Inhibition of the lactic acid transporters MCT1 and MCT4 as an underlying mechanism for drug-induced myopathy

[pattismith]

Inhibition of the lactic acid transporters MCT1 and MCT4 as an underlying mechanism for drug-induced myopathy

© Yat Hei Leung, 2017

Abstract:

Drug-induced myopathy is a serious side effect caused by various widely-administered medications. These muscle-related symptoms range from mild myalgia with or without creatine kinase increase, muscle weakness, myositis, to rare life-threatening rhabdomyolysis.

While mild myalgias can be tolerable, chronic myopathies can affect the patients' quality of life, frequently requiring the cessation of an effective drug

. The underlying mechanism of these drug-induced myotoxicities is known for some drugs but remains unclear for most (e.g. statins).

Statins constitute an effective cholesterol-lowering therapy, but they are known to cause these adverse drug reactions. Various factors increasing statin plasma levels (e.g. high doses, drug-drug interactions, genetic polymorphisms) seem to be linked with a higher occurrence of myotoxicity.

Consequently, systemic drug metabolism and transport, controlling overall absorption, distribution and elimination, can become important.

However, these factors only partly explain the observed muscular disorders.

Although there are several proposed mechanisms for statin-induced myotoxicity, the exact mechanism responsible for this effect is still debated with studies reporting conflicting results.

Since exercise seems to exacerbate muscle pain in patients under statin treatment, the premise of this project is that L-lactic acid transport via the monocarboxylate transporters is involved in the development of drug-induced myopathy.

Since lactic acid is one of the major byproducts resulting from physical activity, its efficient removal from the muscle cells is essential.

Therefore, the administration of drugs competitively inhibiting those transporters may potentially lead to perturbation of L-lactic acid homeostasis and muscular disorders.

The aim of the first part of this study was to assess the inhibitory potential of acidic drugs on L-lactic acid transport using breast cancer cell lines Hs578T and MDA-MB-231, which selectively express MCT1 or MCT4, respectively.

These cell lines allowed transporter characterization with the determination of their kinetic parameters and inhibition.

The main objective of the second part of this study was to confirm the inhibitory potentials of atorvastatin, simvastatin, rosuvastatin and loratadine on L-lactic acid transport in a more physiological setting using primary human skeletal muscle cells (SkMC).

The overall goal of this doctoral project was to better understand the mechanisms behind certain drug-induced myopathies, more specifically those induced by statins and loratadine, by studying monocarboxylate transporters involved in lactic acid transport and pH homeostasis in the muscle.

Loratadine and atorvastatin demonstrated the greatest potency for inhibition of L-lactic acid efflux first in cancer cell lines, an observation confirmed in SkMC.

This inhibition may cause an accumulation of intracellular L-lactic acid leading to acidification and muscular disorders.

Further studies with in vivo models are required to confirm the physiological impact of our findings in a clinical setting. These data will help understand statin- and loratadine-induced myopathy and prevent its occurrence by optimizing treatment strategies.

Collections

• Thèses et mémoires électroniques de l’Université de Montréal [15857]
• Faculté de pharmacie – Thèses et mémoires [349]

 

[pattismith]

High doses of sodium bicarbonate increase lactate levels and delay exhaustion in a cycling performance test
2019

Abstract
Objectives
It is well established that ingestion of sodium bicarbonate (NaHCO3) causes metabolic alkalosis. However, there is no consensus in terms of optimal NaHCO3 doses leading to enhanced performance. This study aimed to determine the effects of different NaHCO3 doses on performance and lactate clearance in non-professional cyclists.
Methods
Twenty-one cyclists performed the following three double-blind trials: 1) ingestion of 0.3 g · kg–1 body weight (BW) of placebo; 2) ingestion of 0.1 g · kg–1 BW NaHCO3 plus 0.2 g · kg–1 BW placebo (0.1 BC); and 3) ingestion of 0.3 g · kg–1 BW NaHCO3 (0.3 BC). Performance was evaluated after warm-up on the bike followed by a performance test until exhaustion. Lactate levels were monitored in blood samples before and immediately after performance tests.
Results
Lactate levels in the blood were significantly higher after exercise in 0.3 BC and 0.1 BC (15.12 ± 0.92 versus 10.3 ± 1.22 and 13.24 ± 0.87 versus 10.3 ± 1.22 mmol/L; P < 0.05) compared with control. Significant improvements in performance were only identified in 0.3 BC group (76.42 ± 2.14; P = 0.01).
Conclusions
The present study found that 0.3 g · kg–1 BW NaHCO3 is effective in improving performance and improving blood lactate levels in cyclists compared with control and 0.1 g · kg–1 BW NaHCO3.

