A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue 2024 Wadsworth et al

[In mice]

Abstract

Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.

eLife assessment
The work by Johnson and co-workers has identified an important role of 2-Hydroxybutyrate in skeletal muscle oxidative capacity in the early stages of exercise. Mechanistically, they show convincing data to support a role of 2-Hydroxybutyrate in the regulation of BCAA metabolism via SIRT4, ADP-Ribosylation, and CEBP. However, whether this is the sole mechanism and if these translate to longer exercise training regimes requires future experiments.

Open access, https://elifesciences.org/articles/92707#s4

 

2-hydroxybutyrate and cysteine were both elevated in Jason et al 2022's pre-illness data study in ME/CFS:

I don't recall seeing it in other metabolomics studies, but on the other hand the design of this one is quite unique.

 

And in the NIH Intramural study, Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

 

I think cysteine is lower there. There are some cysteine-ish molecules that are higher:

cysteine s-sulfate
cysteine-glutathione disulfide
cysteinylglycine

 

Thanks for posting @Andy. This possibly deserves some discussion as to what goes wrong between what is a normal muscle recovery post exercise and what is metabolic abnormality, particularly seeing it is also identified pre ME/CFS onset.

Elevated 2-Hydroxybutyrate (2HB) is usually a sign of pre-diabetes or insulin resistance or hyperinsulinemia. Within 2 years before my ME/CFS onset, I had to do a blood glucose test following an abnormal Hb1c test. My fasting blood glucose tested fine. Within a couple of months post ME/CFS onset, I experienced hyperglycemic events with sweetened food. I can only assume my 2HB was also elevated pre and post onset of ME/CFS.

In the study above I refer to "We show here that 2HB inhibits branched-chain aminotransferase enzymes...".

From the following study:
The mechanism of branched-chain amino acid transferases in different diseases: Research progress and future prospects
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9478667/

 

No difference visible in Hanson's four-timepoint metabolite study for 2-hydroxybutyrate, but a group difference for 2s-3r dihodroxybutyrate that kept increasing the more exercise the particpants did, until healthy control had more.


The above chart taken from my interactive webapp that gives access to the data from that Hanson study:
https://jasemurphy.shinyapps.io/Germainetal2022/

 

Here is the metabolic pathway for the production of 2HB: a byproduct of (excess) 2ketobutyrate (2KB) mediated by lactate dehydrogenase (LDH), the enzymes activity enhanced with high NADH/NAD+ ratio.

[Courtesy of the following link:
Which Role Plays 2-Hydroxybutyric Acid on Insulin Resistance?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703345/]

So, while this might explain (somewhat) why 2HB increases with insulin resistance in response to infection, but why does it increase post exercise, and is there a link between the two involved in PEM? There might be a link here to explain RED-S syndrome too?


I do observe some anomalies with respect to ME/CFS however, in that metabolic studies suggest ME/CFS patients are producing LESS pyruvate and furthermore, there is evidence of reduced lipid oxidation and reduced acetate levels, that more energy is being derived by amino acid catabolism. So how is the NADH/NAD+ ratio impacted by this...high production of NADH via the PPP I assume?

 

@forestglip was 2-hydroxybutyrate significant in that study? Is it possible to get the mann whitney p value for this? I wasn't clear in your post whether it was significant or simply alphabetically at the top of the list of the all metabolites with a positive fold change.

 

Oh, sure. Using wilcox.test(data[[column_name]] ~ data$Group, exact=TRUE):

2-hydroxybutyrate/2-hydroxyisobutyrate 0.8391037


I should make that list more clear what it is showing.