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Pharmalogical activation of AMPK and glucose uptake in cultured skeletal muscle of ME/CFS patients

Demepivo

Dolores Abernathy
Messages
411
Brown AE1, Dibnah B1, Fisher E1, Newton JL1, Walker M2.
Author information

1 Institute of cellular medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom.

2 Institute of cellular medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom mark.walker@ncl.ac.uk.


Abstract

Background Skeletal muscle fatigue and post-exertional malaise are key symptoms of Myalgic Encephalomyelitis ( ME/CFS). We have previously shown that AMPK activation and glucose uptake are impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation, a method which induces contraction of muscle cells in vitro. The aim of this study was to assess if AMPK could be activated pharmacologically in ME/CFS.

Methods
Primary skeletal muscle cell cultures from patients with ME/CFS and healthy controls were treated with either metformin or 991. AMPK activation was assessed by Western blot and glucose uptake measured.

Results
Both metformin and 991 treatment significantly increased AMPK activation and glucose uptake in muscle cell cultures from both controls and ME/CFS. Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared to controls.

Conclusions
Pharmacological activation of AMPK can improve glucose uptake in muscle cell cultures from patients with ME/CFS. This suggests that the failure of electrical pulse stimulation to activate AMPK in these muscle cultures is due to a defect proximal to AMPK. Further work is required to delineate the defect and determine whether pharmacological activation of AMPK improves muscle function in patients with ME/CFS.
 
Last edited:

nanonug

Senior Member
Messages
1,709
Location
Virginia, USA
Together with DCA, I'm going to give high dose resveratrol a try to see what happens.

Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1

Abstract
The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health problem and novel therapeutic strategies are required to prevent and treat T2DM. It has been demonstrated that resveratrol (RSV) may prevent T2DM by targeting Sirtuin type 1 (SIRT1), indicating that SIRT1 may be a novel therapeutic target for T2DM prevention. In the present study, a T2DM rat model was established by administering a high fat diet and streptozotocin (STZ) injections. Measurements of blood glucose and insulin confirmed successful establishment of the T2DM model. RSV was used to treat rats with STZ-induced T2DM and the results indicated that RSV reversed the STZ-induced downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α, SIRT1 and forkhead box protein O 3a. Furthermore, RSV modulated the activity of superoxide dismutase and malondialdehyde, which are associated with oxidative stress. In vitro, cells from the insulinoma cell line clone 1E were pretreated with palmitic acid (PA) to simulate a high fat environment. The results of reverse transcription-quantitative polymerase chain reaction indicated that PA suppressed the expression of SIRT1 in a dose- and time-dependent manner. Furthermore, PA modulated the expression of mitochondrial biogenesis-associated, lipid metabolism-associated and β-cell-associated genes, whereas RSV treatment ameliorated the PA-induced changes in the expression of these genes via SIRT1. The results of the present study suggest that RSV participates in the prevention of T2DM by regulating the expression of mitochondrial genes associated with biogenesis, lipid metabolism and β-cells via SIRT1. The results of the current study provide an insight into the mechanisms by which SIRT1 inhibits T2DM and may be used as a basis for future studies.
 

Wishful

Senior Member
Messages
5,657
Location
Alberta
I can't get excited about it, because I don't seem to suffer from abnormal skeletal muscle fatigue. I do suffer from abnormal cognitive fatigue, particularly during PEM.

I did a quick search for AMPK and cuminaldehyde, since the latter blocks my PEM completely. The link: https://www.neurotalk.org/parkinson...yde-reduces-alpha-synuclein-fibrillation.html might be of interest. Also: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670705/ says: 'It is well recognized that α-syn may also perturb key cellular processes including mitochondrial activity, which may indirectly impinge on AMPK signaling.' I'm not up to following the details, but it's the first link between cuminaldehyde and ME/CFS that I've encountered. Maybe someone who can follow the biochemistry can see if it's a link worth considering.
 

AdamS

Senior Member
Messages
339
I can't get excited about it, because I don't seem to suffer from abnormal skeletal muscle fatigue. I do suffer from abnormal cognitive fatigue, particularly during PEM.

I happen to agree with you. I was really impressed by one of the other studies that Cara Tomas and Julia Newton did recently but this one seems a bit less interesting to me as a patient looking for answers, i'm obviously very grateful for Newton's work, I just wish we could move things on faster.

I still think that Dane B. Cook, Alan Light & co have given one of the best illustrations of the inner-workings of PEM that i've ever seen: https://www.sciencedirect.com/science/article/pii/S088915911730051X
 

Hip

Senior Member
Messages
17,801
According to this Life Extension article, the Chinese herb Gynostemma pentaphyllum (jiaogulan) and trans-tiliroside from rose hip powder increase AMPK activation.

The drug metformin also activates AMPK.

The articles says:
In youth, AMPK is more activated and helps protect against obesity and diabetes.

As we grow older, cellular AMPK activation decreases, weight gain often follows, and we are more likely to succumb to the destructive factors of aging.

