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

[RYO]

I don't know about the rest of you, but my muscles, even/especially when I have been relatively unwell, seem to exercise themselves through involuntary contraction, e.g. fasciculations (twitches), occasional cramps, myoclonus, restless legs, etc.

I don't know whether it is due to cholinergic dysfunction. I suspected early in my then-undiagnosed illness that I had organophosphate poisoning, which involves inhibition of acetylcholinesterase, which increases levels of acetylcholine and thus increased/excessive muscle contraction.

I guess we could be looking at subgroups again, and/or differences due to severity levels?

Muscle fatigue and fasciculations have been major feature of my illness especially hip girdle and quadriceps. I think this study raises good questions. As mentioned in another thread, I had muscle ultrasound performed that indirectly measure glycogen levels. It was only 10 % of normal at rest.

A study using muscle ultrasound on CFS\ME patients with predominant muscle symptoms would be interesting compared to healthy controls.

Certainly less invasive having endured a muscle biopsy.

Hopefully, additional studies in the future may explain muscle metabolic defect.

 

[bertiedog]

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?

Mine was normal on my MAP last year.

Pam

 

[Jonathan Edwards]

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.

Actually lactate and lactic acid are effectively the same thing in the context of body physiology. Lactic acid is hydrogen lactate CH3CHOHCOOH which at pH 7ish will be partly dissociated to H+ and (lactate)CH3CHOHCOO- ions. There will be sodium ions around as well and in solution the lactate ions (CH3CHOHCOO-) do not actually belong to either the hydrogen or the sodium. When solid lactic acid dissolves the release of lactate ions does not involve a redox change - just ionisation.

 

[cmt12]

So now we are getting findings of abnormalities of an enzyme present in muscle contractions, sort of like the findings you would expect from the muscle contractions of an activated freeze response.

The question is what would we expect the implications to be if this mechanism were stuck? Muscle problems, fatigue, cognitive difficulties/brain fog, HPA axis disfunction, immune system weaknesses, anxiety, depression?

 

[globalpilot]

I haven't read through the thread so this may have been posted already.
I read this summary http://www.wellnessresources.com/he...d_in_chronic_fatigue_syndrome_and_fibromyalg/ and not the entire paper referenced earlier.

In it they mention some treatments including CoQ10 of 300mg/day, reservatol (unspecified dose), grapeseed extract (unspecified dose), quercitin (2000mg/day). Haven't many of use with CFS tried similar ? I know I have without clear benefit. I'd have to go check on my doses to be sure as it could be an issue of dosage.

In any case very interesting finding.

 

[melihtas]

I haven't read through the thread so this may have been posted already.
I read this summary http://www.wellnessresources.com/he...d_in_chronic_fatigue_syndrome_and_fibromyalg/ and not the entire paper referenced earlier.

In it they mention some treatments including CoQ10 of 300mg/day, reservatol (unspecified dose), grapeseed extract (unspecified dose), quercitin (2000mg/day). Haven't many of use with CFS tried similar ? I know I have without clear benefit. I'd have to go check on my doses to be sure as it could be an issue of dosage.

In any case very interesting finding.

From the article:

Consider adding in two minutes of vigorous exercise periodically throughout the day which helps turn on AMPK with any of these nutrients to optimize its effect. Even for those who are severely ill with CFS and FM and struggling with exertion intolerance, doing some type of physical activity as vigorously as they can for 30 seconds up to 2 minutes helps to prime and activate AMPK. Vigorous activity may mean 30 seconds of jumping jacks, standing push-ups against the wall, or partial knee bends. It just means doing something as vigorously as you can for very brief period of time to engage the body within your energy envelope.

Why cannot they understand AMPK activation by vigorous exercise works for healthy people and improves their health further but that process is broken for people with ME/SEID? It is unbelievable that they still keep recommending exercise.

 

[wastwater]

Im sure I saw this was related to FOX gene family,im likely to have a problem there.

 

[Dr.Patient]

Diabetes. 2002 Jul;51(7):2074-81.
Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes.
Musi N1, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ.
Author information
Abstract
Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.
http://www.ncbi.nlm.nih.gov/pubmed/12086935

So, does this mean that metformin may be beneficial? Is anybody or has anybody been on metformin , and seen a difference?

 

[*GG*]

Metformin is often touted for a cfew reasons in Life Extension magazine, they are very pro-supplement, so rare/odd for them to talk up drugs!

http://www.lifeextension.com/magazi...veryone-should-ask-their-doctor-about/page-02

http://www.lifeextension.com/search...ncy&f:@fhierarchicalcategory22137=[magazines]

GG

 

[Sasha]

Summary from #MEAction:

UK’s National Health Service collaboration between university and hospitals will hopefully trial drugs for muscle abnormality

Patients in the United Kingdom’s north east could benefit from research put into action.

