Saturday, August 18, 2012

Protons: Lactate

I've been aware for some time that there is a reasonable idea that the brain runs on lactate. Dr Speijer emailed me a link to a very recent paper which supports this concept at the cutting edge of modern research, without having to go back to that old stuff from over five years ago which no one ever reads because it has no lovely photomicrographs and no ultracool transgenic mice.

The editorial has this nice diagram which sums up what might be going on:




Let's get back to electron donors. The brain hates superoxide. It hates fatty acids. It's a bit ambivalent about glucose (gasp). I don't think I would say it rejects glucose, just there are better fuels.

Is there anything the brain does like? Well, ketone bodies seem to be okay, but what the brain really seems to like is lactate. Perhaps I should rephrase all of this and say that the neurons of the brain love lactate. The rest of the brain seems fine on glucose and will even dabble with fatty acids at a pinch. But glucose is fed to neurons, pre digested by the glial cells, as lactate. The FFAs are fed as ketones, yes the glial cells in the brain are ketogenic, it's not just the liver that does this. I suppose the neurons might use glucose directly, but they become quite sick if you knock out lactate supply by eliminating MCT1 (mono carboxylic acid transporter 1).

Neurons are irreplaceable, more or less. They aim for zero superoxide production. This means behaving like a mitochondrial preparation which is being fed on glutamate, a provider of NADH only. Near zero free radical production is the closest you can come to having no mitochondria at all, yet still have the powerhouse of the electron transport chain at your command. When thinking about apoptosis that is. Apoptosis is not a good idea in non-replaceable cells...

This means minimising FADH2 utilisation. Fatty acids, with their beta oxidation derived FADH2, are out. No way in neurons.

Glucose is not ideal either. Why not? Well glucose supplies the best possible neuronal FADH2:NADH (F/N) ratio of 0.2, ie it gives one FADH2 for 5 NADHs. Usually. This is superb for minimising superoxide production (and maintaining insulin sensitivity). But not always. What about glycerol-phosphate dehydrogenase or glycerol-phosphate oxidase? Both of these, in much the same manner as the FADH2 moiety within electron-transporting flavoprotein dehydrogenase, can reduce the CoQ couple and promote superoxide production. That's without thinking about simply over driving the TCA with pathological hyperglycaemia. There is absolutely no doubt that hyperglycaemia generates superoxide production. Unfortunately most of the people discussing this on pubmed have no real concept of F:N ratios or what exactly goes on in the respiratory chain to generate superoxide. There is no nice neat diagram to copy paste. My own assumption is that massive enough inputs of glucose drive huge amounts of NADH production which cannot be accommodated once FADH2 from succinate dehydrogenase reaches a critical level or is supplemented by glycerol-phosphate dehydrogenase based FADH2. At this point a cell says no to glucose calories, ie it makes superoxide and becomes insulin resistant. As has been observed, insulin resistance is an antioxidant defence mechanism, you need it. If pushed hard enough to overcome insulin resistance a cell will take one step closer to apoptosis.

Not so with lactate. Lactate supplies acetyl-CoA (which itself has an F:N ratio of 0.25) along side a couple of extra NADH molecules (one each from lactate dehydrogenase and pyruvate dehydrogenase) which reduce the overall F:N ratio to 0.2, the same as glucose). Yet pre-prepared lactate does not need any glycolysis to take place in the neurons themselves. It has no possibility of supplying ANY FADH2-like input to the CoQ couple, outside of succinate dehydrogenase (complex II) activation in the turning of the TCA. It's the purest of complex I inputs available to any intact organism. No wonder the brain loves lactate. Lactate usage appears to be the best way of postponing apoptosis, short of abandoning mitochondria altogether. Glucose comes second.

I had always though of lactate in the brain as a sort of direct mitochondrial fuel injection system. Lactate dehydrogenase then mitochondrial uptake of pyruvate. Just a fast response time. But looking at FADH2 to NADH ratios gives a much deep insight in to what is going on.

What about fat????? Not for the brain.

But for the rest of the body? What makes mitochondria happy? Hint: It's not glucose.

Peter

58 comments:

Pierre said...

Peter thank you.

If you are ketogenic what do you think happens in the brain?

Chuck Currie said...

Ok, I'm in. So how do we get more lactate to the brain?

Peter said...

Both lactate and ketones pass from the blood stream to the neurons. This might be useful if you have damaged your glial cells. The Nature paper is thinking along the lines of a lactate mimetic, they don't appear to have heard of ketones (also carried by MCT1)! Other than that, don't damage your glial cells, ie maintain normoglycaemia and let glia do the rest. There are a whole stack of other considerations in neurodegenration but the ETC is what interests me at the moment. Only have space for one line of thought!

Peter

Andrew S said...

There's some recent posts from Peter that mention lactate as a byproduct of something or other; when I have time I'm going to dig around for that.

Would lactate from dairy remain in the bloodstream, or would it get processed (by digestion, liver, whatever) into something else?

Edward J. Edmonds said...

It is interesting that lactate is higher after exercise for a short period. I often feel a "burst" of situational awareness after a short bit of intense exercise.

If lactate is important to the brain it would make sense that when you are doing a complex movement like running or something else moderately intense that requires coordination that lactate would elevate so things could fire smoother.

I play this game called Bejeweled, it's like a puzzle game similar to Tetris, I play about 5 rounds and average my score. My average score is always higher after exercise. You would want to be "smarter" when your velocity is higher so you can move and watch so as not to trip on tree roots and eat dirt.

I haven't looked but does smoking elevate lactate?

js290 said...

High intensity (anaerobic) activity will likely raise lactate levels.


BTW, isn't breast milk full of lactate?

Brian H said...

"the glial cells in the brain are ketogenic, it's not just the liver that does this"

I find this electrifying. How far do the glial/hepatic parallels ramify? I mean, lactate in the brain is all very well, keeps one alive and all that...but how would the glia interact with ethanol?

Kindke said...

