The Hydrogen Ion (Confusion) During High Intensity Exercise
High intensity exercise related fatigue is likely caused by a combination of factors including inorganic phosphate, hydrogen ions, and many other ions/metabolites and their interplay in preventing muscular contraction. This piece however will not go further than that on the complicated and yet to be fully elucidated mechanisms of high intensity fatigue. Nor will it be my musings on techniques to confuse our hydrogen ions to elicit greater performance, although that could probably be a bestseller!
The goal here will be to focus on where exactly the hydrogen ions are coming from. I see a lot of opinions and credible sources (including textbooks) which I think are incorrect so I’m going to put my horse in the race and put forth my understanding of the work that’s been done in the area and hopefully make a compelling case that, for all intents and purposes, the paradigm of glycolysis producing lactate and a hydrogen ion during high intensity exercise (high energy need) is correct. I will be combatting the belief that glycolysis is a net neutral reaction and that ATP hydrolysis is the contributor of hydrogen ions and inorganic phosphate (as posited most prominently by Robergs et al but has later come in many forms).
So in order to begin to understand this stuff you may need a primer on energy metabolism (if you are well acquainted you can skip these next few paragraphs). Human energy metabolism exists as it does because we can’t just combust our “metabolic engines” like we can for a vehicle because of the fact that our internal existence relies on being at a pretty tightly held temperature (amongst many other things). So don’t try to set yourself on fire to increase your metabolic rate,
it will work… for a very short amount of time (if you are lucky). Instead of combustion our metabolism uses a series of steps that involve necessary enzymes (in the right environments) which lower the amount of energy needed for reactions to occur. These enzymes do so by using non-covalent (sometimes with covalent intermediates) attractive forces that are mainly electrostatic in nature; they include ion pair interactions, hydrogen bonding, and electronic polarization. Basically, the enzymes quite literally put stress on the bonds which in turn lowers the activation energy needed to help facilitate an otherwise very slow reaction.
These series of steps we call metabolism are relatively remarkable in efficiency when considering that they extract the same amount of energy for us as one would expect if one were to “bomb”/electrocute food in a sealed device and measure the energy by the amount of heat transferred to a tub of water. This process I am describing is of course what is literally done to assess the caloric value of food. What we refer to as a calorie which is more precisely a kilocalorie is the amount of energy needed to raise 1 kilogram of water by 1 degree celsius in a bomb calorimeter. I proposed a different method but it is still in the pipeline to be approved by an IRB for a validation study! Instead of wasting money on a bomb calorimeter I propose we collect the tears of individuals and perhaps take EEG measurements as we burn different foods in front of them. The more tears and sadness we collect the higher the caloric value of the food. Brilliant, I know!
Back to metabolism. The enzymes of energy metabolism are specific to certain substrates, namely our macronutrients; proteins, fats/lipids, and carbohydrates. For the purposes of this discussion we will focus on carbohydrates and mostly glucose and its subsequent metabolic fate.
So… Under conditions that don’t need quick energy and require oxygen glucose (a six carbon molecule) goes through a series of 10 steps called glycolysis and is broken down into two, three carbon molecules called pyruvate. NAD+ is a coenzyme that accepts electrons along the way in the form of hydrogen and becomes NADH, an electron carrier that holds onto these electrons to be later used to produce energy. The two NADH and two pyruvates enter the mitochondria, pyruvate (I will speak singularly from now on but assume these reactions happen twice per cycle) is converted to a molecule called Acetyl CoA which goes through another series of steps called the Krebs Cycle to form more electron carriers (NADH and FADH2). Finally, all these electron carriers are brought into the electron transport chain where these electrons are used to produce ATP; oxygen is the final electron acceptor in the electron transport chain. ~32 ATP are produced from glucose to electron transport chain.
Under conditions where there is a very high need for quick energy pyruvate does not enter the mitochondria but is rather converted to lactate. The reason this occurs is because of speed and also goes back to those electron carriers. Glycolysis is a more prominent fuel source during high intensity exercise because it can get energy to our muscles quickly due to the fact that the reactions take place in the cytosol rather than potential energy needing to be transported into the mitochondria. So while glycolysis produces 2 net ATP which is substantially less than the electron transport chain it does so much more quickly.
