What Happens To FFA While Taking Mildronate/Meldonium?

maillol

Member
Joined
Oct 28, 2019
Messages
388
Mildronate reduces carnitine levels thereby inhibiting fatty acid oxidation.

What happens to free fatty acids if they can't be oxidised?
 
Joined
Nov 21, 2015
Messages
10,501
They are not secreted or burned. The body cells switch largely to sugar burning and ffa is not released much.
 

SB4

Member
Joined
Sep 25, 2016
Messages
288
On wikipedia it says that because mildronate stops LCFA from entering the mito via carnitine inhibition that the burden of burning fats is shifted to the peroxidomes. It is my understanding that the peroxisomes shorten ffa to 8 carbons so that they can enter mito without carnitine shuttle.

So is the benefit from mildronate actually via feeding the mito a higher proportion of SCFA over LCFA instead of via increasing glucose?

"In the mitochondria, the effects of the carnitine shuttle are reduced by meldonium, which competitively inhibits the SLC22A5 transporter. This results in reduced transportation and metabolism of long-chain fatty acids in the mitochondria (this burden is shifted more to peroxisomes). The final effect is a decreased risk of mitochondrial injury from fatty acid oxidation and a reduction of the production of acylcarnitines, which has been implicated in the development of insulin resistance."
 

LeeLemonoil

Member
Joined
Sep 24, 2016
Messages
4,265
@SB4

Maybe both. More SCFA relative to LCFA should in and case also give mitos more time for metabolizing sugar
 
OP
maillol

maillol

Member
Joined
Oct 28, 2019
Messages
388
On wikipedia it says that because mildronate stops LCFA from entering the mito via carnitine inhibition that the burden of burning fats is shifted to the peroxidomes. It is my understanding that the peroxisomes shorten ffa to 8 carbons so that they can enter mito without carnitine shuttle.

So is the benefit from mildronate actually via feeding the mito a higher proportion of SCFA over LCFA instead of via increasing glucose?

"In the mitochondria, the effects of the carnitine shuttle are reduced by meldonium, which competitively inhibits the SLC22A5 transporter. This results in reduced transportation and metabolism of long-chain fatty acids in the mitochondria (this burden is shifted more to peroxisomes). The final effect is a decreased risk of mitochondrial injury from fatty acid oxidation and a reduction of the production of acylcarnitines, which has been implicated in the development of insulin resistance."
Good find.
 
OP
maillol

maillol

Member
Joined
Oct 28, 2019
Messages
388
I found this from a company that sells carnitine so not a particularly unbiased source, but is there any validity to this and therefore a risk with Mildronate?

https://geronova.com/wp-content/uploads/2013/05/Asthmaandcarnitine.pdf

"Carnitine is an antioxidant which is used in asthma due to the increased oxidant stress in asthmatic children. Carnitine deficiency leads to toxic accumulation of long chain fatty acids in the cytoplasm and of acyl CoA in the mitochondria. The accumulated saturated and monounsaturated fats may have different effects on airway inflammation. "
 
OP
maillol

maillol

Member
Joined
Oct 28, 2019
Messages
388
I found this from a company that sells carnitine so not a particularly unbiased source, but is there any validity to this and therefore a risk with Mildronate?

https://geronova.com/wp-content/uploads/2013/05/Asthmaandcarnitine.pdf

"Carnitine is an antioxidant which is used in asthma due to the increased oxidant stress in asthmatic children. Carnitine deficiency leads to toxic accumulation of long chain fatty acids in the cytoplasm and of acyl CoA in the mitochondria. The accumulated saturated and monounsaturated fats may have different effects on airway inflammation. "

@Hans thought you might have some knowledge on this.
 

Hans

Member
Forum Supporter
Joined
Aug 24, 2017
Messages
5,856
@Hans thought you might have some knowledge on this.
Serotonin is one of the main drivers of asthma, not a carnitine deficiency. Very few people actually have too little carnitine, they just have dysfunctional energy metabolism in general.
But a certain amount of carnitine is necessary. We produce it endogenously and it's found in animal sources. But I won't go supplement it right off the bat, but rather fix energy metabolism in general.
 
OP
maillol

maillol

Member
Joined
Oct 28, 2019
Messages
388
Serotonin is one of the main drivers of asthma, not a carnitine deficiency. Very few people actually have too little carnitine, they just have dysfunctional energy metabolism in general.
But a certain amount of carnitine is necessary. We produce it endogenously and it's found in animal sources. But I won't go supplement it right off the bat, but rather fix energy metabolism in general.
That was my thinking too. So you don't think there is a risk of reducing carnitine too much with mildronate?
 

Hans

Member
Forum Supporter
Joined
Aug 24, 2017
Messages
5,856
That was my thinking too. So you don't think there is a risk of reducing carnitine too much with mildronate?
I have not read any reports about that no.
Interesting, mildronate can be therapeutic for asthma [Therapeutic efficacy of mildronate in pulmonary diseases]. - PubMed - NCBI
Also:
A fatty acid analogue targeting mitochondria exerts a plasma triacylglycerol lowering effect in rats with impaired carnitine biosynthesis
"The increase in mitochondrial fatty acid oxidation (in mildronate treated rats) was observed despite low plasma carnitine levels, and was linked to strongly induced gene expression of carnitine acetyltransferase, translocase and carnitine transporter, suggesting an efficient carnitine turnover."
 