Peter,

So are we converging on the theory that mitochondrial dysfunction in adipocytes is a strong cause for weight gain? I.e. by mitochondrial dysfunction in adipocytes we produce less superoxide because of less fat burning and thus our adipocytes spend more time in a relatively insulin sensitive state? Have I got this right? Indeed this has piqued my interest even if the biochemistry is starting to get a bit beyond me :)

Does this have anything to do with obese people
having a higher conversion of glucose to lactate in adipocytes? since glucose to lactate is an anaerobic process, possibly indicating some kind of mitochondrial defective state?

Edward J. Edmonds said...

Lactic acid and running: myths, legends and reality: http://goo.gl/5VRr3

Elevated lactate is not always due to anaerobic activity. Lactate elevates even with gentler activity to prevent hypoglycemia.

Kindke said...

Edward im a tad skeptical of that link. There is "some" evidence that suggests blood lactate concentration determines exercise capacity.

Both obese and T2DM have elevated lactate in the blood and both have reduced exercise capacity.

Further, the PEPCK-C mouse has dramatically increased exercise capacity and a defining feature is it produces almost no lactate during exercise.

http://www.pepck-and-the-ketogenic-diet.com/index.html

Ofcourse, the blood lactate thing could be a red herring, anyway, im more interested in the point about a lack of superoxide causing weight gain because of reduced IR in adipose tissue?

Edward J. Edmonds said...

Sorry for the blog post Peter.

Obese and T2DM have elevated lactate because their glucose metabolism is broke.

Glucose has to come from somewhere even if you are LCHF. And if you're diabetic and aren't LCHF then the situation is worse. I would expect them to have lower exercise capacity because if glucose metabolism is broke and you aren't accustomed to burning fat and you are getting glucose via the Cori cycle or Alanine cycle it would be like trying to drive your car on the Autobahn without a gas tank and instead trying to blow fuel directly in the engine with a straw. You won't be able to blow fast enough. And so your exercise capacity would indeed be reduced.

It is true that if you can't clear lactate fast enough you'll eventually be reduced to a snails pace or in a diabetics case complete malfunction. But from an exercise physiology perspective, lactate metabolism is trainable.

In the early part of the previous decade their was a shift in marathon training with the goal of raising lactate to make the ability to clear lactate more efficient... following that paradigm shift the marathon WR was broke repeatedly. The old school of thought used to be that raising lactate during a marathon buildup was detrimental to performance. Coach Renato Canova and his team of Italian physiologists were mainly responsible for this shift. In fact they take blood from their athletes (mostly Kenyan) to make sure they are getting their lactate where it needs to be. Once you run out of glycogen in a marathon and start burning more fat you can not generate as much force. Keep in mind we are talking about athletes able to run 4:45 per mile for 26 miles. But if you can train lactate metabolism to push glucose into the muscles as efficiently as possible there will be no or minimal decline in speed.

For a regular person who likes to run around an efficient lactate metabolism will not make a difference if your PR for the 5k is mediocre. But if you want to run a 5k in 12:37 you will need lactate. No one will ever break a world record on the track on a Ketogenic diet.

Anybody can run a marathon if you run it slow enough and keep lactate down. But if you want to run it in 2:05 an inefficient lactate metabolism will prevent that from happening.

In other sports like cycling or ultra distance running things are a bit different because the nature of the movement and lower speed, it's not quite the same as running a 3:43 mile. When speed comes into play it is a whole different ball game. The context matters.

Edward J. Edmonds said...

So when we see studies where people are able to perform at close to the same level on a carbohydrate rich diet verses a ketogenic diet we need to consider to what standard it is being compared to. For example I often read studies where they say "trained athletes" or "highly trained athletes" and I look at the results and the times don't reflect elite times. So for example I run a sub 15' 5k to a regular guy that might seem elite, but to a sub 13' guy that is a high school time.

It might seem irrelevant to look at things from the context of an elite athlete, but I think, if we understand what is going on in their bodies that perhaps we can have a clearer understanding of why that metabolic machinery is there to begin with and the nature of the brain.

I think in diabetics lactate will increase because the brain is looking for fuel from an alternative pathway.

Anyway there are a couple good physiology books that discus these things. "Body by Science" is aimed at a different audience not elite athletes. Context is different. Good books heavy in the physiology of running would be ones like:

-Healthy Intelligent Training: The Proven Principles of Arthur Lydiard

-Better Training for Distance Runners

-Winning Running: Successful 800m & 1500m Racing and Training

Renato Canova has one or two books that you have to order from the IAAF.

How much lactate is desirable is a good question though because at altitude lactate can elevate very quickly, there are some anecdotal reports of athletes in Iten, Kenya ~8000ft doing too intense track workouts and never being the same again.

Edward J. Edmonds said...

This is just a speculation but I'd venture to say that lactate is lower on the ketogenic diet after adaptation because it is being cleared faster possibly because it is being used more during the adaptation period. Maybe. I'm not sure.

Edward J. Edmonds said...

A good way to know if that was true is to measure lactate during adaption to see if initial it is elevated.

George Henderson said...

This reminds me of the reverse-Warburg cancer hypothsis:
http://www.ncbi.nlm.nih.gov/pubmed/19923890
"Our hypothesis is that epithelial cancer cells induce the Warburg effect (aerobic glycolysis) in neighboring stromal fibroblasts. These cancer-associated fibroblasts, then undergo myo-fibroblastic differentiation, and secrete lactate and pyruvate (energy metabolites resulting from aerobic glycolysis). Epithelial cancer cells could then take up these energy-rich metabolites and use them in the mitochondrial TCA cycle, thereby promoting efficient energy production (ATP generation via oxidative phosphorylation), resulting in a higher proliferative capacity."

George Henderson said...

The benefits of being fat-adapted:

http://www.meandmydiabetes.com/2012/08/11/western-states-100-low-carber-wins-ultramarathon-steve-phinney-and-jeff-volek-study/

"A 30,000 calorie tank of fuel? On his body?

STEVE PHINNEY: When the starting gun goes off, 30,000 calories of body fat. Now, if you run this race typically your body will burn 10,000 calories over the 100-mile course, so he’s got enough to run the race three times over before runs out of fat fuel. But that’s because he’s a fat-burner. For the carb loaded runners, who are less adapted to burning fat, at the same starting line, even if they’d done their carb loading to the maximum, the most carb calories they’d have in their bodies is 2,000. Now, if you’re running on a carb fuel strategy, and you’ll need 10,000 calories to complete the 100-mile race, that 2,000 calories of carb stored in your body at the start of the race is only 1/5 of the fuel that you need to complete the race."