AMPK Promotes Longevity And Reduces Fat Storage
  • The science of bioenergetics is producing paradigm-shifting discoveries, including the role of AMPK in regulating the ways our bodies use and transform energy.
  • AMPK is the “switch” that is the link between metabolic disease, inflammation, and longevity. This “switch” tells our cells when to store and generate energy-containing molecules such as fat, and when to “hunker down” and use existing energy stores.
  • When switched “on,” AMPK triggers the use of stored energy from fats, enhances removal of fats and sugar from the blood, increases production of mitochondria, and reduces inflammation and cellular “junk.”
  • Calorie restriction and vigorous exercise activate AMPK, shrinking body fat stores (especially in the belly region), lowering blood sugar and lipid levels, and producing other beneficial effects that retard the aging process.
  • The drug metformin also activates AMPK, with similar body-wide results.
  • A pair of natural botanical extracts have now been found to activate AMPK, reducing belly fat, cholesterol, blood sugar, and insulin levels.
  • Instead of combating longevity threats using multiple drugs, supplementation with AMPK-activating botanicals can address these problems at its source.
  • Age-induced risk factors can be tackled efficiently by boosting AMPK activity with Gynostemma pentaphyllum and trans-tiliroside from rose hips.
 

Murph

:)
Messages
1,794
I am quite excited by this line of research.

AMPK is potentially very much central to PEM. Think of AMPK as a switch that gets flicked on when you exercise, changing the way your body deals with energy (i.e. changing your metabolism).

Here's a little excerpt on what it does:

. During exercise, it is activated in skeletal muscle in humans,... by events that increase the AMP/ATP ratio. When activated AMPK stimulates energy generating processes such as glucose uptake and fatty acid oxidation and decreases energy consuming processes such as protein and lipid synthesis. Exercise is perhaps the most powerful physiological activator of AMPK.


There's a couple of things of note in there. One, a link with the Myhill work on a lack of ATP. Two, a link with Naviaux via changes in the AMP/ATP ratio. Three, an explanation for why we tend skinny - protein and lipid synthesis are low priorities when AMPK is stuck on.

This paper also indicates that AMPK is involved in immune responses:

Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.

It's interesting that people are reporting metformin is not helpful in real life. Perhaps the answer might not be as simple as stimulation. Possibly we have hyper-activated AMPK already (due to malfunctioning mitochondria producing too little atp?) and the body has desensitised to the triggers that turn it on. Solving that might be a two step involving reducing the triggers, re-sensitising the sensors, then managing ampk activation pro-actively.
 

M Paine

Senior Member
Messages
341
Location
Auckland, New Zealand
It sounded like from Chris Armstrong's OMF presentation, that longterm AMPK activation can drive bacterial overgrowth in the Colon because protein and fat does not end up processed correctly in the small intestine correctly, due to a lack of bile and enzymes driven by the AMPK switch.

The whole thing is a bit confusing to me right now, Chris's presentation made the case that AMPK may already be activated in patients suffering from CFS, in a long term way which could be driving gut disbiosys.

That could conceivably cause microglial activation via the vagus nerve (causing cognitive impairment). Chris didn't say that specifically, but any sort of overgrowth in the colon could cause some sort of pathology.

I would love to hear Chris Armstrong's view on this treatment strategy, or any other OMF representatives.
 

Murph

:)
Messages
1,794
It sounded like from Chris Armstrong's OMF presentation, that longterm AMPK activation can drive bacterial overgrowth in the Colon because protein and fat does not end up processed correctly in the small intestine correctly, due to a lack of bile and enzymes driven by the AMPK switch.

The whole thing is a bit confusing to me right now, Chris's presentation made the case that AMPK may already be activated in patients suffering from CFS, in a long term way which could be driving gut disbiosys, and subsequently microglial activation via the vagus nerve (causing cognitive impairment)

I would love to hear Chris Armstrong's view on this treatment strategy, or any other OMF representatives.

AMPK hyper-stimulation and desensitisation could be the bridge to bring these two theories together.

If the purinergic signalling theory is right, (and I refer anyone with a million kilotonnes of spare brain power to this thread), cells could be leaking ATP persistently. That leads to a bad AMP/ATP ratio. Too much AMP to ATP is precisely what turns on AMPK.
 

Murph

:)
Messages
1,794
This chart is from the paper and it shows that CFS patients have waaay lower ATP than controls, whether treated with these drugs or not.

Screen Shot 2018-04-17 at 12.34.40 PM.png

Figure 3 Cellular ATP content measured in control and CFS myotubes after treatment. A. 2mM metformin for 16h. B. 1μM 991 for 2h. White bar: untreated, black bar: treated. Data were normalised to untreated. *p<0.05, **p<0.01. n=7 control and 8 CFS assayed in duplicate.
 

nanonug

Senior Member
Messages
1,709
Location
Virginia, USA
It's interesting that people are reporting metformin is not helpful in real life.

Metformin appears to inhibit complex I of the mitochondrial electron transport chain. This results in reduced production of ATP and an increase in the AMP/ATP ratio. This increase leads to activation of AMPK. For people with SEID, who are already presumably in an ATP-deficient state, this mechanism of AMPK activation is quite costly.
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
I mentioned a few AMPK activator supplements in this post https://tipsforme.wordpress.com/2015/10/19/resource-walking-problems/#ampk

Substances which protect plants against infection seem to increase AMPK.

But I don’t claim to understand this area. I have mixed experiences from trying these supplements, though I didn’t record my experience in a systematic Quantified Self way.