Malic acid supplement, sumac

jnmaciuch said:
Yup, I think we're probably dealing with a very complex loop of feedback and compensatory mechanisms. It's entirely possible that a malate-aspartate shuttle impairment is caused by the cell trying to protect itself by shutting down mitochondrial function (though I can only make wild speculations on why that would occur). Or a million other things. That's largely why I'm more interested in understanding the biological mechanism.
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Could it therefore be dangerous to take malic acid do you think?
 
I'd like to make two little points that leave me keen to do structured testing on folk remedies.

1. The idea that "if it worked, we'd know by now" is probably not true for a range of useful treatments. Patients are so variable, approaches to testing common products are so variable (e.g. i misread the thing and used teaspoons not tablespoons) and reporting of effects is so variable.

A group of mixed responses in a forum like this creates the impression: "this probably doesn't work" whereas a treatment that provided a 20% boost to 30% of people would actually be pretty helpful to have.

2. When the theory is not present to explain why a treatment works, evidence gets downgraded. I always think about the banana diet, which existed for ages before coeliac disease was understood and kept a lot of people alive who would otherwise have died, but wasn't taken seriously or used widely (or even used properly, even its proponent thought kids needed to be on it for a year or two max). Is there a banana diet for mecfs out there somewhere, being used half-heartedly and looking ridiculous?!
 
Here's a paper for you @jnmaciuch! These guys find d-malate inhibits metabolism (in mice). This is one of those chirality things ... What's the mix of L and D malate in natural foods vs in supplements?

. 2024 Feb;25(2):524-543. doi: 10.1038/s44319-023-00028-y. Epub 2024 Jan 22.
Microbiota derived D-malate inhibits skeletal muscle growth and angiogenesis during aging via acetylation of Cyclin A
Penglin Li 1 , Jinlong Feng 1 , Hongfeng Jiang 1 , Xiaohua Feng 1 , Jinping Yang 1 , Yexian Yuan 1 , Zewei Ma 1 , Guli Xu 1 , Chang Xu 1 , Canjun Zhu 1 , Songbo Wang 1 , Ping Gao 1 , Gang Shu 2 3 4 , Qingyan Jiang 5 6 7
Affiliations
Abstract
Metabolites derived from the intestinal microbiota play an important role in maintaining skeletal muscle growth, function, and metabolism. Here, we found that D-malate (DMA) is produced by mouse intestinal microorganisms and its levels increase during aging. Moreover, we observed that dietary supplementation of 2% DMA inhibits metabolism in mice, resulting in reduced muscle mass, strength, and the number of blood vessels, as well as the skeletal muscle fiber type I/IIb ratio. In vitro assays demonstrate that DMA decreases the proliferation of vascular endothelial cells and suppresses the formation of blood vessels. In vivo, we further demonstrated that boosting angiogenesis by muscular VEGFB injection rescues the inhibitory effects of D-malate on muscle mass and fiber area. By transcriptomics analysis, we identified that the mechanism underlying the effects of DMA depends on the elevated intracellular acetyl-CoA content and increased Cyclin A acetylation rather than redox balance. This study reveals a novel mechanism by which gut microbes impair muscle angiogenesis and may provide a therapeutic target for skeletal muscle dysfunction in cancer or aging.
 
Daisymay said:
Could it therefore be dangerous to take malic acid do you think?
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Honestly we're very far outside the range of what has been studied, so I can only speculate. It could be equally likely that the malate-aspartate shuttle is shut down by a stressor (it's known that COVID can inhibit the oxidative arm of the TCA cycle, for example) and just isn't recovered in people with ME/CFS because of some genetic anomaly that otherwise would never cause a noticeable effect. My main point was just that it's a complicated system and cellular stress responses can sometimes be a black box before a lot of concerted effort is put into researching them.

Though since multiple pwME have reported taking magnesium malate and tolerating it well, there doesn't seem to be much existing evidence towards it being particularly dangerous.
 
Murph said:
Here's a paper for you @jnmaciuch! These guys find d-malate inhibits metabolism (in mice). This is one of those chirality things ... What's the mix of L and D malate in natural foods vs in supplements?