OP
maillol

maillol

Member
Joined
Oct 28, 2019
Messages
388
I have not read any reports about that no.
Interesting, mildronate can be therapeutic for asthma [Therapeutic efficacy of mildronate in pulmonary diseases]. - PubMed - NCBI
Also:
A fatty acid analogue targeting mitochondria exerts a plasma triacylglycerol lowering effect in rats with impaired carnitine biosynthesis
"The increase in mitochondrial fatty acid oxidation (in mildronate treated rats) was observed despite low plasma carnitine levels, and was linked to strongly induced gene expression of carnitine acetyltransferase, translocase and carnitine transporter, suggesting an efficient carnitine turnover."

Yes I've seen that. That's the main source of my interest in it. I think the reason behind that would be the inhibition of fat oxidation improving metabolism and therefore reducing serotonin like you said.
 
OP
maillol

maillol

Member
Joined
Oct 28, 2019
Messages
388
https://www.google.com/url?sa=t&sou...FjARegQICRAB&usg=AOvVaw170JeLQPmlsX2zUfcfInQA
........read this, it contains info about compensatory mechanism.
Brilliant. Good find. Here are some highlights if other people are interested.

"Interestingly, although the drug causes increase of fatty acids in animals with normal lipid metabolism, it appeared to be capable to normalize plasma lipids in rats with hyperlipidemia "

"Mildronate treatment is followed by compensatory increase of expression in the myocardium of several genes encoding the enzymes of the lipid metabolism – lipoprotein lipase, fatty acid translocase, carnitine palmitoyltransferase I and enzymes of triacylglycerol synthesis "

"Tsoko et al. [67] reported compensatory increases of acyl-CoA synthetase and carnitine palmotoyltransferase I in liver mitochondria and increase of peroxysomal fatty acid oxidation."

"the drug appears to be efficient in 86.9% cases of acute cochleovestibular dysfunction and in 75.0% of cases of chronic disease. "

"It was shown that when administered to rats the drug caused a decrease of carnitine and long chain acylacarnitine in the myocardium, oxidation of 14C-palmitate was also decreased [63]. The effect was reproduced in animals maintained on a fat-rich diet, in the isoproterenol heart failure model [8]" I looked this study up. In these rats an "accumulation of fatty acids in the myocardium were noted". That doesn't sound good. I think it's fair to say that a low fat diet should be followed while taking mildronate. I imagine it's also probably a bad idea if you have a lot of body fat that might be constantly releasing into the bloodstream. Or maybe block it with niacinamide.
 
Last edited:

Broken man

Member
Joined
Sep 11, 2016
Messages
1,693
Brilliant. Good find. Here are some highlights if other people are interested.

"Interestingly, although the drug causes increase of fatty acids in animals with normal lipid metabolism, it appeared to be capable to normalize plasma lipids in rats with hyperlipidemia "

"Mildronate treatment is followed by compensatory increase of expression in the myocardium of several genes encoding the enzymes of the lipid metabolism – lipoprotein lipase, fatty acid translocase, carnitine palmitoyltransferase I and enzymes of triacylglycerol synthesis "

"Tsoko et al. [67] reported compensatory increases of acyl-CoA synthetase and carnitine palmotoyltransferase I in liver mitochondria and increase of peroxysomal fatty acid oxidation."

"the drug appears to be efficient in 86.9% cases of acute cochleovestibular dysfunction and in 75.0% of cases of chronic disease. "

"It was shown that when administered to rats the drug caused a decrease of carnitine and long chain acylacarnitine in the myocardium, oxidation of 14C-palmitate was also decreased [63]. The effect was reproduced in animals maintained on a fat-rich diet, in the isoproterenol heart failure model [8]" I looked this study up. In these rats an "accumulation of fatty acids in the myocardium were noted". That doesn't sound good. I think it's fair to say that a low fat diet should be followed while taking mildronate. I imagine it's also probably a bad idea if you have a lot of body fat that might be constantly releasing into the bloodstream. Or maybe block it with niacinamide.
The accumulation you highlighted is which study please? The thing is that this drug is using for cardioprotection ....
 
OP
maillol

maillol

Member
Joined
Oct 28, 2019
Messages
388
@Broken man

It's from this study [Biochemical characteristics of the anti-ischemic action of the new structural analog of gamma-butyrobetaine 3-(2,2,2,-trimethylhydrazine)propionate]. - PubMed - NCBI

That is an interesting study you posted above too.

"The higher triacylglycerol content found in liver tissue and plasma corresponds to what has previously been observed with other situations of carnitine deficiency [7-8, lo]. It seems obvious that the decrease in hepatic carnitine concentration unbalanced the fatty acid partition between the esterification and oxidation pathways in favour of the former pathway and the very low density lipoprotein formation. "

Sounds like it caused fatty liver and increased VLDL.
 

Similar threads

Back
Top Bottom