Anaerobic Glycolysis and Lactate Metabolism

Today, we exonerate a molecule that has been slandered in physiology for over 150 years. Like the Count of Monte Cristo rising from the dungeons of Château d'If with newfound fame and fortune to reclaim his position in society, we restore lactate to its rightful station atop the biological aristocracy. As oxidative phosphorylation (OXPHOS) slows down, the metabolism shifts towards glycolysis and lactate production to maintain ATP levels and redox balance. This can happen in either aerobic or anaerobic conditions, the latter of which we’ll focus on in this post.

Overview of anaerobic glycolysis

In an anaerobic environment, there isn’t enough oxygen available to accept electrons at Complex IV of the electron transport chain (ETC) in the mitochondria, and electron transport slows down. As a result, ATP production drops and NADH begins to accumulate at Complex I. In an effort to maintain ATP levels and regenerate NAD+, the cell shifts towards glycolysis.

Glycolysis

1 Glucose + 2 NAD+ > 2 Pyruvate + 2 NADH + 2 H+ > 2 Lactate + 2 NAD+  Net: +2 ATP

Remember from the previous blog post, pyruvate is the first molecule produced from the oxidation of glucose that would usually be converted to acetyl-CoA and enter the Kreb’s cycle. In glycolysis however, pyruvate is converted into lactate by an enzyme called lactate dehydrogenase (LDH). NADH gives up an electron to facilitate the reaction, thereby replenishing the NAD+ pool— necessary for the continued oxidation of glucose into pyruvate— and an H+ ion binds to the newly formed lactate molecule. Glycolysis nets a mere +2 ATP in contrast to the +36 ATP produced in OXPHOS.

The "lactic acid" myth 

How many science teachers and athletic coaches have you heard say that muscles burn during intense activity due to lactic acid build up? Or have attributed muscle soreness to lactic acid that still needs to be cleared? Lactic acid doesn’t even exist in the body… When ATP is used (hydrolysis), H+ ions are released. Logically, as activity increases, more ATP is used and more H+ ions are released. The increase in H+ ions lowers the cell’s pH— this is what causes the burning sensation, not “lactic acid”. Lactate actually binds H+ ions accumulating from ATP hydrolysis and transports them out of the cell in an effort to stabilize local pH.

How does the liver process lactate?

So where does lactate go? THE LIVER. It travels through monocarboxylate transporters (MCTs) into the bloodstream and to the liver where it is first converted to pyruvate, and then to glucose via gluconeogenesis. Glucose is transported in the blood back to tissues where it undergoes glycolysis. This process, known as the Cori cycle, is relatively expensive from an ATP perspective (-6 ATP) but the liver is still generating plenty (+36 ATP from OXPHOS), so it’s a price worth paying to get ATP-starved muscles desperately needed energy, albeit only +2 ATP.

What should my blood lactate levels be? 

Understanding this, blood lactate levels often represent the liver’s ability to recycle it, not necessarily the actual rate of its production. Better liver function ensures a stable rate of conversion and therefore a steady supply of glucose and balanced muscle pH for a longer duration/higher intensity. To put this into perspective, a healthy, fasted individual should usually be at a blood lactate of ~1 mmol/L. In an elevated aerobic state, lactate will rise to 1.5-2 mmol/L. ~3-4 mmol/L is considered the anaerobic threshold— this number can rise dramatically after this point depending on intensity of activity. Of course, 1.5 mmol/L for an elite individual may be 3-4 mmol/L for the average person; lactate levels are relative to metabolic function.

Can elevated lactate be beneficial?

As lactate levels increase during activity, they influence a host of other cellular processes, for lactate is not only a pH buffer and fuel source, it’s also a signaling molecule. Tune into any three-hour podcast these days and you’re bound to come to the part about exercise being beneficial, about this or that pathway being activated, insulin sensitivity, enhanced cognitive function etc. etc. To simplify it all, these adaptive responses are triggered by elevated blood lactate.

How does lactate promote autophagy?

Lactate activates the AMPK pathway which has a wide range of effect. We typically associate AMPK with autophagy, or programmed cell death. When we’re able to eliminate dysfunctional mitochondria (those which create excess oxidative stress in ETC) through activation of AMPK via lactate signaling, we are ensuring that only the fittest mitochondria are able to proliferate— a cruel but pragmatic thinning of the herd.

Does lactate increase mitochondrial mass?

AMPK also signals Sirt-1 receptors to deacytelate PGC-1α (we’ll come back to these receptors in the future), the master regulator of mitochondrial biogenesis. Increasing the size and number of mitochondria, referred to as the mitochondrial mass, increases energy production and efficiency. Think: it’s better to have multiple engines running at 60% power than to have a single engine always running at 100%. This improves the metabolic capacity while also limiting excessive oxidative stress.

Can lactate improve cognitive function?

The AMPK cascade is also responsible for boosting brain derived neurotrophic factor (BDNF), the primary target for promoting neurogenesis and synaptic plasticity ie improved mood, learning and memory. This equates to more gray matter in the hippocampus, and augments pattern recognition and resilience to fear conditioning— two things many people seem to be deficient in. You can increase BDNF with supplements like CBD or certain types of mushrooms, but exercise is the most accessible way to accomplish this and comes with a host of additional benefits.

Is lactate anabolic?

“But isn’t AMPK associated with catabolic activity? Exercise promotes mTOR and muscle development.” There exists a lot of crosstalk between AMPK and mTOR that's buried deep within the recent literature. They are typically viewed as antagonistic to one another but can often work together. This is likely due to operating in a temporal nature where AMPK is activated first to meet energy needs, and mTOR is activated after to facilitate recovery. So, even though lactate activates AMPK, it indirectly turns on mTOR by contributing to growth hormone (GH) secretion. GH is necessary for anabolism and regeneration, integral to maintaining youth. Lesson: you don’t need to shoot GH, get Mentzer pilled… seasonally… or else life expectancy drops. It all exists in such delicate (redox!) balance.

Conclusion

Redemption is sweet! At last, lactate realizes victory over those who would have it silenced. This dynamic molecule serves as an energy source, a redox buffer and as a signaling mechanism. It mediates myriad aspects of energy metabolism during anaerobic activity and triggers the adaptive responses to it, bringing new meaning to the expression “feel the burn”. This burn is the hormetic pressure necessary to recruit lactate in joining you on your quest to achieve peak performance.

 

Next up, we travel down the dark and sometimes dangerous rabbit hole that is aerobic glycolysis…