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I am posting from my phone so I only share the first link I found which is Wikipedia article on frucolysis which is the same for fructose than glycolysis for glucose apparently.Not that I know of. Fructose should be getting converted into glycogen pretty efficiently. Do you have any pointers for that claim?
I am posting from my phone so I only share the first link I found which is Wikipedia article on frucolysis which is the same for fructose than glycolysis for glucose apparently.
Fructolysis - Wikipedia, the free encyclopedia
I actually hope that I have uncorrectly understood but according to this article, 25% of fructose is converted into lactate by the liver.
Regarding the topic of lactate, we must always be specific about where in the body were are referring to. The study that Haidut cited focuses solely on lactate in neurons.
Again, we need to be very specific with the exact tissue in question, because the effects of lactate in a particular tissue can be vastly different from other tissues.
I will focus this discussion on brain lactate, with a focus on lactate use in Neurons and Astrocytes. Minor commentary on lactate production elsewhere in the body will be made. However, to be clear, I personally do not see chronic lactate production to be beneficial anywhere outside of the brain. I will thus support the general recommendations to reduce lactate (and avoid common hospital interventions like using Ringer's Lactate solution)
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Lactate Mechanics
It is important to remember that Lactate production is an energetically favourable breakdown product of glucose metabolism. Gibbs free energy of the reaction from pyruvate to lactate is negative, so if the appropriate enzyme (Lactate Dehydrogenase) is present, this reaction occurs very naturally.
This is also why during exercise, when pyruvate is being made faster than it is used, lactate accumulation results. Again, IMO, not a good thing in any other tissue than the brain. (Even the liver needs extra processing to deal with lactate, which it should not be burdened with if possible)
Again, this conversion of pyruvate to lactate occurs very readily given the constraints of biology and physics. The body then exploits this natural phenomena to its advantage. (credit: Chris Masterjohn).
This is to say, that in any tissue which experiences very high energetic flux using glucose as a substrate, you are bound to get lactate being produced in significant quantities. The brain is by far the most energetically hungry tissue (per unit mass) in the body. What you see in muscles exercised to fatigue is constantly happening in the brain. Lactate will be produced, and the brain EXPLOITS that fact for great good
In order to exploit this increased lactate, the brain needs special structures. These structures are not present in fast enough feedback loops in other tissues (they have to rely on the slow Cori Cycle), hence why lactate accumulation in other tissues is horrible.
NOTE: lactate accumulation in the brain is also bad. The Brain just has a higher absolute level of lactate tolerance before a notion of "excess" is reached
Also note that pyruvate to lactate conversion produces NAD+, which regenerates the NAD+ being lost during glycolysis.
What is not shown in the picture below is that oxygen is not needed for this reaction, and therefore it can proceed whenever oxygen is low.
View attachment 3021
This image was taken from the review by Avital Schurr -- Lactate: The Ultimate Cerebral Oxidative Energy Substrate?
The author provides very good evidence for why lactate levels will always be slightly elevated in the brain, and the evidence for mitochondria of both neurons and astrocytes to be rich with Lactate Dehydrogenase (LDH), in a manner that is exclusive to the brain (no other tissue seems to exhibit this behaviour).
The author claims that Lactate is the primary substrate for ATP generation in brain mitochondria. I can see this as plausible, and view this as just another exploitative measure by the brain, when having to deal with so much naturally produced lactate so often.
IMO, the apparent "Aerobic Glycolysis" production of lactate, is purely an artefact of the high metabolism of the brain -- you have sufficient O2, lots of pyruvate, but usually too much pyruvate that you get significant lactate as well, along with good NAD+ levels from lactate formation, and good CO2 levels from the metabolism of either compound.
This is completely opposed to the oxygen and CO2 starved environment seen in other cells when they happen to produce a lot of lactate.