Edward J. Edmonds said...

@George

This is a 100 mile ultra. However, when you look at the marathon PR's of ultra runners there are only a handful that have ever broke 2:30 for the marathon. The world record is 2:03:38. You'd think with all that practice at fat burning and long distance training if indeed it was superior at generating performance that he'd be able to at least get a US Olympic A standard qualification in the marathon which is a quite soft 2:20. As I said cycling and ultra racing are different. You can't nail your intervals required to run a 2:03 marathon on a Ketogenic diet. A good diet will help performance. Ultimately, you have train in an appropriate way and eat in an appropriate way to be able to nail appropriate paces in workouts, your diet will not do it for you.

O Numnos said...

@GH

I agree with EJE

To whit "Now, if you’re running on a carb fuel strategy, and you’ll need 10,000 calories to complete the 100-mile race, that 2,000 calories of carb stored in your body at the start of the race is only 1/5 of the fuel that you need to complete the race."

I appreciate these are not your words. However anyone capable of running an (ultra)marathon is not simply running on carbs are they?

My own experience is that long term keto-adaptation is great for athletic performance (endurance esp) but ultimate max power output suffers - not a great problem for most people in most scenarios.

I didn't comment on "Thiamine in beer makes you fat" - I'm thinking phytoestrogens plus carbs (plus crap diet of heavy beer drinkers).

Not a criticism, your posts go over my head normally so I'm surprised by these two a bit.

CharlesVegas said...

Re Kindke @9:34

"...since glucose to lactate is an anaerobic process, possibly indicating some kind of mitochondrial defective state?"

It's interesting that this same glucose-to-lactate pathway is the basis of glycolytic cancer cell metabolism (Warburg Effect).

Edward J. Edmonds said...

Lactate concentration in plasma and red blood cells during incremental exercise: http://www.ncbi.nlm.nih.gov/pubmed/11071046

I should also mention that even at rest lactate is produced because RBCs lack mitochondria.

I also think though I don't have the study handy that fructose is rapidly converted to lactate in the brain.

Edward J. Edmonds said...

Central lactate metabolism suppresses food intake via the hypothalamic AMP kinase/malonyl-CoA signaling pathway: http://goo.gl/K9xoN

Fructose metabolism in the cerebellum:
http://goo.gl/3lGgl

Edward J. Edmonds said...

Lactate infusion at rest increases BDNF (Brain-derived neurotrophic factor) blood concentration in humans.

http://www.ncbi.nlm.nih.gov/pubmed/21094220

Interstitial lactate levels in human skin at rest and during an oral glucose load: a microdialysis study.

http://www.ncbi.nlm.nih.gov/pubmed/10361615

Eva said...

Also for consideration, just because a strategy works for an ultra elite athlete, does not mean that method of eating is good for the vast majority of the rest of us or even good for the athletes long term. Ultra elite athletes are basically attempting to push their bodies to the ultimate extremes far beyond what they were naturally designed for and far beyond what may be good for long term health. I have yet to hear of any of ultra elite athletes living to be 100 years old. Many women find their periods stop during training and their bones leached of calcium and brittle by age 30. Just because something works to win gold medals does not mean it is actually good for your health long term.

Edward J. Edmonds said...

I think you are correct Eva. In one of Peter's posts on ketosis I had mentioned that in the old days prior to the mid 90's the diets of elite Kenyan athletes was not as carbohydrate rich, it wasn't LC levels, but it was lower than present and their careers spanned much longer. Nowadays the athletes seem to burn out faster as their CHO intake has increased. To be fair, there are other factors that could have caused this. But there was a book I read called "The Longevity Study" and indeed there were no athletes among the oldest lived. I think there definitely is a trade off and I'm certainly not advocating the idea that that type of stress is a good thing. Merely, things that happen in an elite athlete performance (self induced) seem to mimic somewhat things you see chronically elevated in a sick person (pathologically induced). I think there is something to learn there.

Eva said...

Yep, I agree there are many factors including likely doping by many. The rule seems to be any potentially performance enhancing chemical substance there is no test for yet is likely used. Another issue is not just carb level but what kind of carbs? Most carbs are made of wheat these days. You get the calories but also different side effects than if you had only been loading up on bananas, rice, and potato. Plus nowadays seems like a lot of people are guzzling those 'electrolyte' high fructose corn syrup drink concoctions. I have to say that using the term 'electrolyte' was surely a piece of marketing genius!

blogblog said...

Running marthons is very stupid idea. Even Dr Kenneth Cooper eventually decided that running more than 2km was unwise.

blogblog said...

@Eva,

the average modern professional athlete has irreversibly destroyed his or health by age 35.

Peter said...

Andrew, the motor neuron group are looking to develop some sort of drug, possibly an ester of lactate to allow sutained delivery. Like Veech with esters of ketones. There is also an ester of succinate, now that's an interesting drug without enough published data to draw any conclusions.

Edward, dunno, there are a lot of things go on in the brain after exercise, but maybe this might be a facet???

js, It's lavtose in breast milk, lactate in yoghurt. They taste different! I think Emily made a simple mistake in the post. No as bad as thinking The Good Dr is worth listening to!

Brian, I got very drunk with Johnny Roughan one AVA meeting. He thinks consciousness is a phenomenon of K+ flux through glial cells. He means it, not just too much Bushmills. http://www.ncbi.nlm.nih.gov/pubmed/9631559

Kindke, heading that way, though the link to lactate here is new to me. Logic says PUFA generate least superoxide and allow greater insulin sensitivity. Insulin sensitivity, in an adipocyte, says get fat. Lactate would do so too, but far more. What breaks in diabetes seems to be something in complex I allowing superoxide production during forward electron transport, at least that's how I'm thinking at the moment. It's almost certainly in the mitochondrial genome, which sits by complex I if I remember correctly. We'll be back to Nick Lane and what determines longevity/apoptosis/mitochondrial biogenesis etc by then.

