Lactic Acid in Health and Disease

 Introduction

Lactic acid is produced for energy when mitochondria can't use oxygen for aerobic respiration. 

Lactic acidosis develops when you have too much lactic acid in your body. Athletes monitor their blood lactate levels as a way to pace their training.  Chronic resting lactate levels greater than 2 mmol/L represent hyperlactatemia, whereas lactic acidosis is generally defined as a serum lactate concentration above 4 mmol/L.   High levels of lactic acid can cause muscle soreness, fibromyalgia-like symptoms, and anxiety.

Overproduction or Under-removal?

The body naturally produces and consumes lactate: although anaerobic exercise can raise blood lactate levels over 10 mmol/L, resting lactate in health adults is usually between 1 and 2 mmol/liter and is constantly produced and consumed.  High levels of lactic acid can be caused by overproduction or under-removal of lactate.

Resting lactate is usually between 0.5-1.5 in a large (10,000 participant) study of healthy adults.  More info.

Although many organs consume lactate, the liver and the kidney represent the major sites of lactate uptake and clearance as they metabolize approximately 53% and 30% of daily lactate production, respectively. Lactate is metabolized by two main mechanisms: First, lactate can be used as a substrate to regenerate glucose by gluconeogenesis, a process that is exclusive to liver and the kidney. Second, at least 50% of circulating lactate is removed and metabolized by means of oxidation during resting conditions. Unlike gluconeogenesis, which is restricted to liver and kidney, oxidation can take place in many organs, including the heart, brain, and skeletal muscle.

Supplements that affect Lactic Acid

Biotin (B7) is a cofactor required for gluconeogensis.  Aspirin can increase lactate levels by interfering with LDH lactate dehydrogenase, the enzyme responsible for turning lactate into pyruvate for gluconeogensis.   B1 deficiency impairs Citric Acid cycle and leads to accumulation of pyruvate and lactate.  Organic acids involved in the Citric Acid cycle may may provide substrates to better metabolize lactate and may reduce the acidifying side effects of elevated lactate (i.e. reduce Potential Renal Acid Load (NRAL)).  Nutrient deficiencies of CoQ10 and lipoic acid have also been associated with elevated lactic acid levels in both urine and blood.   Magnesium in muscles helps to decrease contractions and lactate buildup.  

Exercise

Slow exercise (i.e. HR below 100) can lower blood lactate and blood glucose levels in healthy adults.

Mitochondrial Dysfunction in Disease

Many diseases, included Type-2 diabetes, Chronic Fatigue Syndrome, and Long Covid, are associated with mitochondrial dysfunction and increased resting lactate levels.  Post-exertional malaise (PEM) is a major symptom of ME/CFS and Long Covid and may be caused by elevated lactate levels.  Although we don’t know the cure, #StopRestPace is the best treatment because only resting and then reducing/pacing activity can lower lactate levels.  

Lactic acid is being investigated as a possible metric of Long Covid and PEM severity.  If it plays a causal role in these diseases, methods that reduce lactic acid buildup may be promising treatments.  

Research

Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome. https://www.nature.com/articles/s41598-019-55473-4

-Patients having ≥1 lactate measurement ≥2 mmol/L defined elevated lactate group. The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group.

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndroms.  https://www.atsjournals.org/doi/full/10.1164/rccm.202108-1903LE

-The transition from fat oxidation to glucose oxidation occurs prematurely, suggesting metabolic reprogramming and dysfunctional mitochondria.

Figure 1 from paper.  Long Covid patients show greater increases in lactic acid at low intensity exercise compared to controls.  Blue and purple are Long Covid patients (with and without comorbidities (like diabetes), respectively) and grey and black are matched controls (with and without comorbidities, respectively).

Flu

We have been sick with Influenza A, apparently of the lineage from the H1N1 pandemic of 2009. The flu vaccine is not effective against it.  The vaccine did work against Influenza B that was circulating in December, only unvaccinated people got sick with that one, but B is milder than A. 