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Isolated In-Vitro studies of Brain Lactate use considered useless
I also do not like some of the research that Ray cites regarding brain lactate (though I agree with his claims in all other tissues). These studies largely isolate various tissues, which for example, does not allow the Astrocyte-to-Neuron lactate shuttle to happen at all. One would then wrongly conclude that "lactate accumulation in astrocytes is bad" by not considering all of these mechanics:
There is complex machinery here to transport lactate between cells, and though not shown in this picture (from wikipedia), then presence of specific mitochondrial LDH isoforms likely means that brain mitochondria can use lactate just as well.
This is the key factor: If brain mitochondria actually make use of Lactate, lactate accumulation in the brain in due to poor lactate metabolism.
Again, I believe this to be the case -- http://www.sciencedirect.com/science/article/pii/S0014579308007783 . See section 1.5, which diagrams the use of Lactate in Brain mitochondria, using up NAD+ and generating Pyruvate.
And while I disagree with Petro's high-level recommendations, his mitochondrial mechanics are correct. I quote him from -- Hyperlipid: Protons (36) Glycolysis to lactate
I've blogged before on the astrocyte-neuron lactate shuttle and why I, from my own personal viewpoint, consider lactate to be the ideal mitochondrial fuel when reverse electron transport through complex I is best avoided.
It behaves like glucose but without easy access to mtG3Pdh. With the exclusion of fatty acids from neurons the only reduction in the CoQ couple other than complex I then comes from complex II, part of the TCA. There is no input from ETFdh or mtG3Pdh. Pure acetyl-CoA, driving mostly through complex I.
I agree. Brain metabolism is all about forward-flow ECT (sometimes called State 3 mitochondrial respiration), and Petro's comments are spot on. Again, I think this is just the brain's way of exploiting inevitably high lactate levels with high-flux glucose utilisation.
NOTE: We can see NAD+/NADH being heavily recycled in all of these reactions, I'll get back to that in the next section.
Regarding lactate accumulation, as Schurr (the author of the first cited study) notes:
Studies using hippocampal slices have clearly shown that any increase in tissue lactate levels due to activation by glutamate is hardly detectable, unless the transport of lactate is inhibited (Schurr et al, 1999).
Lactate transport inhibition, either from astrocytes or the extracellular space, into neurons should cause its accumulation either in the astrocytes themselves or extracellularly.
In addition, N-methyl-D-aspartate (NMDA), an analogue of glutamate not recognized by astrocytic glutamate transporters, while being able to excite neurons, could not mimic glutamate-induced accumulation of lactate in the presence of MCT inhibition (Schurr et al, 1999). This finding supports the premise of the ANLSH that most of the production of lactate during neural activation takes place in astrocytes.
....
It is reasonable to assume that any rise in lactate levels after activation indicates that the rate of lactate production exceeds its rate of utilization. Additionally, when lactate levels increase significantly, as in the case of an anaerobic period (Schurr et al, 1997a,b, 1999; Schurr and Rigor, 1998) or on continuous stimulation (Hu and Wilson, 1997), lactate does become the oxidative substrate of choice on reoxygenation or termination of stimulation.
I think this is a plausible explanation.
Sidenote: what you see in diseased brains is often the inability to relax -- it is running as fast as possible all the time, most likely generating a lot of lactate, with concurrent breakdown of lactate transport mechanisms. This leads to lactate accumulation, and is definitely bad.
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NAD+ and Niacinamide / Nicotiamide
The first question is: Does niaciamide get into the brain?
Yes:
- Niacinamide transport through the blood-brain barrier. - PubMed - NCBI
- The effects of nicotinamide on apoptosis and blood-brain barrier breakdown following traumatic brain injury. - PubMed - NCBI
... and it does generally good things.
I see the usual mechanics here, whereby Niacinamide keeps the NAD+ pool sufficiently high, which supports both Pyruvate and Lactate driven mitochondrial respiration (and if you believe in Lactate used in Brain mitochondria, this also prevents lactate accumulation).
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So yes, I view lactate as a plausible metabolic substrate in the Brain. It should still be avoided in tissue other than the brain.
Lactate accumulation is most likely always bad, but the brain is good at using lactate.
We're back to ensuring good metabolism as a driver of healthy function ...
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@haidut
I have a memory of you talking about selling allathiamine, but I'm not so certain about it or the details. Any new info on that front? I clearly need a form of thiamine that can get into my brain.
