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

[Sidereal]

When Newton disclosed preliminary findings from this trial (that were reported in The Times newspaper several years back), she reported that ME/CFS muscle tissue exhibited abnormal lactic acid accumulation in response to simulated exercise. That outcome was consistent with the findings of her MRI study.

As far as I can see, this paper doesn't disclose what happened to lactic acid levels.

Can anyone explain? Have I missed something? Is this to be reported in a separate paper? Or might this omission suggest that they tested this, and didn't find abnormal lactic acid accumulation?

They didn't report lactate levels in this paper but they did measure lactate dehydrogenase (the enzyme that converts pyruvate to lactate and vice versa) and the levels were normal.

 

[nandixon]

It appears AMPK is widespread throughout different cells and various tissue in the human body, including the brain. So if there's a genetic or epigenetic problem either with AMPK or something that effects it, the problem may not necessarily be exclusively localized to muscle, to my understanding. That's just the particular tissue they were testing in this study.

 

[nandixon]

This study fits with a 2013 study that's the topic of this thread, CFS Discordant monozygotic twins show potential saliva markers (identical twins, both get a flu vaccine at age 31, one immediately develops ME/CFS while the other remains healthy; the study is looking for biomarker proteins by comparing their saliva):

Metabolism
Finally, we observed a down-regulation in CFS of ZAG [Zinc-alpha-2-glycoprotein; gene = AZGP1]... ZAG is mainly known as an adipokine responsible for lipid degradation that causes loss of adipose tissue in cancer cachexia. However, beyond this action, a role of ZAG in the activation of AMP kinase (AMPK), an important regulator of energy metabolism, in human skeletal muscle cells has emerged [56]. The mechanism may be involved in mediating the effects of ZAG in relation to increased energy utilization. This is interesting if we consider that several studies suggest an organic cause for CFS related to defects in oxidative metabolism. In particular, individuals with CFS reach exhaustion (in the presence of reduced sarcoplasmic ATP concentrations) much more rapidly in respect to healthy subjects with resultant acceleration of glycolysis in working skeletal muscles [57]. Moreover, one of the primary symptoms of CFS is muscle pain and weakness; this process is probably the result of cellular changes [57] such as reduction in the number of motor units and atrophy due to disuse. Considering that Russell and colleagues have demonstrated the ability of ZAG to reduce reactive oxygen species (ROS) production and to counter muscle atrophy associated with insulin resistance and other catabolic conditions [58], the decrease of ZAG that we found in WS [whole saliva] seems to support the hypothetical role of oxidative stress in CFS...

Potentially a very nice call by @Snow Leopard in that earlier thread with his post here singling out ZAG.

 

[adreno]

ALA and ALCAR might help:

Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle

Acetyl-l-carnitine inhibits TNF-alpha-induced insulin resistance via AMPK pathway in rat skeletal muscle cells

 

[Sidereal]

ALA and ALCAR might help:

Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle

Acetyl-l-carnitine inhibits TNF-alpha-induced insulin resistance via AMPK pathway in rat skeletal muscle cells

Berberine also: http://www.sciencedirect.com/science/article/pii/S2211383512000871

 

[Marco]

By "primary abnormality in the muscle" they mean the problem is peripheral (in the muscle) rather than central (in the brain). Since the early 1990s we've been fed psychobabbly hypotheses about central fatigue. The fact that muscle metabolism is abnormal in vitro would seem to cast serious doubt on such explanations.

It doesn't rule out a role for 'central fatigue' though even if the primary problem is peripheral. Muscle fatigue signalling by 'alarmins' via toll like receptors is likely to whack microglia. Otherwise it might be difficult to explain how peripheral muscle fatigue might exacerbate cognitive symptoms unless other cells inc brain share the same defect.

 

[Sidereal]

It doesn't rule out a role for 'central fatigue' though even if the primary problem is peripheral. Muscle fatigue signalling by 'alarmins' via toll like receptors is likely to whack microglia. Otherwise it might be difficult to explain how peripheral muscle fatigue might exacerbate cognitive symptoms unless other cells inc brain share the same defect.

Marco, by "central fatigue" they mean stress, mental illness, diminished motivation (secondary gain, malingering) etc., not the stuff you're talking about. The brain is involved obviously.

 

[Marco]

Marco, by "central fatigue" they mean stress, mental illness, diminished motivation (secondary gain, malingering) etc., not the stuff you're talking about. The brain is involved obviously.

That may well be what certain people mean but central fatigue is as legitimate a term as central (neuropathic) pain and doesn't imply any 'psychological' causation. Simply that fatigue or pain is centrally mediated.

 

[Sidereal]

From the discussion:

Recent studies suggest that graded exercise therapy (GET) has benefits for patients with CFS [38] although these benefits have been small. Frequently patients with CFS feel that exercise in fact makes their symptoms worse. Our recent MRS studies suggested that there were at least two muscle phenotypes grouped together through the entirely symptom based diagnostic classification of CFS. This might explain, in part, the limited benefits seen in the PACE trial for GET. We believe that the results of the current study further emphasise the potential for a peripheral component to CFS and the need to fully characterise the muscle phenotypes in CFS before generically prescribing exercise as an effective intervention. Further work is needed to understand the muscle biochemical abnormalities in CFS and the impact that exercise might have upon these.