The most common comment from people who had A this year is that they understand how people die of it.  Ali says she knows now how she will die, not cancer or stroke (her old fears) but just a simple flu.  We both got antivirals and maybe they shortened the duration, but they provide no relief for days. 

The first day you just feel weird, tired, have a slight fever and think you "might" have the flu.  The next day is worse and you have a fever all day and can't eat.  Extreme lethargy sets in.  That night is the worst, fever above 103 and you hallucinate and want to die.  Acetaminophen does nothing for it, but aspirin does help a bit.  On the 3rd day you feel better and can eat a bit, but are easily exhausted.  That night you sweat again all night and now the phlegm gets bad and you wake coughing.  Cough medicine does nothing, but a combination of decongestant and expectant and something to knock you out (antihistamine) lets you rest.  The 4th day is much like the 3rd, and you live in fear of nightime.
You might try to go to work, and you'll get dressed and eat breakfast in a daze, then send in for more PTO and go straight back to bed.  On the 5th day you'll make it in to work and check emails, tell everyone you're not contagious because you haven't had a fever in 24 hours and you washed all your clothes, then get a headache and feel brain dead and go home early.

Its mostly just staring at a wall, watching star trek and trying not to think about anything.  The body has taken over and is going through its reboot sequence and the mind is totally superfluous. The body doesn't want the mind to do anything, but the mind feels it has something its supposed to do, it just can't remember what.  Eventually it realizes the body knows best and the mind finally relaxes, gives up on whatever complicated socially-determined pressures it had programmed itself to believe in, and goes along for the ride.

Why I Plan to Get the Seasonal Flu Vaccine Next Year

Introducing The Virus

Image of flu virus with antigen proteins on phospholipid(?) surface and RNA in the middle. From. http://www.cdc.gov/flu/professionals/laboratory/antigenic.htm. Tamiflu works by binding the purple neurominadse proteins. Tamiflu was developed from shikimic acid, which was originally available only as an extract of Chinese star anise but by 2006 30% of the supply was manufactured recombinantly in E. coli.[54][55]

Vaccine viruses are chosen (i.e., February for the Northern Hemisphere flu vaccine) because it takes 6-8 months to grow them in chicken eggs. Health officials would like to grow them in human(?) cell culture, but that it not currently allowed. Eggs are problematic because viruses may adapt to the egg.

"As a result, Immunologically naïve ferrets) are the most sensitive method available for detecting antigenic differences between influenza viruses."(from http://www.cdc.gov/flu/professionals/laboratory/antigenic.htm)

Evolution and Types of Virus

H3N2 (swine) flu and H1N1 (avian) flu are main lineages. Major outbreaks occur suddenly and unpredictably through transmission of new varieties from animal hosts. Seasonal (common) flus are derived from the same lineage, but generally evolve slowly and predictably. Each year, novel viruses make the leap from animal to human. For example, during the 2013–14 influenza season, one case of human infection with an new strain of H3N2v virus occurred in a child from Iowa with known direct exposure to swine. Birds seem to have co-evolved with the flu virus and do not mount an immune response to it. Therefore (luckily!) it appears to evolve much more slowly in resevoir species than in humans. This has important implications for the dynamics of seasonal and epidemic flu outbreaks.


Influenza A is the most common. It is highly likely that of all the seasonal influenza strains circulating at the present, one of them will multiply and give rise to the entire seasonal influenza populations in around 5 years. The descendants of all other viruses will most likely be extinct.


For example, the 2014–15 influenza vaccines used in the United States have the same antigenic composition as those used in 2013–14. The trivalent vaccines should contain an A/California/7/2009-like (2009 H1N1) virus, an A/Texas/50/2012-like (H3N2) virus, and a B/Massachusetts/2/2012-like (B/Yamagata lineage) virus. (http://www.medscape.com/viewarticle/826572_6)

The lineage of evolutionarily successful viruses is usually termed the trunk of H3N2 influenza’s evolutionary treea:




