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Lactate: The Misunderstood Angel




Imagine blaming someone for decades, only to realize that they have been the good guys all along, yeah that’s lactate. Lactate, or commonly known as lactic acid (which we’ll come to learn are two different things), has been touted as a poison, responsible for “the burn”, muscle soreness, and all things painful during and after exercise. Increasing evidence, however, argues that this is merely a story of misunderstood science and perhaps we’ve been barking up the wrong tree.


Lactate vs Lactic acid


Let’s start off by clearing the misconception that lactic acid equals lactate. An acid (HA) is something that ionizes into a proton(s) (H+ ion(s)) and a conjugate base (A-) in water. Like most present in our body, a weak acid ionizes to different degrees depending on something known as its pKa. Without going too deep into acid-base chemistry, the pKas of the intermediates that lead to the production of lactate are such that it will almost exclusively exist in its base form (lactate), a 3548:1 ratio of lactate to lactic acid to be exact at a physiological pH of 7.4 (Handy, 2006).


Figure 1: Difference between the structures of lactic acid and lactate. Image taken from Techiescientist.


How it all started


It all started from the initial works of Otto Meyerhoff and Archibald V. Hill who showed that a large amount of energy could be produced via the conversion of glucose to lactate during high-intensity exercise (Hill, Long and Lupton, 1924). Consequent studies also verified that lactate levels were higher in the blood the higher the intensity of exercise (Margaria, Edwards and Dill, 1933). This led many to accuse lactate of acidifying the muscles and leading to fatigue. 


The truth behind muscle acidosis


During a process known as glycolysis, our cells break down a glucose molecule, that has 6 carbon atoms, into two 3-carbon pyruvate molecules. This process produces some ATP (the energy currency of the cell) while converting NAD+ into NADH (Chaudhry and Varacallo, 2023). 


Figure 2: Process of glycolysis, which produces a net of 2 ATP and 2 NADH. Image taken from Khan Academy.


Contrary to mainstream biology classes, pyruvate molecules seldom enter the mitochondria directly to produce energy via the Krebs cycle and oxidative phosphorylation. Instead, due to its equilibrium constant, pyruvate molecules are predominantly converted to lactate with the help of the LDHA enzyme, which only then enters the mitochondria via the MCT1 transporter where it is reconverted to pyruvate and oxidized (Rogatzki et al., 2015). At the same time, NADH is also used in oxidative phosphorylation to produce ATP while being converted back into NAD+ (Ahmad, Kahwaji and Wolberg, 2020). 


Figure 3: Reaction kinetics of the reversible conversion between lactate and pyruvate. The diagram shows that at equilibrium, the concentrations of lactate [lactate] exceed the concentration of pyruvate [pyruvate]. Image adapted from “Misconceptions regarding basic thermodynamics and enzyme kinetics have led to erroneous conclusions regarding the metabolic importance of lactate dehydrogenase isoenzyme expression: LDH Isoenzyme Distribution and Lactate Metabolism” (Bak and Schousboe, 2017).


Figure 4: Lactate enters the mitochondrial matrix via MCT1 transporter and gets reconverted to pyruvate to be oxidized. Image taken from ScienceDirect.


In general, human skeletal muscles consist of type I, type IIA and type IIX muscle fibers. If you’ve read our previous article, you’ll know the difference between these (Schiaffino and Reggiani, 2011). Here’s a short summary: type I muscle fibers have low force-producing capacity, and contract slowly, but they have access to a lot of oxygen, have plenty of mitochondria, and rely heavily on oxidative metabolism to gain their energy. This makes them very fatigue-resistant. Conversely, type IIX muscles produce high amounts of force, and contract at high velocity, but have less access to oxygen and mitochondria, having to rely on glycolytic metabolism to gain their energy, making them extremely fatigable. Type IIA fibers on the other hand are sort of intermediate (Pette and Staron, 2000).


Figure 5: Difference between types of muscle fibers. Type IIb fibers are rarely found in humans, and are more prevalent in mice. Image taken from Stronger by Science.


During high-intensity exercise, high amounts of force are produced, which means more recruitment of fast-twitch muscle fibers. Normally, ATP hydrolysis is in balance with ATP synthesis, so the hydrogen ions released during ATP hydrolysis are consumed during ATP synthesis. In this case, however, ATP hydrolysis is so high (to release high amounts of energy) that hydrogen ions start to accumulate, causing muscle acidosis (Robergs, Ghiasvand and Parker, 2004). Besides, the rate of NADH synthesis in these muscles exceeds (as the rate of glycolysis is high) their mitochondria’s ability to generate ATP from them. As a result, the NAD+ required for glycolysis to proceed is depleted. To counteract these two situations, lactate production is increased as this process consumes NADH and hydrogen ions to rejuvenate NAD+ (White and Schenk, 2012). The lactate is then exported via MCT4 transporters from the type IIX fibers and imported via MCT1 transporters into the type IIA and type I fibers (Juel and Halestrap, 1999). These muscle fibers have more mitochondria and hence can convert lactate back into pyruvate via the LDHB enzyme to be oxidized for ATP (Sanchez et al., 2014).