I am developing a topical thiamine supplement in DMSO. It won't be allithiamine but that does not matter as the supplement would work like IV thiamine, which is effective. The problem with regular thiamine is its absorption when ingested orally and that is where allithiamine excels. Once in the blood, they are both equivalent types of thiamine as far as the cells are concerned. The supplement may have some biotin as well, and some other carbonic anhydrase inhibitors to increase CO2 even more.
Would that version of thiamine be able to cross the BBB effectively? My understanding is that's a bit of an issue for oral thiamine, and why I was hopeful for an allithiamine product without all the nasty additives.
Regural thiamine Hcl is as administered to alcoholics in the hospital via IV does cross the BBB. Korsakoff psychosis is a brain phenomenon and since IV thiamine treats it this suggests it crosses the BBB. So, the issue is mostly about getting enough thiamine in the blood, which DMSO can do with specific salts of thiamine.
Regural thiamine Hcl is as administered to alcoholics in the hospital via IV does cross the BBB. Korsakoff psychosis is a brain phenomenon and since IV thiamine treats it this suggests it crosses the BBB. So, the issue is mostly about getting enough thiamine in the blood, which DMSO can do with specific salts of thiamine.
I'm interested! :)I can tell you in more details what I do nowadays if you'd like.
Excellent points!
Niacinamide is indeed one of the simplest ways to avoid lactate buildup in the brain and this may explain a great deal of its neuroprotection profile. There are other potentially useful methods. One of them is to also use some methylene blue, which will also reoxidize NADH back to NAD. However, I don't think methylene blue will resolve the issue with pyruvate buildup, it will just limit its conversion into lactate.
Another (and perhaps more beneficial) way to avoid the conversion of pyruvate to lactate is to dramatically speed up PDH function and use that extra pyruvate for the Krebs cycle. Providing the rate limiting co-factor thiamine as either IV thiamine Hcl or oral allithiamine/sulbuthiamine does the job very well and this is one of the reason oral allithiamine is used as therapy for alcohol psychosis (Korsakoff syndrome) characterized by excess brain lactate/pyruvate. It is also the reason why allithiamine is about to be added to the list of banned performance improving substances beyound a certain dose (~10mg/kg will probably be the cutoff).
Yet another alternative would be to supplement biotin, which is a rate-limiting co-factor for pyruvate carboxylase (PDC) and will convert the excess pyruvate to oxaloacetate and thus also lead to lowering of lactate. The recent study with progressive MS and high dose biotin found that biotin speeds up oxidative metabolism specifically in the brain. Since the progressiveness of MS is tightly correlated with brain lactate levels, this is good evidence that biotin lowers lactate in the brain.
I think lactate buildup is one of the situation where simply supplementing thyroid may not do much good as the excess pyruvate has to be metabolized and used and without proper function of PDH and PDC (which depend on co-factor availability) thyroid is of little use.
Just my 2c.
i agree with no explosion and no bounce at beginning of concentric movement, hence no damage to muscle fibers... but what if just doing concentric part? isnt that better?!I fear that if you go faster on the eccentric, you might end up using too much of a "bounce" on the next concentric rep, which could recruit tendons and ligaments more than muscle
Hi @TCapp04 and @haidut , you guys might want to look into the work of Doug McGuff in Body by Science. After many years of professional water polo and then many more years of Crossfit which, nedless to say, RUINED my health, I am now following his protocol. Long story short: it's a once a week workout, very slow movements, heavy but controlled and safe, no explosion. This prevents the formation of Lactic Acid, so the strength and size gains come from CNS (Central Nervous System) activation instead of Lactic acid accumulation and muscle fiber damage, the pathway through which bodybuilders build muscle.
I've been doing this for 6 months now, along with Peat's guidelines, and my recovery has been going well. Also, all the info that @haidut offers us is nothing short of life changing, so for that I THANK YOU very much my Bulgarian friend! I'd suggest you take a ook at the book, or if you prefer, I can give you some extra guidelines and that should do it. The one thing to take home on strength training is: less is more!