PKM2 accelerated the progression of [CFS] via promoting the H4K12la/ NF-κB induced neuroinflammation and mitochondrial damage 2025 Feng et al

[In virally infected, exhausted and restrained mice.]

Abstract

This study aims to explore the effects and potential mechanisms of PKM2-mediated neuroinflammation leading to mitochondrial damage and its role in the progression of chronic fatigue syndrome (CFS). Bioinformatics methods were applied to predict and analyze PKM2 and downstream signaling factors. In vivo experiments were conducted with mice divided into four groups after different treatments: control group, model group, Model + PKM2-OE group, and Model + PKM2-KD group. Morris water maze and field tests were used to assess cognitive function, grip strength, and rotation tests to evaluate physical strength. HE and Nissl staining were used to observe cellular conditions in the CA1 region of the hippocampus. Immunohistochemistry was used to detect PKM2 levels in the CA1 region. Western blot was performed to assess protein expression, lactate assay kits measured serum and brain tissue lactate levels, and ELISA detected inflammatory factors in brain tissue.

Bioinformatics analysis showed that PKM2 could promote the expression of glycolytic factors, leading to H4K12la histone lactylation modification, which enhances the expression of inflammatory factors such as NF-κB, resulting in mitochondrial damage. Compared to the control group, the cognitive function of the model group significantly declined, while the cognitive function of the Model + PKM2-OE group improved. However, cognitive function worsened in the Model + PKM2-KD group compared to the model group.

The physical strength of the control group was normal, and no significant differences were observed in the model, Model + PKM2-OE, and Model + PKM2-KD groups. Cell quantity and arrangement in the control group were normal, while the model group showed fewer and disorganized cells.

The Model + PKM2-OE group showed further deterioration compared to the model group, whereas the Model + PKM2-KD group showed improvement. Compared to the control group, the model group had increased expression of PKM2, H4K12la, H4, IL-1β, and TNFα. Compared to the model group, these markers were even higher in the Model + PKM2-OE group, but significantly reduced in the Model + PKM2-KD group. Serum lactate levels increased in the model group compared to the control group, but there was no significant difference between the Model + PKM2-OE and Model + PKM2-KD groups. Brain tissue lactate levels increased in the model group, further elevated in the Model + PKM2-OE group, but decreased in the Model + PKM2-KD group.

PKM2 in hippocampal cells enhances glycolysis, lactate accumulation, and H4K12la/NF-κB-mediated neuroinflammation, leading to mitochondrial damage and accelerating the progression of chronic fatigue syndrome.

Open access

 

Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME), is a complex disorder primarily characterized by persistent fatigue that cannot be alleviated by rest. CFS affects millions of people worldwide. However, due to its unknown etiology and diverse symptom presentation, its diagnosis and treatment pose significant challenges. Patients often exhibit other symptoms, such as cognitive impairment, muscle pain, sleep disturbances, and autonomic dysfunction, which severely impact their daily lives and work capacity1.​

1 = https://www.s4me.info/threads/effec...es-in-patients-with-cfs-2022-xie-et-al.28899/

 

They have transfected mice with (human?) PKM2, plus overexpressor and knockout groups, and then made them to do exercise. How is that ME?

?

 

CFS is persistent fatigue so inducing persistent fatigue is CFS is a sort of logic I guess? They do seem to have invented a new way of torturing mice anyway.

While I’m very wary of their definitions of this being CFS let alone ME/CFS, trying to understand induced fatigue seems a fair enough and perhaps useful goal in of itself? They do seem to have taken a series of assumptions and are testing a ‘what if’ scenario for those assumptions, which again could be interesting*. Is that fair?

*Interesting assuming that is you skip the bits about them saying this is (ME/)CFS and that you’re not a mouse.

 

There may be a contradictory findings or wording in the paper. Something which was flagged in one of my LLM generated summaries I listen to and I think can be seen in the abstract. I need to check the paper to confirm though and can’t quite get my head around it atm but…

Here’s some quotes from the paper

 

So there are four groups

• control group
• model group with no genetic changes NC (Model)
• model group with the PK2 gene knocked down/with reduced expression (Model + PKM2-KD)
• model group with the PK2 gene over expressed (Model + PKM2-OE)

The title and hypothesis is “PKM2 accelerated the progression of chronic fatigue syndrome” but as far as I can tell the abstract and results imply over expressing PKM2 helped cognitive function while changes elicited no difference in physical function. Is that right? Or have I missed something?

There seem to be differences in lactate but does this mean anything given the above findings?

The other bit of the abstract I quoted may be a red herring as I think it’s referring to cells. I’m confused as to what the deterioration or improvement is here, maybe it’s poorly worded or maybe it’s because I’m not a biologist…

“Cell quantity and arrangement in the control group were normal, while the model group showed fewer and disorganized cells. The Model + PKM2-OE group showed further deterioration compared to the model group, whereas the Model + PKM2-KD group showed improvement. “

 

if we read this in good faith there might be nuance lost in translation. it's possible

to me this paper is telling us about the specific role of a particular protein in relation to particular outcomes, some of which may be relevant to ME as common symptoms, but ultimately may not recapitulate the whole clinical picture.