Think about why it's making glucose. Muscle needs energy, but has low O2, so it's going to produce lactate using LDH which converts NADH + H to NAD. Lactate is transported to the liver through the Cori cycle. Liver LDH converts lactate to pyruvate thus producing NADH + H. This hydrogen produced in the liver is what causes your pH levels to increase (lower pH value). The end result is that pyruvate can go through gluconeogenesis and supply more glucose to the muscle. Since your liver is not using excessive amounts of oxygen, NADH can go through the electron transport chain to make massive amounts of ATP. Massive ATP hydrolysis also increases pH levels.
You are not accounting for the fact that acidosis during strenuous exercise is mostly a muscle tissue specific phenomenon. While your blood pH also decreases, your
muscle tissues are going to be at a lower pH than the rest of your body. Your liver pH theory 1) does not show an additional proton being made and therefore how a systemic acidosis came about, and 2) does not address the lower pH for muscles for the localized acidosis either.
Good point,it is 1 to 1. The key then is transferring lactate to the liver. That produces the NADH necessary to feed into ATP hydrolysis which is the source of the hydrogen as everyone else is saying. I believe excessive CO2 production in the muscle also contributes to increasing [H+] or lowering pH.
Edit: That goes along with what you're saying. The excess CO2 in ox-phos should cause plasma CO2 levels to rise. This causes H+ to be liberated from Hb and HCO-. This would favor more O2 unloading.
I do agree that production of CO2 would contribute to the metabolic acidosis in addition to ATP hydrolysis.
I'm amused by the irony about thinking critically and about how you say it makes one a great physician if they can reason. You made me think critically and argue with my own reasoning so I must thank you.
2,3 BPG(negatively charged) stabilizes deoxyHB by binding to HIS residues(positively charged) on the B chain. Favoring the deoxy state(or stabilizing HB) releases oxygen thus increasing p50(it's like Km...lower=more tightly bound, higher=less tightly bound) and results in a right shift.
A left shifted curve decreases p50, so your Hb will hold onto oxygen more tightly (higher saturation of Hb) when your partial pressure of oxygen is lower. When you have no air in the atmosphere (low partial pressure) or metabolically active tissue, you do not want Hb to have a left shift. You'd have decreased unloading which is why people don't feel too hot when they first arrive at a high altitude location. BPG is increased in response to low O2. High CO2 or low pH has the same result but acts through a different mechanism.
Fetal Hb gamma is left shifted, think lower p50 and higher Hb saturation (at all levels), because it's competing with maternal Hb A so it needs to be able to grab more oxygen from maternal circulation. In this case, it can simply grab more oxygen out of it's high CO2 chamber. Adult mice have to adapt which takes longer while Hb gamma is already produced with a low p50 or high affinity for oxygen.
Like my biochem professor, you are simplifying delivery of oxygen to 2 points and a transporter - e.g. lung for pickup and "tissue" for target, and Hb for transporter.
Problem with that is that
tissue is not one point in reality, it has a arterial side and a venous side and many points in between. While it is true that right shifted Hb is able to unload at a higher pO2, it is also true that
in high altitude hypoxia you do not have enough molecules of Hb bound O2 for all of your tissues.
If you were to unload them earlier on the arterial side of the tissue, your Hb are going to be deoxygenated by the time it reaches the venous side - those tissues are going to die. On the other hand if you have a left shifted Hb, you'd hold onto your O2 until the pO2 dictates the release of O2 from Hb, and therefore as more even distribution of O2 under hypoxic stress. (
Think of it as food rationing in famine, rather than handing out the limited amount of food for whoever yells hungry first - everyone is hungry, except in this case you are handing out oxygen.)
This is not even taking into consideration that a
right shifted Hb has lower ability to bind O2 in the lungs, so your total supply of O2 is going to be decreased in a state when you have low amounts of O2 to begin with.
2,3-BPG is helpful with the allocation of O2 when availability isn't an issue, but it does not address the problem caused by the lack of availability of O2. You can facilitate the unloading all you want - it still doesn't change the fact that don't have enough to unload in the first place. And
in high altitude hypoxia, availability is the problem, not the allocation.
The fetal hemoglobin example proves exactly what I'm saying - if you have a left shifted Hb curve (neonate mice with more fetal Hb), you are going to survive longer. E.g.,
LEFT shifted curve is protective vs. this kind of hypoxia.
And look under the hemoglobin section in this article:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154690/
And I mean, just think about how ridiculous the oxygen dissociation curve is in the context of oxygen delivery - you are moving oxygen from Hb to Mb - which isn't affected by 2,3-BPG. However,
Mb isn't the endpoint, it has to still deliver it to the mitochondria - so it's obvious that the pO2 experienced by the mitochondria is the ultimate driving force for oxygen delivery and not whether there is 2,3-BPG. That's just there to make sure that Hb to Mb isn't the rate limiting step, which in most cases it isn't.
All in all, every source of hydrogen, except for ATP, seems to either balance and/or cancel out so... as much as I don't like it, that is where I think I'm landing until I see something different.
Just a little thing on the side - it's a little confusing to follow along what you write, because you use hydrogen/proton/etc. interchangeably, and we have to try to figure out exactly what you meant by "hydrogen".
It might be easier to follow if you clearly distinguish between:
H+ as proton
H- as hydride
H. as hydrogen radical
H2 as hydrogen (gas)
it will be easier to recall in the future.