The tree is based on hemagluttin protein sequence evolution, colored according to estimated geographic location, indicating high permanence of the trunk in China and Southeast Asia. The genetic changes occur on the neuroamidase and hemoagglutin virus surface proteins, causing antigenic drift. The truck of the H3N3 tree with a single dominant lineage contrasts with more branching trees of other flu types where different varieties often co-circulate, such as H1N1, and Influenza B and C. This graph and these findings are complicated by whole-genome sequencing: a new graph shows overall viral genome evolution in The evolution of epidemic influenza by Martha I. Nelson and Edward C. Holmes Nature Reviews.
Figure courtesy of Lemey P, Rambaut A, Bedford T, Faria N, Bielejec F, et al. http://theglobalscientist.com/2014/11/03/what-can-data-science-tell-us-about-influenza/


Current Trends - CDC FluNet


http://www.cdc.gov/flu/weekly/


Is flu increasing...

This chart is from the same page....http://www.cdc.gov/flu/weekly/. The periodicity of flu seasons and epidemics is still being studied. Peaks occur during the winter in northern latitudes at ~2–5 year intervals, usually during H3N2-dominant seasons, since the 1968 pandemic. Recent phylogenetic analysis of viruses from single populations has shown that the virus does not ‘over-summer’, but dies out at the end of each seasonal epidemic, and that subsequent seasonal viral re-emergence is ignited by imported genetic variation.

Or decreasing?

Weekly Map

http://www.cdc.gov/flu/weekly/usmap.htm

Core biochemical methylation pathways.

Two common mutations can cause decreased levels of BH4. The first mutation increases the activity of CBS, which converts Homocysteine to Cystathione and eventually to cysteine and then taurine.  The second mutation is directly involved in the regeneration of BH4 in the methylation pathway.

But before I get ahead of myself, why is BH4 so important?

Tetrahydrobiopterin (BH4) has five major responsibilities as a cofactor.  It is needed to work with:

Tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP)
Phenylalanine hydroxylase (PAH) for conversion of L-phenylalanine (PHE) to L-tyrosine (TYR)
Tyrosine hydroxylase (TH) for the conversion of L-tyrosine to L-DOPA (DOPA)
Nitric oxide synthase (NOS) for conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide (NO) in the Urea Cycle
and
Alkylglycerol monooxygenase (AGMO) for the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol

The first three reactions are critical to producing adequate levels of serotonin and dopamine. Low levels of BH4 can impair neurotransmitter production and lead to the build up of toxic intermediates, like phenylalanine.



This chart shows that without BH4 phenylalanine (found in all foods) is not converted to tyrosine. Tyrosine one of the 22 amino acids used to build protein and is normally non-essential. It is found in most foods.

BH4 is synthesized in four ways:



BH4 is involved in the major biochemical cycles:



Methionine is a major source of sulfur groups in the diet, so limiting methionine-rich foods helps limit problems from an overactive transulfuration pathway (i.e. overactive CBS enzyme). Other sulfur rich foods include crucifer vegetables and onions and garlic.

BH4 is tangentially involved in both the urea cycle and the folate cycle.

The urea cycle in detail: Arginine from our diet or from protein metabolism is converted to ornithine and urea by the enzyme Arginase. Ornithine is then converted to citrulline by ornithine transcabamoylase (OTC). Citrulline is converted back to arginine. This cycling of Arginine through the various intermediates is what converts ammonia to urea. (More info)


Source.

Arginine is also required for the production of Nitric Oxide (NO) by the enzyme nitric oxide synthase (NOS or eNOS). This reaction is dependent on the levels of BH4 available from the BH4 cycle. Remember two molecules of BH4 are needed to generate Citrulline and NO. One molecule of BH4 will in turn generate peroxynitrite and if there is no BH4, super oxide is formed. (Source. )

The Urea Cycle and the Nitric Oxide Cycle are interconnected by arginine as follows: Citrulline, made from ammonia (and ornithine), is recycled to arginine in the Urea Cycle. That arginine can then enter the Nitric Oxide Cycle where it is converted to nitric oxide by nitric oxide synthase using tetrahydrobiopterin (BH4). (Note that citrulline is also generated during the formation of nitric oxide from arginine.)

From this we can conclude that a deficiency in BH4 does not impact ammonia detoxification in the urea cycle.