Edward, haven't time to read the whole comments string but the quote near the start: "Obese and T2DM have elevated lactate because their glucose metabolism is broke" is spot on. Complex II seems fine otherwise high fat diets would be a disaster. Which they ain't.

Got to go look after the baba now.

Oh, George, reverse-Warburg. Lots to post on that but it seems miles away at this stage. You have no idea how utterly intrinsic to cancers in the whole fibroblasts appear to be. There is so much there. Luckily if you nuke the fibroblasts with metformin you are essentially forcing them the LC and I think this will still allow LC to be used as a tool, even if the cancer cells are using OxPhos. It also ties in to Nick Lane and the lack of mitochondria in cancer cells. This needs rephrasing as there are no mitochondria in immortal cell lines. I suspect many cancer cells themselves will not imortalise, do really use OxPhos/mitochondria, and skew the literature by about a million miles. Way to go on that line of thought. But blocking the reverse Warburg effect with metformin looks like LC to me!

O Numnos, agree, I'm no athlete but if I hill climbed on my pushbike beyond by cardiorespiratory O2 delivery the world started going grey/red from the edges of my vision inwards (when keto adapted). But at the top of the climb there was no payback time, no need to rest, just carry on along the top of the North Downs. I had to limit my climb rate. But, as I said, I'm no athlete nowadays.

Now really gotta go, sorry if there are a million typos!

Peter

Kindke said...

Lactate inhibits lipolysis in adipose tissue via GPR81 receptor. From what I can make out from the original study I linked, glucose conversion to lactate has something to do with the insulin sensitivity of the adipocyte, if the adipocyte is enlarged and insulin resistant, it converts more glucose to lactate and releases it back into the blood, but if the adipocyte is small and insulin sensitive more glucose is converted to CO2 and triglyceride in adipose tissue.

Apparently, the antilipolytic affect of insulin is reduced if you knock-out the GPR81 receptor in fat tissue, indicating that high levels of lactate acting on GPR81 in fat tissue help increase insulin's fattening affect.

http://www.ncbi.nlm.nih.gov/pubmed/20374963

Boyd et al. (25) hypothesized that plasma lactate produced during intense exercise is a direct signal to fat to decrease lipolysis during a time when other factors are trying to increase the further release of FFAs.

A physiological rationale for this feedback is to limit the supply of FFAs (which have a greater oxygen requirement per mole of ATP produced than pyruvate) during times when glycolysis rates exceed mitochondrial respiration rates.

During exercise, there is a shift in fuel utilisation by muscle from lipid to carbohydrate, but this does not appear to be a result of the inhibition of lipolysis in the main adipose tissue depots by muscle-derived lactate. It is suggested instead that a putative autocrine lactate loop in myocytes may regulate fuel utilisation by muscle during exercise,

So it looks like blood lactate concentration does in part determine exercise capacity mainly because blood lactate seems to be acting as a signal to the body that we need to turn on glucose and anaerobic metabolism.

http://www.ncbi.nlm.nih.gov/pubmed/21902860







Edward J. Edmonds said...

@Eva

Doping is a problem in Track & Field but it’s actually quite uncommon in longer distance racing because it doesn’t make a difference; it interferes with your ability to train correctly. In other sports it’s a bit different. The context matters here once again.

“Another issue is not just carb level but what kind of carbs?”

The diet of a Kenyan athlete is still very traditional. I can only speak on the diet of the athletes I can’t tell you what the rest of the locals eat. The bulk of the diet is brown rice and beans, potato, banana, greens (very similar to spinach), red meat at least once a week, banana and melon. Eggs are uncommon. Everything is heavily salted. The beverage of choice is milk. Tea boiled with milk is almost mandatory. Brown sugar is added to the tea. A LOT of brown sugar. It’s almost unbearably sweet. I would say that out of 6000-8000 calories a day about 20-25% comes from brown sugar. Coffee is for enjoyment but not a lot, it interferes with training. Everything is grown locally. I’d point out once again that how an elite athlete trains is completely and utterly worlds apart from what you see in popular running magazines and the like. It’s not the same at all. And at least in Iten, Kenya these athletes are not drinking Gatorade and eating Gels. These guys are drinking water. These are the best in the world. Caffeine in the long term interferes with aerobic development.

“Plus nowadays seems like a lot of people are guzzling those 'electrolyte' high fructose corn syrup drink concoctions. I have to say that using the term 'electrolyte' was surely a piece of marketing genius!”

When I still ran 100 miles a week I never used anything but water, I always thought sports drinks and gels were stupid. Again I can only speak here about the Kenyans, but water was the only thing drank in even the longest of the long runs. No food. Or anything like that. I would say that the cleanliness of their diet plays a big role in their performances because they are never injured like the Western runners are. No injuries means more training.

Again what you see in magazines etc., is not an accurate reflection of the habits of the best in the world. Most of it is bull.

@blogblog

“the average modern professional athlete has irreversibly destroyed his or health by age 35.“

I'm not sure I'd agree. Here again the context matters. Maybe that is true in the United States and other western countries. The world consists of more than just the United States. The data is slightly skewed. In Kenya there are plenty of runners from the old days still healthy and vibrant. And they still are heavily involved with the training of the younger generation of runners. I ran 100 miles a week on average for years. I had my heart scanned. My pipes are clean, very clean and moist and flexible. Of course I never ate garbage. And I always ate plenty of yolks and butter.

Edward J. Edmonds said...

@Kindke

I’m really enjoying this exchange Kindke, sincerely, I love to think about this stuff. I’m not sure if you are disagreeing with me completely or partially or just adding more context?

O.k. I’m not sure what it is we are trying to discover/show here. Lactate is a) always produced even at rest b) increases with activity but is not always proportional, speed/duration are variables c) clearance can be made more efficient i.e. the ability to handle larger workloads using more lactate d) lactate is elevated in sick (stress) people much like it is elevated in self-induced stress (exercise)

The key phrase is “lactate concentration”. No doubt when you are getting over 4mmol/L blood lactate that exercise capacity will be limited but it’s limited to how fast you can clear it i.e. you can’t go on forever because the limiting factor is how fast lactate can be cleared (4mmol/L is rather arbitrary some can handle more some less it really depends). When lactate production is equal to lactate clearance this is called “Maximal Lactate Steady State”.
This is back to the straw analogy, you cannot rely 100% on lactate metabolism. When you are diabetic or obese lactate is elevated because glucose metabolism is broke. Energy cannot be delivered fast enough to support physical activity. The brain and other vital things take precedence. If physical activity is high in an obese or diabetic lactate is going to skyrocket and ultimately won’t be able to be cleared fast enough. If you can’t clear lactate fast enough you’ll be laying on the floor sucking wind and most likely seeing the world through a tunnel or pinhole.

