Energy metabolism Part 9 - What happens during the Cori cycle?
Many of us have experienced muscle soreness at some stage, and we may have heard that
it’s related to lactate production in the muscle.
Nowadays, the general consensus is that muscle soreness is caused by microtrauma to the muscle
fibers and not through lactate.
Though, lactate has retained its image as an undesirable metabolic product.
Maybe it’s time to help clear things up: In our last episode, we learned that lactate
production is part of the oxygen-independent generation of ATP in the body.
In glycolysis, glucose is initially degraded to pyruvate.
In aerobic metabolism, the pyruvate dehydrogenase complex synthesizes acetyl-CoA from pyruvate,
which can be converted to carbon dioxide in the citric acid cycle.
Physiologically, the conversion of pyruvate to acetyl-CoA is irreversible.
However, anaerobic pyruvate conversion isn't: Here, lactate dehydrogenase catalyzes the
conversion of pyruvate to lactate.
Lactate dehydrogenase exists in five forms in the body.
These isoenzymes are abbreviated with LDH and numbered from 1 to 5.
Although they all catalyze the same reaction, their occurrence varies depending on the tissue.
LDH1 and LDH2 are found mainly in cardiac muscle cells, erythrocytes, and kidney cells.
LDH3 is found in the cells of the lungs, the lymphatic system, and platelets, whereas LDH4
and LDH5 are present primarily in liver and skeletal muscle cells.
The lactate dehydrogenase reaction is reversible under physiological conditions.
In the presence of NADH and H+, LDH forms lactate, thereby providing NAD+, whereas in
the presence of NAD+ pyruvate is formed, yielding NADH and H+.
The ratio of NAD+ and NADH and H+ in the cell, therefore, determines in which direction the
lactate dehydrogenase reaction proceeds.
So, the enzyme adjustably adapts to the current metabolic state in the cells.
As mentioned at the beginning of this episode, lactate was long considered mainly as an end
product of anaerobic metabolism, which needed to be broken down rapidly to prevent hyperacidity.
Currently, it’s generally assumed that this perspective falls short:
Lactate can be used as a source of energy by the body.
It’s also a precursor of gluconeogenesis.
Finally, it appears to take on the role as a signaling molecule in which it impacts the
expression of various genes, thereby regulating lipolysis.
To highlight its role as a signaling molecule, it’s occasionally referred to as lactormone.
Let’s take a closer look at the role of lactate in energy metabolism.
In skeletal muscle cells that depend on aerobic metabolism, the electron transport chain is
unable to oxidize NADH and H+ back to NAD+.
This results in an excess of NADH and H+.
The lactate dehydrogenase in skeletal muscle cells then converts pyruvate into lactate,
generating NAD+ in the process.
The amount of NAD+ is just sufficient to maintain glycolysis.
However, lactate can’t be further metabolized in skeletal muscle cells.
Therefore, it’s transferred into the bloodstream.
In cardiac muscle cells, there’s an excess of NAD+, so the cells can use the lactate
circulating in the bloodstream, and absorb it.
In cardiac muscle cells, lactate dehydrogenase converts lactate back into pyruvate.
This produces the reducing equivalent NADH and H+, which can be used for ATP synthesis.
By the way, during physical activity, cardiac muscle cells meet more than half of their
energy requirements through the oxidation of lactate.
So, this is an example of how lactate can be used as a source of energy.
If lactate isn’t required as an energy source, it’s degraded.
This process occurs primarily in the liver.
There’s also an excess of NAD+ in the hepatocytes.
The lactate resorbed from the blood can therefore be oxidized to pyruvate by lactate dehydrogenase
in the liver, and be used to form glucose.
The biosynthesis of glucose is called gluconeogenesis.
Because it’s a vital part of energy metabolism, we’ll be placing special focus on gluconeogenesis
in the next two episodes of this course.
So, as we can see, lactate has a second function in energy metabolism, namely as a precursor
for gluconeogenesis.
The glucose produced in the liver can be stored as glycogen and released back into the bloodstream
when needed.
This way, it’s transported to various tissues that use glucose, including skeletal muscle
cells.
With this, the metabolic cycle of lactate and glucose production is complete.
This interplay between the liver and skeletal muscles is also termed the Cori cycle.
Lactate dehydrogenase is not only important for energy metabolism, it’s also clinically
relevant.
Its concentration in blood serum, the LDH level, can be easily determined and used for
diagnostic purposes.
The LDH level measures the combined amount of all LDH isoenzymes in serum and is low
in healthy individuals.
It’s usually between 45 and 200 U/L. An increase in LDH levels can be due to several
causes: First, in vitro hemolysis of erythrocytes during blood collection and handling should
be excluded.
Otherwise, elevated LDH levels indicate cell damage in the body.
Depending on the cause, different isoenzymes are affected: An increase in LDH1 and LDH2
suggests myocardial infarction, myocarditis, hemolysis, or renal infarction.
In contrast, increased LDH3 points to pulmonary embolism or platelet destruction.
Elevated serum LDH4 and LDH5 are mainly found in liver disease or skeletal muscle injury.
Also, levels of LDH3, -4, and -5 may be increased in malignancy.
However, since LDH levels have poor specificity, they’re not widely used in clinical practice
for an accurate diagnosis.
Accordingly, in cases of elevated LDH, other organ-specific parameters are measured for
clarification, rather than determining the affected isoenzymes.
Besides that, the various LDH isoenzymes are degraded at different rates, which need to
be considered in LDH analysis.
While LDH5 disappears from serum within 24 hours, LDH1 can still be detected after several
days.
Therefore, it can be used in the delayed diagnosis of myocardial infarction when other cardiac
enzymes, such as troponin, are no longer detectable.
Now, let’s move back from our clinical note to the biochemistry of the Cori cycle and
to the question: What are the most important take-home messages?
We’ve summarized the five most important facts for you:
The reversible conversion of pyruvate to lactate, which is most important for anaerobic metabolism,
is catalyzed by the enzyme lactate dehydrogenase.
If there’s an excess of NAD+, lactate dehydrogenase forms pyruvate; in the case of excess NADH
and H+, pyruvate is converted to lactate.
Lactate can be used as an energy source or serves as a precursor for the biosynthesis
of glucose.
The Cori cycle is the process in which lactate and glucose are exchanged between muscles
and the liver.
The Cori cycle comprises three important metabolic pathways, which we discuss separately in this
course, namely, glycolysis, anaerobic metabolism with lactate production, and gluconeogenesis.
Would you like to review your knowledge of the Cori cycle before moving onto the next
topic of this course?
Then get ready for the quiz on the next slide.