 

[sb4]

@pattismith So the bicarbonate helped transport lactate out of the cell resulting in higher blood levels but lower intracellular levels?

How does this happen? Do the electroneutral cotransporters depend on each other? Is the alkaline effect of NaHCO3 in the blood or in the cell or both?

 

[pattismith]

@pattismith So the bicarbonate helped transport lactate out of the cell resulting in higher blood levels but lower intracellular levels?

How does this happen? Do the electroneutral cotransporters depend on each other? Is the alkaline effect of NaHCO3 in the blood or in the cell or both?

Good questions, I think I have to dig a bit more into this muscle pH homeostasis.
I wonder if PEM has something to do with bad myocyte lactate clearance...Do we have any study about myocytes pH during effort test in ME?

 

[sb4]

@pattismith One symptom that I have that I'm not sure how many others have here is instant lactic acid build up from minimal activity. Do you have this? Even stretching caused intense burning / lactic acid build up. I wonder if this burning feeling is from lactate building up in the cell or if it is cells producing more lactate rapidly,

 

[pattismith]

@pattismith One symptom that I have that I'm not sure how many others have here is instant lactic acid build up from minimal activity. Do you have this? Even stretching caused intense burning / lactic acid build up. I wonder if this burning feeling is from lactate building up in the cell or if it is cells producing more lactate rapidly,

I have muscle problems, cramps, stiffness, and get pain when trying to exercise. The harder I try, the more I have burning pain. My thyroid was low, and now I went hyperthyroid, but still have these symptoms.
I also have a kind of myotonia at my trapezius percussion, but still don't know if it could be a genetic problem or something else...

 

[pattismith]

In this 2015 study, "Statins inhibited transport of L-lactate via MCT4 in a concentration-dependent manner. Statin-induced cytotoxicity was associated with intracellular acidification and caspase-3/7 activation. On the other hand, bicarbonate suppressed statin-induced pH alteration, caspase activation, and morphological change."
So bicarbonate can protect from excess lactate/acidity in the myocyte, just by lowering pH inside myocytes.

One other interesting system for pH homeostasis is Carbonic anhydrase.
Carbonic Anhydrase helps controlling and restoring pH during and after exercise stress, so underactivity may be involved in muscle fatigue.
" Increasingly evidence is showing that the role of the CA isozymes in pH regulation is not simply limited to a catalytic function in reversible hydration of CO2. Despite some doubt about whether direct binding of CAs and acid-base transport proteins occur (19), convincing in vitro data using animal and cell models indicate an important functional interaction between CAII, CAIV, and MCT1/4 (9, 42); between NBCe1 and CAII, CAIII, and CAIV (1, 85); and possibly also between CAII, CAIV, and NHE1 "

There is also a chaperone protein Basigin, that help MCT1 and MCT4 work.

 

[pattismith]

@pattismith One symptom that I have that I'm not sure how many others have here is instant lactic acid build up from minimal activity. Do you have this? Even stretching caused intense burning / lactic acid build up. I wonder if this burning feeling is from lactate building up in the cell or if it is cells producing more lactate rapidly,

I had some burning muscle some days ago, so decided to try some pharmaceutical sodium bicarbonate. Not the bigger dose they used in the study, but the lower dose (0.1g/kg). It worked!
This confirms me that some of us really have a problem with too much lactic acid in some of our cells, and especially our muscle.

 

[sb4]

I had some burning muscle some days ago, so decided to try some pharmaceutical sodium bicarbonate. Not the bigger dose they used in the study, but the lower dose (0.1g/kg). It worked!
This confirms me that some of us really have a problem with too much lactic acid in some of our cells, and especially our muscle.