Running examples. No matter how well trained a runner’s lactate metabolism is, if the intensity is great enough lactate will start to accumulate faster than it can be cleared. Indeed, when this happens, lactate will limit exercise capacity, up to a point though it enhances performance (or you could say that more work can be done because more work is being spread over different metabolic pathways). That is why you can’t sprint forever. But the way I’m interpreting you is that lactate at any amount will limit exercise capacity. That, if that is what you are implying is simply not true. It limits exercise only when it can’t be cleared as fast as production and intensity or metabolic damage will determine how fast it accumulates.

Yes, lactate will inhibit fat burning, but in the sense that fat cannot deliver intensity so you are forced to rely on other “faster/sloppier” pathways. (It's interesting that in the sick, sucking down glucose makes this worse) Once you shut off fat, it’s back to the straw analogy you can’t rely on it 100% there is too much going on at this intensity for it to meet the demands of everything and you shut down. So I’d agree with that observation. And it explains completely reduced capacity in the obese and diabetic and at the tail end of a running performance poor lactate clearance is ultimately what limits how fast you can go for how long.

js290 said...

Going anaerobic in an endurance event seems completely suboptimal. Given that fatty acids produce more ATP than glucose, I don't see how it's possible to perform worse burning fat than glucose (even if it comes from lactate). Burning fat would be glycogen sparing, which could be useful for the sprint to the finish.

Edward J. Edmonds said...

Dynamics of Blood Lactate

Lactate has a varied role in metabolism that is appropriate to review here, as part of the anaerobic threshold controversy has revolved around the notion by some that no anaerobic metabolism (and thus no lactate production) occurs at rest. This is incorrect, because lactic acid is being produced even during the quietest of resting states, as well as in increasing amounts as exercise intensity increase. Red blood cells are one well-known source, as they are capable of glycolysis but have no mitochondria. Thus, pyruvate and lactate, instead of accumulating, diffuse out of the red blood cells into the plasma. Lactate can be also produced and released into the bloodstream by the intestines and skeletal muscles. Along with the production of lactate is its use as a fuel. Nonexercising skeletal muscle will metabolize lactate. So will the liver, the kidneys, and also the heart. Even exercising skeletal muscle can metabolize lactate. We know it is an important energy source, released from both FT and ST skeletal muscle cells and usable as a fuel especially by ST muscle cells. Thus lactate is not some kind of gremlin molecule to be maligned as an internal poison. Rather it is produced in a well-understood manner and usable as an important energy source.
The blood lactate level measured at rest or at any particular level of exercise represents a balance between its rate of production and release into the blood and its removal; in biochemical terms this balance is called lactate turnover rate. This turnover rate determines the baseline lactate concentration in the blood. And untrained individual in an overnight fasted state who has a sample of blood collected in the morning from and arm vein before any exercise has a lactate level ranging from about 4 to 15 mg/dl. (Many clinical laboratories express lactate level in millimoles per liter [mmol/L, or mM/L]. Because 1 mg/dl = 0.1112 mmol/L, this resting blood lactate level can also be expressed as 0.44 to 1.7 mmol/L.) We find that our trained elite distance runners typically have a lactate level near the low end of this range (around 3 to 5 mg/dl, or 0.3 to 0.6 mmol/L) if they are not overtrained. (However, one residual effect of either a very hard single training session or a period of overtraining is a morning postabsorptive lactate level that is either very high normal or clinically elevated.” p. 99, http://amzn.com/0880115300

--

This is from the Chapter “Heart, Lung, and Blood Adaptations to Running”. It very clearly lays out the physiology. In distance running you are almost never truly anaerobic even when lactate is elevated. A percentage of energy comes from multiple metabolic pathways, shifting with intensity. I currently don’t have access to a scanner but I will scan the entire chapter and provide a link if you are interested.

Edward J. Edmonds said...

Renato Canova on Lactate

-http://youtu.be/WObrtaR9D3s
-http://youtu.be/NQyFGcECbEY
-https://docs.google.com/open?id=0B1wyy-gxfSdsYUc5SUZmQ2dpUlU

George Henderson said...

@ EJE,
I introduced the runner to show that fat adaptation is a real thing, and allows proper access to bodily reserves. I actually think we can extrapolate from this to obesity to some extent.
100mi is a long race and all 100mi marathons can't have equal gradients and climate, so comparison between different events probably doesn't go far.
Tim Olson was up against the best carb-adapted athletes and beat them.
Because he needed to eat less while running, so had fewer digestive problems.

George Henderson said...

@ Peter,
" You have no idea how utterly intrinsic to cancers in the whole fibroblasts appear to be"

If this applies to hepatocellular cancer and the activated stellate cell (a glial cell type which has morphed into a myofibroblast cell type) is said fibroblast, this is a very promising line of inquiry.

Edward J. Edmonds said...

Lactate metabolism:

http://jp.physoc.org/content/558/1/5.full.pdf+html

john said...

So ultra-endurance athletes seem to do fine on low carb. Middle-distance events are tough. What about sports/events that require very short bursts? I'm wondering about weightlifting and sprinting (60-100m).

It is common to say max power is reduced on ketogenic diets, but why would that be for something as short as above? Training lactate metabolism would seem to have no effect as those two things hardly produce any extra...?

Muscle mass and "neural factors" tend to be most important for max power. The only reason I can see as to why ketogenic could be worse would be do with muscle fiber type, which seems to be affected by glucose metabolism factors: t3, insulin, etc. Going a bit further, what about a 200m sprinter or a football player?

Edward J. Edmonds said...

Another interesting paper.

Lactate as a fuel for mitochondrial respiration:
http://www.ncbi.nlm.nih.gov/pubmed/10759601

blogblog said...

js290 said...