Professor Julia Newton, Clinical Professor of Ageing and Medicine at Newcastle University, who also works within Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, led a team who found an abnormality of a protein which could lead to the development of new drugs and treatments.

Researchers have found for the first time that patients with the condition have a defect in a molecule associated with the production of a protein known as AMP kinase (AMPK).

“Our study focused on whether there were any biochemical changes so that we can start to understand what happens in the muscle with fatigue,” Professor Newton said. The study looked at 20 Fukuda-definition patients and 20 controls.

“What we have been able to identify is that production of AMPK is impaired in patients with CFS compared to those without. This is an important finding because there are drugs that are currently already available that we know will modify this abnormality. The next step is to carry out experiments to see whether or not we can reverse changes in AMPK with drugs that might ultimately form the basis of clinical trials…this is an exciting step towards that holy grail of trialling medicinal products,” Professor Newton said.

The new partnership brings together Newcastle Hospitals and Northumberland, Tyne and Wear NHS Foundation Trusts with Newcastle University, the newly-formed ‘Newcastle Academic Health Partners’ will deliver healthcare through collaborative scientific research, education and patient care.

“A real strength in the North East is that the University and hospital trusts work closely together, pulling on each other’s academic and clinical strengths so that we can be sure our work is of the very highest quality to help patients,” added Professor Newton.

Click here for more information on the partnership.

Note that these are Fukuda patients, not CCC.

A comment on the thread (not from me - another Sasha!) says:

The NHS information didn’t mention which drugs can correct this abnormality but this paper made about AMPK makes interesting reading, mentioning drugs and natural plant products which activate AMPK:
http://diabetes.diabetesjournals.org/content/62/7/2164.full

 

[Sasha]

Here's an existing thread:

http://forums.phoenixrising.me/inde...d-skeletal-muscle-cells-from-individua.36688/

My bad - I see that thread started in April, though. I wonder why #MEA have it as a news story? It popped into my email this morning. Anyway, any further discussion should be on the original thread.

 

[aimossy]

@Sasha maybe it is new about the partnership and actual research going to happen regarding the findings and possible drugs being looked into. I wonder if anyone has heard if more funding is going Julia Newtons way regarding this area of research. I didn't see anything on the videos from CMRC about it.

 

[Sasha]

@Sasha maybe it is new about the partnership and actual research going to happen regarding the findings and possible drugs being looked into. I wonder if anyone has heard if more funding is going Julia Newtons way regarding this area of research. I didn't see anything on the videos from CMRC about it.

That's maybe a question to post on the CMRC thread - I listened to the broadcast but couldn't hear much. Maybe an attendee will respond.

 

[wastwater]

FOXO1 is this mentioned in Griffith and Julia newtons work

 

[Snow Leopard]

FOXO1 is this mentioned in Griffith and Julia newtons work

Not specifically no. (nor FOXO3 which I was more interested in)

 

[aimossy]

This paper is finally being followed up - via ME Research UK
'Investigating abnormalities in AMPK activation'
http://www.meresearch.org.uk/our-re...vestigating-abnormalities-in-ampk-activation/

"Prof. David Jones and Prof. Julia Newton went on to look more closely at the function of muscle cells. To achieve this, they took muscle cell biopsies from ME/CFS patients, and cultured them to provide sufficient numbers of cells to examine in standardised laboratory conditions without the influence of other complicating factors.
A series of electrical pulses was applied to these cultured muscle cells to simulate the muscle contraction that occurs during exercise, and the researchers found two defects in their function.

Activation of AMP-activated protein kinase (AMPK) and glucose uptake were both impaired; AMPK has an important role in regulating energy in the cell and is normally activated during muscle contraction, while glucose is an important energy source.

Although AMPK was not activated by simulated muscle contraction in these cells from ME/CFS patients, later experiments showed that it could be activated by treatment with metformin, a drug known to have this effect in healthy cells. This raises the possibility of whether a treatment such as this could improve muscle function in patients.

Following on from these fascinating results, ME Research UK has awarded further funding for Dr Audrey Brown and Prof. Newton to continue investigating these abnormalities in AMPK activation.

Their new project will use specific AMPK activators (used in the treatment of other diseases such as diabetes) to explore the mechanism through which AMPK is activated pharmacologically, but is not activated by muscle contraction. The researchers will also examine the function of the mitochondria (the powerhouses of the cell) in ME/CFS patients and healthy control subjects."