I recently took a decent amount of sodium bicarbonate but it made my stomach nauseus and quite gastroparesis-y so I stopped immidiately. I figure it lowered the acid in my stomach which caused this issue. I took it at night, quite some time after my last meal. Maybe I will try it again though. It was also years out of date but I am not sure how much that matters with sodium bicarbonate.

 

[pattismith]

I recently took a decent amount of sodium bicarbonate but it made my stomach nauseus and quite gastroparesis-y so I stopped immidiately. I figure it lowered the acid in my stomach which caused this issue. I took it at night, quite some time after my last meal. Maybe I will try it again though. It was also years out of date but I am not sure how much that matters with sodium bicarbonate.

I can't say for the date.

My husband is recovering after 1.5 year of chemotherapy and he has some muscle and joints pains now.
Conventional treatment failed for his muscle pain, so he tried the same dose of sodium bicarbonate than I did, and it seems to work for him too.
We were able to stand and walk for hours this last two days, so this gives me hope we will be able to exercise more in the future with this help. (many things don't hold on the long run, so I will update)

 

[sb4]

I can't say for the date.

My husband is recovering after 1.5 year of chemotherapy and he has some muscle and joints pains now.
Conventional treatment failed for his muscle pain, so he tried the same dose of sodium bicarbonate than I did, and it seems to work for him too.
We were able to stand and walk for hours this last two days, so this gives me hope we will be able to exercise more in the future with this help. (many things don't hold on the long run, so I will update)

I searched for transdermal delivery of NaBicarbonate and found this. They are using a transdermal sodium bicarbonate cream to enhance performance in athletes. They claim they got significant decreases in heart rate and percieved exertion with the cream and increases in lactate.
This sounds interesting however looking at the graphs they provided the diferences look absolutely minimal to me, but then again I am not good at reading studies.

Do you think regular NaCO3 + DMSO would work?

 

[sb4]

This is the product in question. I assume the study was paid for by the company and this could be why they are making a big deal out of results. I guess that doesn't matter too much if it seems to be working in you.

What dose you taking @pattismith ?

 

[pattismith]

This is the product in question. I assume the study was paid for by the company and this could be why they are making a big deal out of results. I guess that doesn't matter too much if it seems to be working in you.

What dose you taking @pattismith ?

I can't say about transdermal product, I never tried it. But I am very sensitive to oral drugs, and so my husband is, and we were able to tolerate 5 mg bicarbonate (in water, with a bit of lemon juice to help with the taste at the bigining).
If you are easily nauseous you can fractionate the dose.
If 5mg had failed for me, I had planed to take up to 15 mg (0.3mg/kg), the higher dosage in the study.

 

[Cipher]

I can't say about transdermal product, I never tried it. But I am very sensitive to oral drugs, and so my husband is, and we were able to tolerate 5 mg bicarbonate (in water, with a bit of lemon juice to help with the taste at the bigining).
If you are easily nauseous you can fractionate the dose.
If 5mg had failed for me, I had planed to take up to 15 mg (0.3mg/kg), the higher dosage in the study.

I think you mean grams instead of milligrams.

I recently took a decent amount of sodium bicarbonate but it made my stomach nauseus and quite gastroparesis-y so I stopped immidiately. I figure it lowered the acid in my stomach which caused this issue. I took it at night, quite some time after my last meal. Maybe I will try it again though. It was also years out of date but I am not sure how much that matters with sodium bicarbonate.

Citrate is metabolized in the liver to bicarbonate, so that could be an alternative. Sodium citrate is still alkaline though and neutralizes gastric acid, but it generates no carbon dioxide. One way to avoid the gastric acid neutralization might be to use enteric-coated capsules. You might need a lower dosage though as it avoids being partially neutralized by the gastric acid.

 

[pattismith]

I think you mean grams instead of milligrams.

yes, thank you for correcting me!

