substrates.
Some organs and tissues are able to use only a
limited number of substrates for energy
production; for example, the brain relies
almost exclusively on glucose for oxidative
ATP production. In contrast the heart is able
to use a wide range of substrates for energy
production, including glucose, fatty acids,
ketone bodies, lactate and pyruvate. Despite
this, the often stated view, which has changed
little for many years, continues to be that
the predominant fuels for cardiac energy
production in vivo are long chain fatty acids
and glucose (Neely & Morgan, 1974). In part
this perception is sustained by the belief that
glucose and fatty acids are the only substrates
available in vivo. However, at rest circulating
lactate concentrations are approximately 1 mM
and during exercise can easily reach to 3–5 mM
(Kemppainen et al. 2002). Even higher serum
lactate concentrations may be seen after
surgery. More than 20 years ago Drake et al.
(1980) showed that the uptake of lactate by the
heart in vivo is directly proportional to its
serum concentration. We and others have
shown in the isolated perfused heart, that
lactate contributes significantly to acetyl-CoA
formation often contributing more than
glucose (Chatham et al. 1999).
Despite the evidence that lactate may be an
important fuel for myocardial energy
metabolism, there is remarkably little
information, either in vivo or in vitro, on the
interactions between lactate and glucose
utilization or lactate and fatty acid oxidation.
This represents a significant gap in our
knowledge of metabolic regulation in the
heart, especially in light of recent interest in
manipulation of cardiac metabolism as a
potential therapeutic intervention. Evidence
is accumulating to suggest that increasing
DOI: 10.1113/jphysiol.2002.
PERSPECTIVES
myocardial carbohydrate utilization and
decreasing fatty acid metabolism improve the
outcome following myocardial ischaemia
(Stanley et al. 1997). However, much of the
experimental data used to support this
mechanism are based on studies where glucose
and fatty acids are the only substrates
considered. Consequently, it is unclear whether
the conclusions from such studies are relevant
to in vivo conditions where lactate may be
present in significant concentrations.
In this issue of The Journal of Physiology
Kemppainen et al. (2002) use positron
emission tomography (PET) to quantify
cardiac and skeletal muscle glucose uptake and
phosphorylation in healthy human subjects at
rest and at three different intensities of
exercise. As expected they found that increasing
exercise in skeletal muscle was associated with
increased glucose metabolism. However, in the
heart, although glucose uptake was slightly
increased at low or moderate exercise levels, at
the highest exercise level it was no different
from rest. At rest and at the lowest exercise
level there was a negative correlation between
serum free fatty acid concentration and
myocardial glucose uptake in accordance with
the classic glucose–fatty acid cycle originally
proposed by Randle et al. (1963). However, at
moderate and high exercise levels this correlation
disappeared; this was associated with a
significant increase in serum lactate at these
exercise intensities. They concluded that during
high intensity exercise, substrates other than
glucose, such as lactate, might contribute
significantly to cardiac energy production.
This conclusion was supported by a negative
correlation between serum lactate levels and
glucose uptake at moderate exercise intensity.
An important issue that the work by
Kemppainen et al. (2002) illustrates is that the
regulation of substrate selection by the myo-
cardium is a dynamic process. That is the
contribution of different substrates to energy
production will change depending on the
physiological milieu. Whilst this may seem
obvious, it should be put in the context that
much of our knowledge of cardiac metabolism
is based on the use of a limited range of
substrate and hormone concentrations as well
as limited mixtures of substrates. The use of
only a single concentration of substrates may
result in erroneous conclusions regarding the
impact of a specific physiological or patho-
physiological state on cardiac energy
metabolism. For example, we found that
cardiac fatty acid oxidation was markedly
increased following diabetes, at low fatty acid
concentrations compared with the non-
diabetic group, but was significantly depressed
at high concentrations (Chatham et al. 1999).
The use of only a single fatty acid concentration
would have resulted in an incomplete under-
www.jphysiol.org
standing on the effects of diabetes on cardiac
fatty acid metabolism. This demonstrates the
importance of using of a range of substrate
concentrations to characterize the metabolic
phenotype of the heart.
There are some limitations with the study by
Kemppainen et al. (2002) that should be
noted. For example, the measurement of
2-[18F]fluoro-2-deoxy-D-glucose uptake by
PET reflects the uptake and phosphorylation
of glucose by the heart, but not necessarily
glucose oxidation. Furthermore there are no
measurements of lactate metabolism by the
heart. The use of 14C- or 13C-labelled lactate and
glucose would provide a quantitative measure
of substrate oxidation. Such methods are
routinely used in isolated heart preparations
and have also been performed in human
subjects (Gertz et al. 1988). However, in
humans this requires cardiac catheterization,
which is clearly invasive and associated with
substantially increased risk compared with
PET. Despite these limitations, the study by
Kemppainen et al. (2002) is an important
reminder that lactate, primarily considered a
metabolic waste product and typically ignored
as a potential fuel, may be an important
substrate for cardiac energy metabolism in vivo.
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Acknowledgements
I would like to thank Drs Des Roisers, Gao, Lloyd
and Seymour for constructive comments on the
manuscript. The work in my laboratory is supported
by grants from the National Institutes of Health and
the American Heart Association.