 

[Sidereal]

That may well be what certain people mean but central fatigue is as legitimate a term as central (neuropathic) pain and doesn't imply any 'psychological' causation. Simply that fatigue or pain is centrally mediated.

Yes, but the way in which this term has been used in the CFS field was to imply "psychological" causation and prescribe antidepressants and exercise as therapy. The people doing that have also confidently asserted on many occasions that there is no muscle pathology in this illness.

Thankfully things are changing now and people are beginning to look for legitimate central mechanisms for fatigue/pain/malaise like microglial activation. (As an aside, my experience with microglial inhibitors like LDN and ibudilast has been that while they reduce sickness behaviour, they do virtually nothing for my muscle fatiguablity.)

 

[Marco]

It appears AMPK is widespread throughout different cells and various tissue in the human body, including the brain. So if there's a genetic or epigenetic problem either with AMPK or something that effects it, the problem may not necessarily be exclusively localized to muscle, to my understanding. That's just the particular tissue they were testing in this study.

Sorry @nandixon. I missed this when I commented on 'central/brain' involvement.

I wonder why they didn't also consider stochastic (autoimmunity) in addition to genetic/epigenetic.

Experimental autoimmune encephalitis (the MS animal model) may be one precedent (after a 2 minute Google search - there may be others) :

Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity.

http://www.ncbi.nlm.nih.gov/pubmed/19486896

Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis.

http://www.ncbi.nlm.nih.gov/pubmed/19494326

 

[Marco]

(As an aside, my experience with microglial inhibitors like LDN and ibudilast has been that while they reduce sickness behaviour, they do virtually nothing for my muscle fatiguablity.)

Probably deconditioning

 

[Sidereal]

Probably deconditioning

 

[Keela Too]

It's great to see work such as this producing results that have nothing to do with mere "perceptions", which can be so easily manipulated and misinterpreted.

Of course there is a possibility that some of the changes could be deconditioning ....

However, if I remember rightly NASA were asking for healthy people to voluntarily lie in bed for a year (?) as part of their studies... Getting a sample of their muscle tissues to test this way would be very interesting.

 

[nandixon]

I wonder why they didn't also consider stochastic (autoimmunity) in addition to genetic/epigenetic.

Yes, and there is endothelial AMPK that's important for generation of nitric oxide. So AMPK could potentially also be tied to the Norwegian work of possible autoimmunity with respect to an endothelial aspect.

 

[Simon]

I wrote about this research for AfME last year if you'd like more of a lay summary.
Action for M.E. | Research | Laboratory muscle gym

As far as I can see, this paper doesn't disclose what happened to lactic acid levels.

The team had reported elevated acid levels before (in my article) but these didn't make the paper, while the myogenin changes detailed in this paper [myogenin is a gene regulator that co-ordinates muscle development and repair] weren't in the orginal reports.

 

[Marco]

Yes, and there is endothelial AMPK that's important for generation of nitric oxide. So AMPK could potentially also be tied to the Norwegian work of possible autoimmunity with respect to an endothelial aspect.

Funny you should mention that :

Nitric oxide is a potential down-regulating molecule in autoimmune disease: inhibition of nitric oxide production renders PVG rats highly susceptible to EAE.

http://www.ncbi.nlm.nih.gov/pubmed/9688317

 

[WillowJ]

I am also wondering about this. If (relatively) less glucose is absorbed, then why is lactate higher? It seems a contradiction. So maybe it wasn't higher in this test bed. Which raises questions about how much this might reflect in vivo muscle metabolism, that is how it works in the body.

The lactic acid cycle runs off pyruvate, not glucose specifically. We can get pyruvate from other source(s?) like muscle catabolism. Though I'm not sure to what extent this muscle catabolism is happening in cases that are not severe or getting close to being severe. Doctors would notice. There are some patients who fit this very noticeably, but not everyone.

They didn't report lactate levels in this paper but they did measure lactate dehydrogenase (the enzyme that converts pyruvate to lactate and vice versa) and the levels were normal.

maybe there are different subgroups.

Otherwise it might be difficult to explain how peripheral muscle fatigue might exacerbate cognitive symptoms unless other cells inc brain share the same defect.

I have not studied brain metabolism particularly, but AMP kinase tends to show up everywhere. However I think there are many different sorts of such kinases.

 

[Sidereal]

The team had reported elevated acid levels before (in my article) but these didn't make the paper,

I wonder why. If I recall correctly, PLoS doesn't have a word limit.

Edit: Perhaps they're hoping to squeeze an extra publication out of lactate findings.

 

[WillowJ]

I have not studied brain metabolism particularly, but AMP kinase tends to show up everywhere. However I think there are many different sorts of such kinases.

ps, but I do like CNS inflammation theories like the microgilal stuff. It makes sense to me based on my experiences and history. But I always thought there was a cellular aspect, too.