"Going anaerobic in an endurance event seems completely suboptimal.'

All athletes will go eventually anaerobic at a pace greater than jogging. It is unavoidable.

blogblog said...

Kenyans are brilliant distance runners because they are Kenyans not because of their diets or training methods.

It is an open secret in sports science that genetics are the overwhelming factor for success in many sports. In fact in some sports (eg rowing) it is quite common to turn complete novices into world class athletes in less than two years - as long as the have the right physique and physiology.

js290 said...

There are two aspects of training: skills and metabolic training. In skills training, the purpose it to become as efficient as possible so as to not go anaerobic until absolutely necessary. Again, I'm still not sure how it's possible to be more efficient aerobically (TCA cycle) burning a less efficient fuel at producing ATP that is glucose.

In metabolic training, the purpose is to increase your anaerobic capacity and push the lactate threshold, i.e. get stronger. Trying to combine skills conditioning with metabolic conditioning may be sub optimal at best and dangerous at worst (injuries, etc).

It was either Mike Mentzer or Arthur Jones (one of the early HIT proponents, anyway) that said, if a bodybuilder hasn't reached his genetic potential in two years, he is doing something wrong. So, turning a novice into a world class rower within two years doesn't seem that far fetched.

Peter said...

George, fibroblastic involvement is massive in so many neoplasias that the paper on reverse Warburg effect immediately struck a cord. I'm glad it looks interesting to you. I guess you've seen

http://www.ncbi.nlm.nih.gov/pubmed/22840388

Of course PET scanning is hardly going to differentiate between glucose metabolism in a cancer cell and that in a metabolically coupled fibroblast. They are all essential parts of the pathology. If the direct Warburg effect hits the coupled fibroblasts rather than the cancer cells themselves (how do you then define a cancer cell in these terms?)...

On the down side I remember Stan commenting that we might just prolong the demise rather than get cures, but ketogenic eating looks more fun than doxrubicin to me.

Peter

blogblog said...

@js290,

The training of fighter pilots is probably the best example of scientific training of elite "athletes". The method of creating a fighter pilot has been perfected over more than 90 years.

- select an intelligent, confident and very highly motivated young adult using a battery of physical and psychological tests.

- use world class experts to train them from the very beginning.

- push them to the point of failure in EVERY training session.

- immediately cull all those who don't satisfactorily pass every test.

It only takes about 150-300 hours flying to produce a highly competent fighter pilot and about 1000 hours to produce an world class fighter pilot.

Most athletes probably spend the majority of their training time "unlearning" bad techniques and overcoming injuries caused by inadequate coaching during their formative years.

Paul said...

Edward,
Thanks for info on Kenyan athletes.
Just a question: Why do you think coffee interferes with aerobic development?

Paul

Edward J. Edmonds said...

"It is an open secret in sports science that genetics are the overwhelming factor for success in many sports. In fact in some sports (eg rowing) it is quite common to turn complete novices into world class athletes in less than two years - as long as the have the right physique and physiology."

That has been looked at extensively in Kenyan athletes. A very famous coach quipped, let them (Westerners) think we have some type of natural advantage or some secret training method... that is our advantage because they will never challenge us as long as they think that, that is their excuse.

Americans can be very competitive at the shorter distances as they were in this years Olympics.

In longer events like the marathon it is harder because Americans don't nearly run as much millage as the East Kenyans and the East Kenyans have been running since primary school that tends to make a difference later on in life because they have huge aerobic bases (very efficient fat burners) by the time they are 20 years old. Westerners do not and you see that difference in their marathon performances. Altitude plays are role but not as big a role that some make it out to be.

"Again, I'm still not sure how it's possible to be more efficient aerobically (TCA cycle) burning a less efficient fuel at producing ATP that is glucose."

Aerobic conditioning is essentially training to teach the body to do more work with fat and spare glycogen. Two ways to do that, long distance training 90-120+ minutes run, or long distance training running with LCHF. OR just LCHF. Different muscle fibers like different metabolic pathways. Training enhances that. There are some people who think you can run a world record performance off intervals (HIT) alone, that was tried too, Coach Gerschler of Germany tried this in the first half of the 20th century., it's not the same type of conditioning. That flawed type of thinking mainly comes from high fat circles. In the 80's/90's this idea of HIT resurfaced again among Westerners and the Africans continued high millage training, Kenyans and Ethiopians dominated for almost 15 years. That seems to be a common thing with American distance running. Westerners trust science regardless of results and the Africans trust experience verified with results. It is interesting that this generation of American runners is doing more millage than the previous generation and this Olympics was the first time for an American to medal in the 10,000m in decades.

Edward J. Edmonds said...

"Why do you think coffee interferes with aerobic development?"

Today unlike yesterday I do not have enough time to answer this. But I will get back with you on this shortly.

blogblog said...

Edward said,

In longer events like the marathon it is harder because Americans don't nearly run as much millage as the East Kenyans and the East Kenyans have been running since primary school that tends to make a difference later on in life because they have huge aerobic bases (very efficient fat burners)

Aerobic potential is mostly inherited and is barely affected by training. In fact it takes less than six months of serious training for an athlete to reach their VO2max potential.

Biomechanics experts tend to argue that Kenyans are very good distance runners because they have very short gastrocnemius muscles and very small calves. This in turn is reflected in their very high runnning efficiency (5-10% better than elite Caucasian runners).

Rob de Castella, a former elite marathon runner is currently training central Australian aboriginesaborigines who have very similar physiques to Kenyan runners.

Paul Tergat the legendary Kenyan didn't start running until he finished high school. Here's what he said in a 1999 interview:

“Every time you read papers and magazines, that’s what people say, but it is a myth about kids running many kilometres to school.

“In my case, home to school was just 800m. In fact, I didn’t even like running at school and I wasn’t particularly good at it. It was only when I went into the armed forces and I was made to run that I discovered I had a talent for it.”

http://mg.co.za/print/1999-03-26-running-the-kenyan-training-myths-into-the

http://en.wikipedia.org/wiki/Paul_Tergat

blogblog said...

