Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individua

[Valentijn]

But what i dont understand is, if the muscle cells genetically change to be "worse" than normal, why do the responders to Rituximab function at previous level again?

It should be the genetic expression which is changing, not the actual genes. Basically genes create enzymes, and something can happen to produce more or fewer of the enzymes, or to somehow cause the enzymes to become more or less effective.

So if something else in the body is causing the enzymes made by a gene to misbehave, things should go back to normal once that "something else" is fixed.

 

[Gijs]

A researcher on the norwegian CFS facebook group proposed that the muscle cells have adapted to autoimmunity, she thought the cellular changes probably arent short term, but the kind that lasts a while. So some sort of epigenetic adaptation. This is at least a view that could fit for those where their CFS is of autoimmune origin. I like it, was my first thought as well..

You can test this. Measure the findings from Julia Newton take muscle cells before and after using Rituximab. Still adaption make no sense to me because the cells were cultured in the lab before exercise.

 

[Marky90]

You can test this. Measure the findings from Julia Newton take muscle cells before and after using Rituximab. Still adaption make no sense to me because the cells were cultured in the lab before exercise.

Can i get a link to that study?
Well i think it still make sense if genetic expression can last long, even when the cause is gone. But im not really qualified to speculate on these matters..

 

[Sidereal]

Lacking the biochem background to fully understand this discussion, I'm wondering whether levels of pyruvate (in urine) as measured by Metametrix would be higher or lower than expected. What about levels of the other metabolites mentioned? Thanks. I surely appreciate you all for these analyses!

I would imagine pyruvate could be elevated though that may not be so if you're on a low carb diet or supplementing tons of biotin.

 

[aimossy]

Can i get a link to that study?
Well i think it still make sense if genetic expression can last long, even when the cause is gone. But im not really qualified to speculate on these matters..

The link to the paper was at the start of the thread, it is open access here:
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982

 

[Jonathan Edwards]

There are different subgroups that makes thinking about the puzzle so difficult. Some have autoimmunity others do have mitochondrial problems. We have different diseases even here on this forum. I really can't fit the puzzle with the findings of Julia Newton and rituximab, it doesn't make any sense to me.

I agree that the persistence of a muscle defect in culture does not seem to fit with an improvement after rituximab. As suggested by others, it might be different patient subgroups with different diseases.

 

[Bob]

It would be interesting if Julia Newton were to pick out the sample that is creating the most acid and utilising the least glucose (i.e. the most severely affected sample, for want of a better phrase) and have it tested for viruses. Perhaps comparing it to a healthy sample. I suppose all sorts of tests could potentially be carried out on these samples, e.g. epigenetics; proteomics; metabolomics etc.

 

[Marco]

It's anyone able to explain how lactate could possibly be a fuel for energy metabolism in the brain, if it's usually considered a waste product of energy metabolism? What am I missing?

Hi Bob

It's just a running blog but this might be useful :

LACTATE FUELS THE HUMAN BRAIN DURING EXERCISE

"Long ago it was thought that this lactate was responsible for causing muscle soreness, but this belief has not held up as our understanding of the process has increased, and in fact lactate is used by our muscles for fuel. One of the things known now to contribute to muscle soreness during exercise is an accumulation of H+ molecules from energy production, and lactate actually helps to stop this accumulation of H+. That we use lactate for fuel in our muscles is now rather well-understood, and having more and better mitochondria helps with using up the lactate."

https://evolvedrunning.wordpress.com/2014/05/21/lactate-fuels-the-human-brain-during-exercise/

(I'd like to see the science behind that excerpt!)

and this :

Human Brain Feeds On Lactate Not Glucose During Exercise

"The finding challenges a long held view that the brain is strictly a glucose fuel burner and that only the muscles switch to the lactate alternative. It also adds weight to the idea that lactate is not just a toxic byproduct of exercise, but a rich supplemental source of energy and that the body has sophisticated mechanisms for optimising where it gets energy from."

http://www.medicalnewstoday.com/articles/125590.php

This abstract is a fairly recent summary of this highly debated subject :

Brain lactate metabolism: the discoveries and the controversies.

"Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an 'opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain."

http://www.ncbi.nlm.nih.gov/pubmed/22186669

 

[Bob]

Thanks for that, Marco. A good bit of investigation there! So it seems that lactate may have various uses including recycling NAD+/NADH and possibly as a fuel supply when other sources are in short supply.

I think I could study this subject endlessly and still not understand metabolic pathways.

 

[MeSci]

Thanks for that, Marco. A good bit of investigation there! So it seems that lactose may have various uses including recycling NAD+/NADH and possibly as a fuel supply when other sources are in short supply.

I think I could study this subject endlessly and still not understand metabolic pathways.

Not lactose, @Bob - that is milk sugar!

I get confused over the interchangeable use of lactate and lactic acid. If my ME-fuddled brain serves me correctly, lactate is the oxidised form of lactic acid. If you see a chemical name ending '-ate' it will usually indicate the oxidised form of the equivalent '-ic acid', I think.

I would guess that lactate will be reduced to lactic acid in an acidic environment - where H+ ions are on the loose looking for oxygen to bind to - and lactic acid will be oxidised to lactate where...my brain has packed up now!

This 2008 paper with the same name as the blogpost cited by @Marco may throw some light on things (or may not), as may/not this page on lactic acidosis.