Figure 6: ATP hydrolysis produces hydrogen ions as a byproduct that contributes to muscle acidosis. Image taken from Semantic Scholar.


Let's summarize for a bit, lactate is produced constantly, and in fact exists at 10x higher concentrations than pyruvate, even at rest (Henderson et al., 2004). Lactate is also not the cause of muscle acidosis but instead helps buffer the effects of the actual culprit, high rates of ATP hydrolysis.


Another short thing to add is that the muscle soreness we experience after an intense exercise session is also not caused by lactate, but instead by microtrauma to the muscle fibers and sensory neurons in the muscle spindle (Sonkodi, Berkes and Koltai, 2020).


Other beneficial effects of lactate


Since lactate is constantly being produced and circulated in the blood, it’s not strange that it has many beneficial effects on other organs. 


Recapping on our previous article, lactate can induce beneficial adaptations to exercise in skeletal muscles through the activation of factors such as HIF-1α, VEGF (Hunt et al., 2007), and PGC-1α (Hoshino et al., 2015). The short summary is these factors helps promote the growth of new capillaries, which increases oxygen delivery to the muscle (Shibuya, 2011), increases mitochondrial function (Geng et al., 2010), increases lactate flux in and out of muscle fibers (Benton et al., 2008), improves glucose uptake (Sakagami et al., 2014), and many more.


Circulating lactate can be taken up by astrocytes and shuttled to neurons too. In fact, it seems that the preferred fuel source of neurons is lactate (Wyss et al., 2011). This astrocyte-neuron lactate shuttle seems to play a key role in the formation and maintenance of long-term memory (Bergersen, 2007). Animal studies have also propose that lactate has neuroprotective and therapeutic effects in some encephalopathies (Carrard et al., 2016). Furthermore, lactate has been shown to accumulate around the hematoma, increasing neurogenesis and angiogenesis after induced cerebral ischemia in rats (Zhou et al., 2018).


Figure 7: Potential beneficial effects of exercise-induced lactate release on brain health. Image taken from “Effect of Exercise on Brain Health: The Potential Role of Lactate as a Myokine” (Hashimoto et al., 2021)


Besides, organs such as the liver, or heart can also take up circulating lactate. The liver can take up lactate to be converted back into glucose through the Cori cycle, or store it as glycogen (Rubin, 2019), whereas the heart can use lactate as an energy source (Gertz et al., 1988). In response to lactate, adipocytes also secrete TGFβ2, which could be a contributing mechanism to the increased glucose tolerance as a result of exercise (Takahashi et al., 2019).


Lactate has also been shown to promote reparative angiogenesis through mechanisms including recruitment of endothelial progenitor cells, stimulation of endothelial cell migration, activation of procollagen factors, and enhancement of collagen deposition in the extracellular matrix. Lactate induces the release of mediators such as VEGF, IL-1, and TGF-β, all of which consequently stimulate angiogenesis and promote wound healing (Constant et al., 2000, Hunt et al., 2007, Porporato et al., 2012).


The gut microbiome may also play a role in lactate’s positive effects on exercise adaptations. A team of researchers has proposed that the bacterial strain Veillonella atypica found in elite athletes metabolizes lactate into propionate which improves exercise performance (Scheiman et al., 2019). 


Figure 8: The gut microbiome can use lactate as a fuel to produce short-chain fatty acids (SCFA) that improves performance. Image taken from “Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism” (Scheiman et al., 2019).


Aside from that, lactate also plays a role in immunity modulation. Lactate can promote macrophages to take on an M2-phenotype which helps reduce inflammation after the initial phase of inflammation to fight off pathogens by suppressing the transcription of proinflammatory genes (Zhang et al., 2019).


Figure 9: Possible mechanisms by which lactate can induce M2-phenotypes in macrophage involves HIF-1α stabilization and inhibition of the NLRP3 inflammasome and NF-κB. Image taken from “Lactate and Immunosuppression in Sepsis” (Nolt et al., 2018).


Conclusion


Like everything, too much of something good can be bad too. Just like how lactate helps many different cell types function efficiently, it has been similarly implicated in cancer survival. For example, the same induction of homeostatic anti-inflammatory M2 macrophage phenotype that reduces inflammation can be misused by cancer cells to suppress our immune system (Certo et al., 2020). That being said, it’s high time that people stop believing in the myths regarding lactate being an evil molecule and enact justice for our wrongly demonized ally, lactate!

 

Article prepared by: Jared Ong Kang Jie, R&D Director of MBIOS 2023/2024


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