But why lactate? The reason lactate is important is because the continuation of glycolysis depends on it; in order to continue the reactions of glycolysis pyruvate accepts the hydrogen's/electrons from NADH and thus frees up NAD+ to accept more electrons during the reactions of glycolysis, while also preventing the accumulation of pyruvate.
Now for the hydrogen ion. During the pyruvate dehydrogenase reaction NADH donates one hydrogen and one proton creating lactate and NAD+. It is true that this reaction specifically does not procure a hydrogen ion. However, the net glycolytic reactions do in fact produce
hydrogen ions. During the phosphoglycerokinase reaction (that occurs twice) ADP produces an ATP without consuming a hydrogen ion, 2H+ unaccounted for, creating a net 2H+ during
glycolysis and making the final formula for “anaerobic glycolysis”: Glucose → 2 lactate + 2H+ (or what some may term lactic acid). I know now the next question, knowing you… digging in deep all the time, you will ask about the other ATP formed during the pyruvate kinase reaction and what happened to the hydrogen ion there. As shown below you will notice that the hydrogen ion is accounted for in this reaction.
There is also some debate with the use of the term “lactic acid” (sometimes because terms colloquially used are improperly defined before discussion) because there is the question of whether lactic acid is present/formed at all. It is a bit of a semantic argument because what we do know is; formed for a very short time or not, under physiological pH, lactic acid would dissociate into lactate and a hydrogen ion.
Some have posited instead that ATP hydrolysis is a large/the only contributor of the hydrogen ion and “anaerobic glycolysis” is net neutral. This is very highly likely to be false, there is no
evidence to support this conjecture and more than sufficient evidence to refute it. ATP even during intense exercise stays in relative homeostasis which means that whatever is broken down
is matched by subsequent build up so that ATP levels do not drop appreciably. This means that while ATP hydrolysis does release a hydrogen ion, this hydrogen ion will instantaneously be consumed (by the creatine kinase reaction). This is of course unless the hydrogen ion is not consumed because of a reaction in glycolysis (as stated previously).
Technically the hydrogen ion is liberated from ATP, but as Boning et al. points out, net reactions are what matter in chemistry, “A similar case is the secretion of gastric juice: Cl− and H+ are secreted or produced by completely different reactions, but does anybody doubt that
hydrochloric acid is present in the stomach?” This point is further corroborated with in-vivo methods showing that lactate and its associated hydrogen ion track linearly in their concentrations in both human (here’s another) and animal models under conditions where if correct, one would expect the paradigm (lactate + H+) to hold true mathematically. These experiments (and others) pretty clearly point toward ATP homeostasis and the linear relationship between lactate build up and hydrogen ion release.
ATP being in equilibrium also means it couldn’t be the contributor of the inorganic phosphate (a major player in fatigue). The inorganic phosphate is the product of what is called the Lohmann reaction which illustrates the complex interplay between the ATP hydrolysis reaction and the
PCr reaction which may result in net PCr splitting. The algebraic sum α+ β defines the proton stoichiometric coefficient y of the coupled Lohmann reaction. Even without understanding the complex chemistry we can see experimentally that as PCr concentration goes down inorganic phosphate concentration goes up.
We also know that mice completely deficient in creatine kinase (CK-/- mice) have fast-twitch muscles with higher Pi concentration at rest but no accumulation of inorganic phosphate which you see in mice with CK intact.
We shouldn’t vilify lactate, we know now that it is an important metabolite. However let’s not posit that the hydrogen ion is of different origins creating other downstream mistakes in understanding. All this to say, let's not reinvent the wheel…
The net reaction of glycolysis is Glucose → 2 Lactate + 2H+ 2NAD+. The coinciding concentrations of lactate and its associated hydrogen ion have been demonstrated on several occasions with different models and conditions.
ATP hydrolysis is not the contributor of the hydrogen ion due to the fact that ATP is in relative homeostasis.
ATP is not the contributor of inorganic phosphate, inorganic phosphate is the product of PCr splitting/Lohmann reaction.
Fatigue is a complicated topic, let’s not muddy the waters more than they need to be by not accepting things that have been strongly validated, especially if the alternative model is untenable.