Race horse trainers spend vast amounts of money buying expensive yearlings. The reason is that they know genetics are far more important than training in producing champions. It is far more time and cost effective to spend $500,000 on a single yearling with a stellar racing pedigree than train a vast number of cheap horses in the vague hope of finding a champion.

It is totally implausible that humans are unlike every other species and win primarily based on their training rather than their genetics.

Edward J. Edmonds said...

Good morning blogblog, you had some interesting comments:
“Aerobic potential is mostly inherited and is barely affected by training. In fact it takes less than six months of serious training for an athlete to reach their VO2max potential.”
--
VO2max has no bearing on elite performances. The best predictor of performance is previous race times. VO2max varies wildly amongst elite runners. Wildly varies. Some of the best marathoners had very low VO2max. Usually but not a hard and fast rule, the more efficient the runner is the lower the VO2max. That is why they say if you want to run fast you have to train fast, you can’t run 3 hours a day slowly and expect to run a sub 2:20 marathon. In fact the cutoff seems to be about 2:40-2:45, in other words you can run as fast as that off of base millage and no track work but below that you have to start working on exploiting other metabolic pathways. I’ve seen maxes vary by 20 points in runners with the same exact times.
Further aerobic capacity takes years of development not 6 months. It is true that during each season 3-6 months of base building is about the most time you can spend working on base before you stop improving. But from year to year this capacity increases. That is why as the runner ages he/she gets slower at short distances and faster at long distances.

Edward J. Edmonds said...

Noakes, T. D., Myburgh, K. H., & Schall, R. (1990). Peak treadmill running velocity during VO2max test predicts running performance. Journal of Sports Sciences, 8, 35-45.
The poorest predictors were: VO2max (r = -.55 to -.81) and VO2 at 16 km/h (r = .40 to .45).
Conclusion. There may be no unique physiological characteristics that distinguish elite long-distance (10 km or longer) runners as is often promoted. Other factors determine success in high level sports among exclusive groups of superior athletes.
Implication. Running performance is the best predictor of running capability in elite long-distance runners. Physiological laboratory testing gives less information than does actual performance. Even the fastest speed of running on the treadmill is a better predictor than any physiological measure. This suggests that for at least endurance-dominated sports, actual performances in a variety of performance-specific situations will give more useful information than that which can be obtained in any physiology laboratory test.”

“Biomechanics experts tend to argue that Kenyans are very good distance runners because they have very short gastrocnemius muscles and very small calves. This in turn is reflected in their very high running efficiency (5-10% better than elite Caucasian runners).”
--

Edward J. Edmonds said...

Biomechanics. I will agree with you there but not because of calves or body shape. This has more to do with lifestyle factors that are conducive to excellent biomechanics than anything else. I can think of countless examples of elite runners with bodies that have absolutely no business running who broke world records.
Paul Tergat the legendary Kenyan didn't start running until he finished high school. Here's what he said in a 1999 interview:

“Every time you read papers and magazines, that’s what people say, but it is a myth about kids running many kilometres to school.
--
I never said they run to and from school. Indeed that is a myth. So is the shoeless thing. Kenyans also view the lack of shoes as a disadvantage.
I said they are running since primary school. I have a training schedule of the Kenyan schools in Iten and Eldoret; they are running almost 6-7 hours a week from the get go. Girls and boys. This is a complete 180 from the low volume kids their same age are doing in America.
Paul Tergat. Paul Tergat used to run 3-4 times a day, more than making up for his lack of running in his younger years. Further Tergat is being conservative because even as a youngster he was still very active. They use their legs for everything and often spend a great deal of their life doing a lot of labor intensive tasks. This is called “farm work”. Western runners have to do things like strength training and plyometrics to make up for lifestyle factors. Kenyans already have this strength from their lifestyle and it plays very little in their day-to-day training. Further Kenyan Armed Forces training camps are brutal often 3 sessions a day during the specific period.
I’d say that if at this point you still think genetics and body shape plays a significant role in performance that you take the time to travel down to Iten or Eldoret for 3-6 months. These kids are set up from a very young age to be able to train extremely hard because it is a part of their culture and their life as youngsters is a very physical existence. That is their advantage.
Arthur Lydiard during his coaching years noticed in New Zealand that as the children became more sedentary with modernization that they were not able to handle as much training when they were older. Their bodies simply were not prepared for extreme training that the older generation seemed to be able to handle perfectly fine.

Edward J. Edmonds said...

Things are changing though in the United States, coaches are beginning to understand these lifestyle differences and are now on average increasing the volume the kids are running and stressing the idea of being more active and subsequently these newer generations are getting more competitive with the East Africans.
Biomechanics. Biomechanics has more to do with relaxation and neurological factors than how the body is actually moving. I had an athlete who trained at a fairly high volume and had a PR of 1:08 for the half-marathon. He could not break 1:08 for years. He is 36. 1:08 is not super fast but still is a very decent time. Anyway the guy looked like he was running around with a seat glued to his ass. It was a wonder that he could even run 1:08. In 4 weeks after teaching him how to relax he dropped his PR to 1:04. I taught his brain how to run fast while keeping his training exactly the same. So biomechanics does play a role but biomechanics is trainable and not a genetic factor. He still looks like he a seat glued to his ass but now it doesn’t look as uncomfortable and he is much looser. Ultimately it his his lifestyle of sitting that will limit his performances not genetic. In the old days Western runners still did a lot of walking as a part of their training, they didn’t know why it mattered but they knew it made a difference. Walking uses different muscles than running and I speculated that it worked because it hits a lot of stabilization muscles that you can’t hit as hard with running. Particularly the hips and lower core. When you are sitting they are almost always deactivated and atrophy over time forcing you to rely more on the quads and back for stabilization rather than the gluts and hips. You’ll see this difference between American and East Africans. Americans are more upright and Africans have a more forward lean allowing them to generate more power with less of an energy requirement. That is why Africans tend to float across the ground and Americans tend to pound holes in the ground.
A good example of this difference can be seen here:
http://youtu.be/_P1Y6b1RXM0
http://youtu.be/VadD3-Nzim0

Edward J. Edmonds said...

