Yesterday, I looked at a review article that explained some of the issues that you will face if you try to get a handle on the literature on the anaerobic threshold. In that post, I referred to an influential researcher in the field called George Brooks.
George Brooks is the originator of the Lactate Shuttle Hypothesis, an alternative theory to the original lactic acid build-up and oxygen debt theories. Let’s take a closer look at George and his theory today.
Awesome photo by familymwr
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What’s the study?
The study is called Intra- and extra- cellular lactate shuttles, by George Brooks, Medicine and Science in Sports and Exercise, 2001.
It’s really a review article of a number of different studies and an explanation of how the Lactate Shuttle Hypothesis came to be. It discusses some of the recent research and describes why the lactic acid build-up and oxygen debt ideas are no longer considered to be valid.
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Introduction to the Lactate Shuttle Hypothesis
George explains that the Lactate Shuttle Hypothesis was first introduced to the world at a congress in 1984. A paper appeared in the congress proceedings published the following year, called Lactate: glycolytic product and oxidative substrate during sustained exercise in mammals—the “lactate shuttle,” by George Brooks, in: Comparative Physiology and Biochemistry: Current Topics and Trends, Gilles, (ed.), 1985.
So how was the hypothesis developed?
George found in a series of isotope tracer studies conducted on laboratory rats, dogs and humans that oxidation was the major route of lactate disposal during steady rate exercise and recovery from exercise. Conversion to glucose and glycogen accounted for most of the remainder during exercise and recovery, respectively.
George therefore created the hypothesis that much of the glycolytic flux during exercise passed through lactate and defined it as follows: “the shuttling of lactate through the interstitium and vasculature provides a significant carbon source for oxidation and gluconeogenesis during rest and exercise.
What does this mean?
It means that lactate appears to get involved in most if not all reactions following glycolysis. It acts as a medium or a “shuttle.”
So, in other words, the idea that glycolysis leads directly to pyruvate and then on through the Krebs cycle is not really correct. Lactate appears to get involved whether there is oxygen there or not. So the concepts of anaerobic and aerobic respiration as currently stated are not really valid.
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So how was the hypothesis received?
George describes the he initial reaction to his hypothesis as “mixed,” which I assume is a polite way of saying that he got quite a lot of stick.
He notes that researchers who maintained the theories of oxygen debt and anaerobic threshold had trouble with his hypothesis because those theories “held that lactate is produced in muscle because of a lack of oxygen and that lactate produced during exercise was a dead-end metabolite that could only be removed during recovery.”
Anaerobic threshold - we noted yesterday in our review of the concept of the anaerobic threshold that the anaerobic threshold researchers have since come to terms with this idea.
Oxygen debt - we have also seen the fall-out of the studies done using oxygen debt. Inmy review of the study called Energy system contribution in the 200m – 1,500m, I noted that many previous studies had underestimated the contribution of aerobic respiration because of the use of oxygen debt as a way to measure the anaerobic component of performance.
As we stand today, I suspect more people support George’s hypothesis than reject it. And I suspect that you would have to hunt quite hard to find someone who would defend the oxygen debt theory.
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A summary of the early research
George notes a large number of research studies that underlie the early development of the Lactate Shuttle Hypothesis. I’ll just note a couple of the studies here:
Electrically stimulated dog muscle preparations studied in situ release lactate on a net basis when contractions start, but switch to net consumption as contractions continue (Oxygen debt in contracting dog skeletal muscle in situ, Welch and Stainsby, Respiratory Physiology, 1967).
So it seems clear that the driver for whether lactate is produced cannot be oxygen presence or absence, as oxygen was present at both the beginning and during the period of contractions.
Measurements using NADH fluorescence on electrically simulated canine muscles studied in situ indicate that lactate production occurs under fully aerobic conditions (Oxidation of NADH during contractions of circulated skeletal muscle, Joebsis and Stainsby, Respiratory Physiology, 1968).
Another indicator that oxygen presence or absence has nothing to do with whether lactate is produced.