. 2024 Feb;25(2):524-543. doi: 10.1038/s44319-023-00028-y. Epub 2024 Jan 22.
Microbiota derived D-malate inhibits skeletal muscle growth and angiogenesis during aging via acetylation of Cyclin A
Penglin Li 1 , Jinlong Feng 1 , Hongfeng Jiang 1 , Xiaohua Feng 1 , Jinping Yang 1 , Yexian Yuan 1 , Zewei Ma 1 , Guli Xu 1 , Chang Xu 1 , Canjun Zhu 1 , Songbo Wang 1 , Ping Gao 1 , Gang Shu 2 3 4 , Qingyan Jiang 5 6 7
Affiliations
Abstract
Metabolites derived from the intestinal microbiota play an important role in maintaining skeletal muscle growth, function, and metabolism. Here, we found that D-malate (DMA) is produced by mouse intestinal microorganisms and its levels increase during aging. Moreover, we observed that dietary supplementation of 2% DMA inhibits metabolism in mice, resulting in reduced muscle mass, strength, and the number of blood vessels, as well as the skeletal muscle fiber type I/IIb ratio. In vitro assays demonstrate that DMA decreases the proliferation of vascular endothelial cells and suppresses the formation of blood vessels. In vivo, we further demonstrated that boosting angiogenesis by muscular VEGFB injection rescues the inhibitory effects of D-malate on muscle mass and fiber area. By transcriptomics analysis, we identified that the mechanism underlying the effects of DMA depends on the elevated intracellular acetyl-CoA content and increased Cyclin A acetylation rather than redox balance. This study reveals a novel mechanism by which gut microbes impair muscle angiogenesis and may provide a therapeutic target for skeletal muscle dysfunction in cancer or aging.
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Thanks for the link, and good question! The wikipedia page states that only L-malic acid is found naturally in foods but I wasn't able to find where in the references that claim was coming from...either way, in the chemical composition studies I've browsed quickly, it seems like L-malic acid is the dominant type listed
 
MeSci said:
One problem that I think pwME have when trying supplements is that they sometimes work well for, say, a couple of years, and then stop working.
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That happened to me with L-glutamine. It worked well in calming stomach problems for quite a while (I can't remember how long exactly), then I started getting very severe and very painful stomach cramps. When I stopped the L-glutamine those problems went away.
 
Turtle said:
@jnmaciuch
Can I try sumac when I also have diabetes?
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I don't think there's enough information to predict exactly how it would affect you with any confidence. I experienced the need to eat frequently on the full supplement dosage so it seems like it might affect blood sugar, but I don't have diabetes. At this point it's a "try at your own risk" type of thing
 
I am probably over cautious about trying anything new. I guess with supplements they could be initially tried in small quantities. Given sumac is an increasingly common flavouring it should be OK for most, though with ME it can be that all bets are off.

It is great @jnmaciuch, that you are investigating this option and I hope you get funding to progress this investigation.

But also the forum rule not to give ‘medical advice’ is important, so if anyone has any concerns about the safety of any supplements ideally they should discuss it with their own physician first.
 
jnmaciuch said:
I don't think there's enough information to predict exactly how it would affect you with any confidence. I experienced the need to eat frequently on the full supplement dosage so it seems like it might affect blood sugar, but I don't have diabetes. At this point it's a "try at your own risk" type of thing
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Have you studied it enough then to ask people to try it. Try at your own risk does not sound professional to me.
 
Turtle said:
Have you studied it enough then to ask people to try it. Try at your own risk does not sound professional to me.
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People post on forums like these all the time sharing their experiences about supplements or treatments that have not been explicitly and rigorously studied in the context of ME/CFS. Every person who reads a post about, say, L-glutamine and decides to try it themselves is doing it at their own risk. I was just asking for people to share their experiences with it if they made the decision to try it themselves, and shared full disclosure of my experiences, background, and the scope of available knowledge on the subject.