The American is running like he has a seat glued to his ass. The Africans run as you can see much more fluid and look as if they are purposely moving forward whereas Meb looks uncomfortable. Notice his much higher arm carriage to generate more power to move over the ground whereas the Africans are able to generate more power using their glutes while keeping arm carriage lower keeping the motion more forward than up and down. All throughout an Africans career they do relaxation runs, runs at a very slow pace where they focus on landing each foot exactly the same way and learning to become comfortable, these are long runs that strengthen the weak muscles these runs are not for fitness but rather to train the brain to become familiar and comfortable with that movement. So even though the Africans have stronger hips and glutes because of lifestyle they still practice efficiency. It makes a huge difference because if you are able to move forward more efficiently you will use less energy and last longer and be able to run faster over longer distances.
I think genetics does play a role as far as the starting metabolism and different muscles fiber compositions of runners. But even with that I can provide examples of exception. We cannot know for sure until we eliminate other variables to see how much difference it makes and we don’t know what came first the current genetic profile or the training that gave those adaptations. And when we look at the history of the sport, the different body types, the varying VO2 maxes, the different forms, it really makes the entire genetic thing an extremely weak excuse, because there are exceptions and paradoxes everywhere. The horse example is a good example yet I’ve been around racing horses and there are definite lifestyle differences. Ultimately I can agree with you on one very small hand but I think your oversimplifying things. The Russians tried that approach once and so did Hitler. Not to mention the effect that psychology has on performance and how much of a training effect you can get out of a session just off differences in attitude.

Edward J. Edmonds said...

Put another way is I think genetics does play a role but only at the very top levels when all training avenues have been exhausted. Because training changes from year to year as the athlete develops and because you can never know exactly how an athlete is going to respond to a specific type of training you are always answering questions. In other words training is the question not the answer. You are always a step behind because you are always in observation mode. To me (not a world class running coach) and other world class coaches even it does make a difference it is a moot point and an excuse at best because things change with training and it interferes with the mentality of the athlete. And there are very good examples of athletes who had everything going against them, asthma, metabollic disorders, late start, etc., that went on to break records. There are too many variables to sift through. Things that make a huge impact should be sifted through first before we start going down a road of which we have little understanding about. It’s speculation. I’ve seen athletes struggle for years thinking that that was the best they could do only to change training methodology and have a major breakthrough. If you talk to Alberto Salzar or Canova they will tell you flat out that if genetics does play a role it plays a very very small one. And they, Canova in particular have trained the best athletes and record holders in the world. Further I trust their real world experience and results much like I trust my ancestors that eating eggs, fat, and meat, is healthy despite contrasting theories. The other question we have to ask is if there is a genetic advantage how can it be exploited? Was the athlete who had the breakthrough, was some genetic factor exploited through training that allowed him to have that breakthrough? I would say that genetics is the last path to explore before we start telling people when they are 5 years old that they will never be a good athlete. People have this funny thing, you tell them they can’t do something and they go and do it.
Anyway, if you want to discuss this more you can e-mail me at edward.edmonds@gmail.com and I’ll be more than happy to engage you in a more detailed fashion.
http://www.sportsscientists.com/2007/12/running-economy-part-i.html

Edward J. Edmonds said...

“It is far more time and cost effective to spend $500,000 on a single yearling with a stellar racing pedigree than train a vast number of cheap horses in the vague hope of finding a champion.
It is totally implausible that humans are unlike every other species and win primarily based on their training rather than their genetics.”
That’s a good point blogblog, good food for thought. Maybe we know more about horses than humans because right now the only way we know if a runner has talent is from prior performances. But we don’t at this point know what genetic markers make for a good runner because so much of it is trainable. And even in the case of runners who we do have good genetic profiles for or runners that come from running families, too many times those runners who show similar potential don’t live up to their genes. I don’t know blogblog that’s a tough one. Maybe in a perfect world where every single variable could be controlled we could reduce better performance to genetic factors but for now we don’t live in that reality. And humans are rather romantic creatures. But then we take one of the greatest runners in the world with a very long career and he has asthma or we take one of the most consistent marathoners in the world he has a metabolic disorder. Not to mention world class runners with major differences in limb length between the right and left who outperformed their more symmetrical opponents. That is quite the paradox from what we would expect from a fine pedigree. Then we have runners who show great promise, come from good families, and do nothing but disappoint, only to be beaten out by some dark underhorse. I don’t know maybe the asthmatics and diabetic and dark underhorses have the better genes and that’s why the United States sucks at distance running, because we are looking for the wrong things or expecting the wrong things. One of the fastest white American runners to go under 27’ minutes for the 10k has asthma and allergies. He also happened to get silver in the 10,000m in this year’s Olympics. Then we also have a long string of runners who were alcoholics and smokers who outperformed their training partners who did everything right. Maybe their genetics were so superior that had they did everything right they would have performed even better. Who knows. Some of the best runners literally rose out of the trash, then they had kids and their kids sucked, maybe that combination of good genes with a shitty environment was what got them to the top, and maybe that good environment for their kids plus the good genes doesn’t get the same results because there is not real drive for survival, winning a race to make money for their family, in which case genetic potential for a human would mean nothing if it is never given the right reasons to want it, which pretty much levels the playing field. You make an excellent point on horses but in humans I don’t see that reflected in reality or exploitable in any practical way.
http://therunningclub.files.wordpress.com/2012/02/galen-rupp-mask1.jpg
Genetically superior?

Edward J. Edmonds said...

http://www.sportsscientists.com/2008/04/fatigue-series-introduction.html

Lactate, etc., is discussed.

blogblog said...

@Edward,
"You make an excellent point on horses but in humans I don’t see that reflected in reality or exploitable in any practical way."

In Australia we produce large numbers of elite rowers by a careful selection process. Potential rowers are often found by open recruiting sessions at universities or occasionally approached by scouts. They are measured (height, weight, reach, lung capacity, flexibility etc) and tested (on a rowing ergometer) Those who are considered suitable are offered an intensive training programme.

As an experiment the Australian Institute of Sport created a female skeleton team to compete at the 2006 Winter Olympics. They invited over 100 complete novices from a wide of sporting backgrounds to be tested. Five were seolected for further training and one placed 13th at the Olympics at her first attempt.

http://en.wikipedia.org/wiki/Skeleton_sport_in_Australia