Sunday, January 10, 2016

Not really much about swimming underwater

*****MAJOR ERROR********

Down in the comments section Mateusz has very kindly found the error in my arithmetic for me. It makes the whole of this post completely incorrect and requires a great deal of working through posts based on this conclusion to correct my mistake and the implications this has for blood supply and oxygen consumption.

Fats require around about 5% more O2 per ATP cf glucose.

With apologies to everyone.

I know I said (first paragraph) that I would take this post down in embarrassment if I'd made an arithmetical error but, on balance, I think it should stay as a warning, to me as much as anyone else.

So I’m going to leave this post up unchanged, with this edit, as a warming to the immense power of confirmation bias. There’s a lot to do.

*****MAJOR ERROR********







Just before I hit post: I think the arithmetic and the logic here are sound on a ball-park basis but if anyone can point out any major flaws I stand to be corrected and will take the post down in embarrassment. But this is so simple in concept that I don't see why it's not standard fare... Here we go.

In the comments after a previous post it became pretty obvious that several LC eating folks noted a significant improvement in their ability to breath-hold while running their metabolism on fat rather than on glucose. Although this is rather counter intuitive based on the RQ (more oxygen is required per unit CO2 generated when you oxidise fat compared to glucose) what matters is the generation of ATP per unit oxygen or ATP per unit CO2 produced. I started with oxygen. Arithmetic goes like this:

Glucose oxidation is simple. Six carbons give 2ATP from glycolysis and a mix of NADH and FADH2 from the TCA:

6(CH2O) + 6O2 = 6CO2 + 6H2O      
RQ: CO2/O2 = 6/6 = 1.0
2 ATP + 10NADH + 2FADH2


A theoretical six carbon section of a chain of a fully saturated fatty acid gives this:

6(CH2) + 9O2 = 6CO2 + 3H2O        
RQ: CO2/O2 = 6/9 = 0.67
15NADH + 6FADH2


Three of the FADH2s are from acetyl CoA turning the TCA, the other three are from beta oxidation. For PUFA a theoretical alternating sequence of single and double bonds yields this:

6(CH1.5) + 8.25 O2 = 6CO2 + 4.5 H2O
RQ: CO2/O2 = 6/8.25 = 0.73
15NADH + 3FADH2


The first step of beta oxidation for PUFA yields no FADH2, so we just have the three from the TCA. Assuming the ETC works efficiently we pump these protons from our hydrogen supply:

NADH = 12H+
FADH2 = 8H+

And, very crudely, let’s assume at complex V, ATP synthase, we have 4H+ = 1 ATP (not true IRL!)

So we can calculate protons pumped, what this is worth in ATP and combine this with the O2 needed (from the chemical equations above) giving:


Glucose protons
10NADH = 120    2FADH2 = 16, total = 136 H+
ATP 34 + 2 = 36

ATP-gluc/O2 = 6.00

Saturated fat protons
15NADH = 180     6FADH2 = 48, total = 228 H+
ATP = 57

ATP-sat/O2 = 6.33

PUFA protons
15NADH = 180 3FADH2 = 24, total = 204 H+
ATP = 51

ATP-pufa/O2 = 6.12


Clearly fatty acids are better at generating ATP per unit O2 consumed. If a 70kg person, at rest, is consuming 200ml of oxygen per minute to produce a given amount of ATP while burning glucose they should be able to maintain that same amount of ATP on less oxygen.


But the difference seems pretty small. How small?

Through sins of education I tend to think of O2 consumption for an anaesthetised, mechanically ventilated patient. That person needs about 200ml/min of oxygen.

200ml O2 gives 6.00 x10bw ATP if running on glucose (where 10bw is a crude scalar to whole body ATP needs). On saturated fat:

200ml O2 gives 6.33 x 10bw ATP

Or, more realistically:

190ml of O2 gives 6.00 x 10bw ATP on fat, equivalent to 200ml O2 used on glucose. An oxygen sparing effect of 10ml/min is underwhelming on first consideration. It’s a 5% improvement. But this should be maintained at VO2 max. When oxygen delivery is the limiting factor in performance, running on fat gives you a 5% advantage.

This is simple arithmetic applied to the most basic of biochemistry processes.

Is butter a performance enhancing drug?

Yes, provided it displaces carbohydrate.

Should folks with ischaemic problems eat butter?

Yes, provided it displaces carbohydrate.

Does it taste good?

Yes, unqualified.

Of course, once you add in ketones, magic starts to happen to the energy yield of ATP hydrolysis. Ketones are not as arithmetically simple as fatty acids but we all know, from Veech and D'Agostino's work, that magical indeed they are.