I wish I had the resources to run a full trial examining tolerability across different comorbidities--and if I had that, I wouldn't need to ask folks on a forum for their experiences.
 
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The wikipedia page states that only L-malic acid is found naturally in foods but I wasn't able to find where in the references that claim was coming from.
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When I used to have a question like this, I'd look it up in the Merck Index or Ullmann's Encyclopaedia, one of which would always have the most salient references. My old copy of Merck has L-malic acid as the naturally occurring form:

malic2.jpg
 
I had a mild headache until about lunchtime so didn't take any sumac (1 tsp again) until 1310. ( I have had a mild headache a few times recently.) Have a bit more energy but my eyes are rather foggy.

I do seem to be getting more thirsty than usual, so maybe low blood sugar? (I've got a glucose monitor but am too fuzzy to be able to use it at the moment!)
 
MeSci said:
I do seem to be getting more thirsty than usual, so maybe low blood sugar? (I've got a glucose monitor but am too fuzzy to be able to use it at the moment!)
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Thanks so much for sharing your data! I didn't realize until you mentioned, but I think I did find myself drinking more water on the malic acid supplement. It seems to scale with the dosage--I'm drinking maybe a little bit more than usual now that I've titrated down to 1/3-1/2 of the supplement at a time.
 
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Murph said:
Here's a paper for you @jnmaciuch! These guys find d-malate inhibits metabolism (in mice). This is one of those chirality things ... What's the mix of L and D malate in natural foods vs in supplements?
Click to expand...

Just an update on this: I asked the supplement producers about the composition of their malic acid supplement and they finally responded that it is 50%-50% D and L-malic acid. As far as I can tell, I don't seem to be experiencing any of the effects re: blood flow or muscle tone (I've been taking it for a few weeks now) described in that article, so it might be something that is: specific to mice, counteracted by having both L and D-malic acid, dosage-dependent, or perhaps these effects are dependent on having a functional TCA cycle in the first place.

It seems like DL-malic acid is commonly used as a food preservative, and there don't seem to be any formal complaints about negative effects from this supplement that I could find.
 
Additional updates from my experience:

I occasionally have to walk 10-15 minutes to get to the train station. Normally I can manage it on my stimulant but I end up out of breath and exhausted by the end of it. A few days ago was the first time I had to make the trip since starting the supplement and I noticed that there was no shortness of breath whatsoever! I felt like I could have walked farther if I needed to.

I also sometimes have some wine with dinner on special occasions and since I got sick, 1 glass of wine is enough to really feel drunk and very fatigued (I only do this on a very good day). Yesterday I was able to have nearly 3 glasses of wine across a 2 hour period. I felt like my normal alcohol tolerance returned--just a pleasant tipsyness without the sleepiness.
 
If you're taking a psychostimulant, have you considered that the different supplements & foods may be affecting the pharmacokinetics/metabolism of the stimulant? Amphetamines have been known for decades to be sensitive to urinary pH, for instance, and there are a variety of foods & supplement ingredients that inhibit or induce various CYP isoforms, such as the well-known example of the furanocoumarins in grapefruit juice inhibiting CYP3A4. I haven't looked at the effects of these specific foods & supplements specifically & not sure which stimulants, but something to consider?
 
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Nightsong said:
If you're taking a psychostimulant, have you considered that the different supplements & foods may be affecting the pharmacokinetics/metabolism of the stimulant? Amphetamines have been known for decades to be sensitive to urinary pH, for instance, and there are a variety of foods & supplement ingredients that inhibit or induce various CYP isoforms, such as the well-known example of the furanocoumarins in grapefruit juice inhibiting CYP3A4. I haven't looked at the effects of these specific foods & supplements specifically & not sure which stimulants, but something to consider?
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It's a possibility. Anything that affects norepinephrine is also going to influence rates of glycolysis, which in addition to the things you listed, would be a very direct confounding factor.

I have one piece of evidence to the contrary: the friend I mentioned who also experienced a huge boost from the sumac does not take any stimulants, so I don't think the effect of the malic acid is dependent on the stimulant--though it could still cause some differences in our experience.
 
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