 

[MeSci]

This abstract is a fairly recent summary of this highly debated subject :

Brain lactate metabolism: the discoveries and the controversies.

"Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an 'opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain."

http://www.ncbi.nlm.nih.gov/pubmed/22186669

I like the look of that last abstract - full text available too. Will try to have a look at that when my own brain is working again. Or maybe save it for later.

 

[Bob]

Not lactose, @Bob - that is milk sugar!

Ooops!

I get confused over the interchangeable use of lactate and lactic acid. If my ME-fuddled brain serves me correctly, lactate is the oxidised form of lactic acid. If you see a chemical name ending '-ate' it will usually indicate the oxidised form of the equivalent '-ic acid', I think.

Yes, I wondered about that as well. I think I read that lactic acid becomes lactate when dissolved in water, so the terms are fairly interchangeable.

 

[wastwater]

I've never had any muscle problems

 

[MeSci]

I've never had any muscle problems

That's surprising to me. I thought that everyone with ME/SEID had muscle problems as a major component of their illness.

 

[wastwater]

I think I have an energy production problem,probably a metabolic dysfunction,that can sometimes be connected to autistic spectrum disorders but I feel it is very similar to the one seen in me/cfs guess it just doesn't effect my muscles but I do feel constantly eneryless,guess it effects my brain and overall stamina more with severe PEM

 

[Snow Leopard]

Is anyone able to explain how lactate could possibly be a fuel for energy metabolism in the brain, if it's usually considered a waste product of energy metabolism? What am I missing?

As it said in the article you quoted, it is a potential substrate to maintain metabolic cycles. Specifically, lactate can be oxidized to pyruvate and used as a substrate for the Krebs cycle.

 

[Bob]

AMPK = 5’-adenosine monophosphate-activated protein kinase.
ATP = Adenosine triphosphate
NADH/NAD = Nicotinamide adenine dinucleotide

I've just noticed what these all have in common: adenine.

"Adenosine (ADO) is a purinenucleoside composed of a molecule of adenine attached to a ribose sugar molecule (ribofuranose)moiety via a β-N9-glycosidic bond." (http://en.m.wikipedia.org/wiki/Adenosine)

Random brain storming again: Perhaps there could be an enzyme related to adenine or adenosine, that could be dysfunctional in ME/CFS patients?

Reading about adenosine, it seems to be related to energy, sleep and arousal, and blood flow to organs (via vasodilation). (Do those factors ring any bells?)

"Adenosine plays an important role in biochemical processes, such as energy transfer — as adenosine triphosphate (ATP) and adenosine diphosphate (ADP) — as well as in signal transduction as cyclic adenosine monophosphate (cAMP). It is also a neuromodulator, believed to play a role in promoting sleep and suppressing arousal. Adenosine also plays a role in regulation of blood flow to various organs through vasodilation.[1][2][3]" (http://en.m.wikipedia.org/wiki/Adenosine)

Edit: I'm sure I'm being over-simplistic. Adenine is used in many metabolic pathways.

Looking at the role cAMP (Cyclic adenosine monophosphate) plays in biological pathways, it's involved in incredibly complex systems that would suggest a multitude of health issues if there was a problem metabolising adenine.

 

[Bob]

I've just spotted another recent study that investigates AMPK, in relation to Fibromyalgia:
http://forums.phoenixrising.me/inde...endent-restoration-of-mito-dysfunction.37056/

 

[CFS_for_19_years]

Life Extension has a long article about AMPK, waaaaaaay more reading than I'd ever want to plow through, plus they have a product designed to activate AMPK, called AMPK Activator:

http://www.lef.org/Vitamins-Supplements/item01907/AMPK-Activator

I'm not going to shell out the bucks for this product, but if anyone feels adventurous (or rich), there's a money-back guarantee. The reviews are mixed and a lot of people seem to be taking it for weight loss.

Now, for the article which includes 106 references for AMPK research:

http://www.lifeextension.com/Magazine/2014/SS/AMPK/Page-01
AMPK
The Cellular Enzyme That Promotes Longevity And Reduces Fat Storage

In many ways, AMPK acts as a traffic cop, efficiently moving excess fat and sugar into our cells to be burned for energy. When we are young, AMPK keeps our metabolic functions running smoothly. Ideally, we are slim and disease-free. But as we age, AMPK signaling declines, which may quickly lead to an excess buildup of blood glucose and dangerous fat accumulation.7 This turns into a lethal combination for many aging humans.


With reduced AMPK signaling, a range of damaging conditions begins to take over a previously healthy body, often leading to an early death. These damaging conditions include:

• Increased belly fat,47,48
• Chronic inflammation,7,47,48
• Elevated blood sugar,47-50
• Insulin resistance,7,47-50
• High cholesterol and triglycerides,47,48
• Decreased numbers and function of mitochondria,7,47,48
• Increased accumulations of abnormal or damaged proteins in our cells that lead to neurodegeneration.7,51

 

[Bob]

As the authors point out, the lack of activation of AMPK during ‘exercise’ in muscle cells from ME/CFS points to a muscle abnormality at the level of AMPK (which is normally activated during muscle contraction) or in other regulatory enzymes further up the biochemical pathway, and they plan to investigate these as well using the experimental in vitro muscle system they have already developed.

http://www.meresearch.org.uk/news/muscle-cell-abnormalities/

Interesting & exciting: They're already using their "in vitro muscle system" to investigate for further abnormalities further up the AMPK biochemical pathways.