The AMPK-related findings seemed to be corroborated in other work by this group, in
2018 and
2020
I wouldn't say so, to be honest
Study 1) AMPK activity not found to be increased after exercise
Study 2) AMPK is activatable pharmacologically (one would expect this in the absence of concrete evidence of a defect)
Study 3) Differences in phenotypes when provisioned with different substrates. Messing with AMPK doesn't, to my eye (an eye that has performed enough seahorse assays over a decade to know how to do multi-day protocols, start to finish, with different tissues without referencing instructions) seem to do anything unique, mitochondrially, in the ME vs HC samples. The no treatment/treatment trends in the seahorse data look the same to me, just moved upwards with AMPK activation in both groups which you'd expect.
These are all pretty different angles.
Back to study 1, the phospho AMPK westerns have been done in only a small sample (7 controls 8 ME/CFS) and haven't been replicated. I don't see anything about technical replicates within the experiments here either, for even reliable assays you want to do things at least 3 times and westerns are notoriously variable and tricky. Given:
-the blot images (the uneven intensity in phospho band 4 in 2A for example is indicative that optimisation is needed, could be issues during either transfer or development. It's particularly notable because the increase in phospho AMPK at the previous time point disappears before this final time point band, and you can see in the band that what signal is there is thick and bright as with the previous but looks like it hasn't developed or transferred well because the rest of the lane is giving no signal)
-and the apparent lack of replicates (Again, I can't see any info about replicates) it doesn't look too compelling
For what it's worth we have done phospho ACC (a key AMPK substrate) assays in hundreds of cell lines across multiple tissues from pwME + HC and nothing clear has stood out from it iirc
If I had to give a comment on where we are at with current knowledge relating to a potential role of AMPK in ME/CFS I would say that we know very little. Main things sticking out in my memory from the literature where relevant differences were found:
1) Study 1 above where electrical pulse stimulated muscle cells in small cohort didn't show detectable AMPK activation (with all the caveats mentioned)
2) Consistency of reports of abnormal fatty acid usage by different ME/CFS immune cells suggests AMPK is involved, but as cause or consequence of something else is is unclear
3) The idea of a glucose metabolism bottleneck from this group's work and some other stuff, particularly Chris Armstrong's work, is an area to explore further
Basically we don't know much, yet. There could be something, but I am not convinced that we can see anything specific about AMPK itself based on current evidence. Maybe there's something in its downstream targets relating to fatty acid and glucose usage for making energy. That's the only sensible guess I can give. But as with anything relating to energy metabolism this is highly cell type specific, even down to different types of immune cells let alone different tissues. So it is also hard to generalise anything systemic here.
While I agree with JE's recent comments that musings are important (else I wouldn't be here) I think we really just need more data to say anything much about AMPK.
Also relating to the discussion of whether this got followed up or not, didn't this group run out funding? I remember hearing that some years ago, probably on here. Correct me if I am wrong. I know that Cara moved on to industry.