Peter

Oh, I calculated CO2 per unit ATP produced too. On carbs ATP/CO2 = 6.00 as you would expect but on saturated fat the amount ATP produced per unit CO2 evolved is 9.5. CO2 build up makes you breathe, you make less per minute on fats. Breath holding is, arithmetically thinking, expected to be easier running on saturated fat. This is what we find.

*****EDIT*****

Hans pointed out in comments that the TCA provides a molecule of GTP which can convert to ATP from each acetyl-CoA. This gives two extra ATP's per glucose and three more ATP's per six carbons from saturated fat. I can't be *rsed to re do the math, but you get the picture.

*****END EDIT*****

19 comments:

Unknown said...

Fascinating!

Last time I was at a GP, I saw a poster about some drug that forces the heart-muscle to switch its metabolism solely to glucose. Fatty acid metabolism is forcibly turned off. Supposedly to help angina. What would happen if someone taking this stuff were also diabetic and had a hypo? Can't be good.

mommymd said...

Local tissues have their own O2 reserve- myoglobin and neuroglobin. Perhaps running on fat increases these molecules and thus these serve as an extra reserve during a breath hold.

valerie said...

Your last paragraph sums up what I was going to write as a comment: it's CO2 accumulation that triggers the urge to breathe, not lack of O2. Given the huge difference in CO2/ATP ratios between carbs and fats, it could very well explain the anecdotes left by commenters about swimming under water.

raphi said...

Wouldn't one prediction be that we would expect to see shorter breath holds when insulin is spiked?

Peter said...

Valerie, yes. Raphi, not sure. Insulin phosphorylates the ETC which increases metabolic efficiency. I'd have to go to Veech's isolated rat hearts to think about this one a bit more. Insulin resistance + glucose metabolism supported by hyperglycaemia as a drive for non-insulin mediated glucose uptake/metabolism suggests you might want to keep your hair dry!

Unknown, possibly acipimox. Diabetics have no right having hypos. Just eat more sugar and all will be fine!

Mommymd, I'd not really thought about this but why not? I'm just working at the back-of-an-envelope level of thinking here. Ultimately it's CO2 which makes you head for the surface (trained free divers excepted). It's brain hypoxia which makes you pass out on the way up there as ppO2 drops as you approach the surface, if you play Octopush (which I don't). The delay on passing out should be slightly improved, your ability to get there would be improved!!!!

Peter

Betsy said...

Peter, LC sounds like a good way to reduce our carbon foot print.

I will nominate you for the Nobel Peace Prize.

Malcolm said...

Run heart muscle on glucose???! Ugh!
I appear to have recently started getting atrial fib (any comments Peter? I gather racehorses get it - high vagal tone, no heart disease but sometimes they get arrhythmias. Is it electrolytes / inflammation / overactive parasympathetic system / genetics?? Or some other thing?) and apparently one of the effects is that atrial muscle starts adapting to the more intense workload and storing glycogen :-( I don't like that idea at all.

But back on topic; when I lost weight using a low carb diet and started running to get fitter, after a while I found that breathing just wasn't a problem (unless I was doing obviously shorter/faster work). I could run at what I thought was a reasonable pace for a "not skinny" guy and feel like I could keep going for ever. I haven't done a marathon yet (and maybe won't now) but I did a half and felt like I could have run at least 50% further. I always assumed the fat adaptation gave me the stamina, but now I see why the breathing seemed relatively easy.

JohnN said...

Peter,
I have reviewed your calc but like to offer another rational on how ketosis is more oxygen-efficient (albeit temporarily).
Not all beta oxidation is going toward ATP production if you consider increased uncoupling/heat production due to reduce delta psi.
If RQ = CO2(expel)/O2(consumed) then lowering RQ by ketosis cannot be responsible for improved breath holding.
My guess is that diirect access to stored fat (ketosis) means less total consumed oxygen because of idling organs not having to process food intake.
John

JohnN said...

I have not reviewed...
It should be said.
John

Unknown said...

I noticed a drop in resting respiratory rate from 10-11 to eight after adopting a ketogenic diet. My analysis was the same as yours: more ATP per unit CO2. As you and others note, to first order we breathe to rid ourselves of carbon dioxide.

PhilT said...

Dominic D'Agostino works in this area on keto supplementation for Navy Seals using rebreathers for covert underwater swimming.

I haven't followed the maths but have heard him say how ketosis allows greater efficiency of O2 utilisation and endurance from less CO2 accumulation.

Peter said...

Phil, AcA+BHB does, BHB alone doesn't, in that paper. You have to go to Veech and his isolated rat hearts (using AcAc+BHB) and he does the math for us. Under mixed ketones the energy yield from ATP hydrolysis is increased, so cardiac work/O2 consumed increases. I'm very interested in whether Veech's prep would show the poorer performance of BHB alone that was noted by D'Agostino. And why.... NADH:FADH2 ratio???????????? I think we can be pretty sure Veech knew exactly what he was doing when he included the AcAc. I sort of like AcAc, cheap to test too!