@Hip found 4 g = 1 level tea spoon here
but with my tea spoon, it's 5 g.
I take it in a small glass of water,
(and I take it with high amount of carnitine, which I found is helpful for my headache)

 

[Mary]

@sb4 - re transdermal NaBicarbonate - an alternative is to soak in a bath to which you've added baking soda. Drinking a solution of baking soda as @pattismith describes has helped me on several occasions when my muscles have gotten achy I assume due to lactic acid buildup. Once I know the achiness was due to acidity caused by very high dose vitamin C, though I don't know if lactic acid was involved here, but taking baking soda orally did help.

Anyways, for unknown reasons this past week I've been extra achy and so the other morning I took a bath and added baking soda to it, and within 10 minutes or so the achiness was resolving. I have to be careful taking baking soda orally because it can tend to raise my BP. And I always take it well away from food. It does neutralize stomach acid.

Actually, dissolving 1/4 or 1/2 tsp. baking soda in 8 ounces of water and drinking it is a simple test to check your stomach acid. This should be done on an empty stomach. If you don't burp within a few minutes of drinking this, it can be an indication of low stomach acid.

And I found this article which references using baking soda in a bath to help with lactic acid build-up: https://draxe.com/nutrition/baking-soda-uses/ (see item 15)

 

[sb4]

Not sure how connected it is but my urine PH on test strips is always really low. Even when I was supplementing with large doses of potassium citrate.

"Urinary bicarbonate and pH were within the range of those at 0 time (baseline levels) from the beginning until 30 minutes after the exercise. However, they began to increase abruptly about 30 minutes after the exercise, and continued to increase extensively for 2 hours thereafter. Such marked increase in urinary bicarbonate and pH seemed to be correlated with the aerobic metabolism of lactate in the muscles, liver, and kidney, finally producing CO2. It was also suggested that the measurement of urinary bicarbonate and pH may be useful for the estimation of physiological changes in the body after submaximal incremental cycling exercise loading. "

This seems to say that as exercise increases and lactate goes up then PH in urine goes up. The increase in pH is apparently from bicarbonate which comes from CO2 from metabolism of Lactate. What happens if you don't metabolise the lactate very well? Less CO2 and urine PH drops due to lactic acid somehow?

 

[sb4]

"The elimination of 1 to 2 gm. of lactic acid involves the removal from the body of 11 to 22 &M of base because lactic acid is practically completely combined with base at the reaction of the urine. This is an appreciable quantity of base to be furnished in addition to the quantity necessary to form the salts of hydrochloric, sulfuric, and phosphoric acids. Replacement of lost base is most simply accomplished by an increased CH of the urine which permits the excretion of phosphate with the minimum amount of base, and by the increased elimination of ammonia. Such an adjustment was probably at work in the control experiment of Subject W. on May 30 (reported in the previous paper), carried out in the afternoon after a double exercise experiment in the morning. The pH of the urine was 5.3 whereas in all other experiments in which the same individual was the subject the pH was found to range between 6.2 and 7.4 at the same time of day. In the morning 2.16 gm. of lactic acid had been excreted with the removal of 24 mM of base."

"SUMMARY
The excretion of lactic acid in urine after 2 to 3 minutes of strenuous exercise was studied in 10 and 15 minute periods. The excretion reached maxima varying from 86 to 630 mg. during the second 10 minute period after exercise. Thereafter, the elimination diminished and normal values were reached in 30 to 50 minutes. The total quantity of lactic acid excreted after one period of exercise varied from 140 to 1370 mg. A second period of exercise following shortly after the first yielded similar quantities. The lactic acid was shown to be the dextro form. "

It appears this study suggests that lactic acid is excreted in the urine during exercise and I think if I am parsing that first paragraph correctly, the lactic acid removes base from the body and lowers urine pH to 5.3 in one subject. Interestingly my urine pH is quite consistently 5.75 although I haven't checked in a while. Could it be low due to constant lactic acid excretion eliminating my buffers?

 

[pogoman]

I have the myopathy described, right now the treatment is with autoimmune drugs.
On rituximab every 6 months and this cycle I've really started to feel better.
I have tried the baking soda route before and it didn't help.
B2, coq10 and all three forms of L-carnitine and other mito supplements have helped tho.
I believe my lactic acid levels were tested before and they were within limits.