During continual, progressive exercise working human muscle is a site of net lactate production and release as well as the site of blood lactate appearance (Systemic lactate turnover during graded exercise in man, Stanley, Gertz, Wisneski, Morris, Neese and Brooks, in American Journal of Physiology, 1985).
And just in case you thought humans might be different, here’s a study to show that we are just the same as the dogs.
During constant rate, submaximal exercise working human muscle first releases lactate on a net basis when exercise starts but then switches to net lactate uptake as contractions continue (various studies).
And again, the idea that at the beginning there is more lactate than during the period of activity comes up. Yesterday, we thought that this might be due to some sort of inertia in the “aerobic” mechansim. Whether that is a valid conclusion under George’s hypothesis, I am not sure.
Working healthy cardiac muscle is a net consumer of lactate, but free fatty acids are the major energy substrate for the heart in resting subjects. However, during exercise when arterial lactate rises, exogenous (arterial) lactate becomes the major fuel for the heart (Myocardial lactate metabolism: evidence of lactate release during net chemical extraction in man, by Gertz, Wisneski, Neese, Bristow, Searle and Hanlon, in Circulation, 1981.)
So during activity, the heart prefers to use lactate rather than glucose? And at rest it prefers free fatty acids? Very interesting.
Lactate, not glucose is the preferred substrate for hepatic glycogen synthesis (Glycogen synthesis via the indirect pathway in periportal and via the direct glucose utilizing pathway in the perivenous zone of perfused rat liver, by Bartels, Vogt and Jungerman, in Histochemistry, 1988).
And the liver, too, prefers lactate? This is a strong indication that lactate must be functioning in some way as a mediator, as George argues.
Hopefully, those studies give some colour to how the Lactate Shuttle Hypothesis works. It seems to me that the mechanisms are still unclear but the indication that lactate is functioning as some sort of mediator are all there.
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The end of the idea that lactate forms because of lack of oxygen
Just to be absolutely certain, George dedicates an entire section of his review to kill off the idea that lactate forms because of a lack of oxygen.
He refers in detail to a set of studies that he was involved in. To attack the old theory, he rather cleverly made use of the effects of altitude on endurance performance. Everyone knows that there is less oxygen at altitude. So how would some subjects respond to the same cardiovascular test, done at different altitudes?
In 1988, and again in 1991, George studied men during cycling at 50% of VO2-max at sea level. He then flew the subjects to an altitude of 4,300m and tested them once again and then a third time after three weeks of acclimatisation.
He noted that, at altitude, the same power output elicited 65% of VO2-max (i.e. much more lactate was produced). He also noticed that the three week acclimatisation period did not change VO2-max but the residency period lead to a reduction in the VO2-max percentage to roughly half-way between the two. Thus, none of the changes in blood lactate response could be attributed to a lack of oxygen.
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So why does the study refer to intra-cellular shuttles?
During more recent research, George has noted that skeletal muscles simultaneously consume lactate on a net basis and convert glucose to lactate. He interprets this observation to mean that most glycolytic flux is converted to lactate and disposed of as lactate within a muscle fibre.
Thus, the Lactate Shuttle Hypothesis has been modified to include an intra- as well as extra-cellular component. The science of this goes way out of my comfort zone so if you want to learn more you are going to have to dig the study out for yourself!
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Wrapping up
The important things I have taken away from this study are:
- The Lactate Shuttle Hypothesis was initially rejected by those researchers who held to the theories of oxygen debt and anaerobic threshold because those theories “held that lactate is produced in muscle because of a lack of oxygen and that lactate produced during exercise was a dead-end metabolite that could only be removed during recovery.”
- However, it has been found that lactate is heavily used throughout the body to mediate the transfer of energy from one place to another. This is the Lactate Shuttle Hypothesis.
- The concepts of anaerobic and aerobic respiration as currently stated are not really valid and need to be modified, as lactate is produced for most reactions following glycolysis, not just those in the absence of oxygen.
- And just to be clear, the absence of oxygen is not the determining factor when it comes to the production of lactate.
If that all comes as completely new to you, I sympathise. If it’s all stuff you already knew, I’m impressed.