Peter

Elaine in Big D said...

Martin, your afib comment caught my attention...this may interest you...

http://www.afibbers.org/atrial_fibrillation.htm

The vagus nerve is a wild and crazy kinda guy. Goog "Dr Datis Kharrazian gargling" for interesting info.

Violent coughing can trigger afib. A pulmonologist will agree with that statement. A cardiologist will think you're nuts and say the afib caused the violent coughing.

Where is James Herriot when you need him?!? Ok, he didn't mention afib anywhere but steady common sense is what we're making these days.

Godspeed your good sinus rhythm!

Peter, thank you for your service! My Pappy was 19, a MM1 on the St. Louis at Pearl Harbor on the day that still lives in infamy. She was the first ship to return fire, not waiting for official command to do so.

Unknown said...

The paper by Bartlett and Lehnhard (2010)
https://www.researchgate.net/publication/231794233_The_lactate_paradox_a_review
comes to different results:

Glucose: 5 ATP/O2
Fat: 4.7 ATP/OS

I don't have enough knowledge to explain the difference, but I would be interested to learn.

Hans

Unknown said...

Rich (2003)
http://www.biochemsoctrans.org/content/ppbiost/31/6/1095.full.pdf
comes to the following result for glucose

"Oxidation of the whole ten NADH and two succinate would result in translocation of 112 H+, giving an overall yield, with two ATP from two GTP, of 29.85 ATP/glucose (or 29.38 ATP/glucose if the GTP-derived ATP also has to be exported)."

Hans

Peter said...

Thanks Hans. Clearly the GTP are acetyl-CoA derived so the two GTPs from 6 carbons from glucose will be "beaten" using 6 carbons from a section of saturated fat as we then three acetyl-CoA derived GTPs from saturated fat, and some improvement from PUFA. With this sort of arithmetic it is very hard to explain the (multiple) models of ischaemia/reperfusion in which glucose wins over palmitate every time excepting that metabolism in mammals is not adapted to anoxia except via glycolysis... It's something I keep thinking about and if this is the only hole in my math I'm well pleased.

Ta, Peter.

Anonymous said...

I believe there is a mistake in your calculations comparing ATP/O2 when oxidating glucose and six-chain carbon of activated saturated fat.

Oxidation of glucose:
===
6 CH₂O + 6 O₂ → 6 CO₂ + 6 H₂O
2 ATP + 4 NADH + 2 acetyl-CoA
2 ATP + 4 NADH + 2 (3 NADH + FADH₂ + GTP) → 10 NADH + 2 FADH₂ + 4 ATP

RQ = 6/6 = 1.00
10 NADH + 2 FADH₂ + 4 ATP

Glucose protons:
10 NADH → 120 H⁺; 2 FADH₂ → 16 H⁺; total 136 H⁺
ATP = 136/4 + 4 = 38

ATP-gluc/O₂ = 6.33

Oxidation of activated sat-LCFA 6-carbon chain:
===
6 CH₂ + 9 O₂ → 6 CO₂ + 6 H₂O
3 beta-oxidation → 3 (NADH + FADH₂) + 3 acetyl-CoA
3 (NADH + FADH₂) + 3 (3 NADH + FADH₂ + GTP) → 12 NADH + 6 FADH₂ + 3 ATP

RQ = 6/9 = 0.67
12 NADH + 6 FADH₂ + 3 ATP

Saturated fat protons:
12 NADH → 144 H⁺; 6 FADH₂ → 48 H⁺; total 192 H⁺
ATP = 192/4 + 3 = 51

ATP-sat/O₂ = 5.67

The mistake seems to be with my '12 NADH + 6 FADH₂ + 3 ATP'
and your '15NADH + 3FADH2'.

Regards,
Mateusz

Peter said...

Hi Mateusz,

Thanks for that, you are correct. Over the last week or so, by complete coincidence, I've been looking at http://cardiovascres.oxfordjournals.org/content/cardiovascres/97/2/251.full.pdf and the absolute certainty expressed that fatty acids need more O2 per ATP than glucose does. I'd gotten as far as Mosby's Crash Course in Metabolism and glucose producing 32 ATP/6 O2 vs palmitate generating 106 ATP/ 23 O2.... So now I have a great deal of work to do! Partly corrections and partly trying to work out why fasted animals do so much better than fed animals after traumatic brain injury or coronary vessel ligation.

Many thanks, better late than never I guess.

Peter

M & M said...

The oxygen demand and CO2 production while at rest RQ:
0.74
0.84
0.86

https://zapodaj.net/28322d042f382.jpg.html
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