What is the significance of lactate?

From ugly duckling to proud swan

“Hans Christian Andersen’s ugly duckling is now a proud swan”. This quote according to Rabinowitz and Enerbäck, 2020 aptly describes how an “unimportant waste product of anaerobic metabolism”, lactate, has become an important energy supplier in the muscle cell as a result of its oxidation and, due to its diverse influence on metabolism and the expression of genes, an extremely important messenger substance, a hormone with intra- (autocrine), intercellular (paracrine) and endocrine effects beyond organ boundaries.

If our view of lactate has changed so much, what can we still do with the lactate threshold concept?

The usefulness of the lactate threshold concept for training control has been proven in a large number of publications. With the current state of knowledge, the importance of lactate is increasing considerably! If one reduces the many, minimally different procedures of the lactate test, its evaluation methods and its nomenclature (in which the terms aerobic and anaerobic should really no longer appear!) to a measure adapted to the methodology of lactate determination, then the lactate test is more valuable than ever!

Lactate as a source of energy

Examples: Heart and brain

It has been known since the early 1990s that lactate is an important source of energy for the heart (> 10 %) and the brain even at rest! (Kaijser & Berglund, 1992).

Under stress (in the figure approx. 70 % of the possible maximum load), the heart not only requires more energy, but also increases the energy utilization from lactate to significantly more than 60 %. (Kaijser & Berglund, 1992). The lactate is taken up by the heart muscle cells and processed in the inner mitochondrial membrane via an enzyme complex containing a mitochondrial lactate dehydrogenase and a monocarboxylase transporter (_MTC1); pyruvate is released inside the mitochondria, which is usually oxidized in the citric acid cycle (also known as the TCA cycle). The amount of lactate used by the heart increases more than 15-fold under the conditions specified here! The use of lactate for energy production in the brain also increases under stress, but not as immensely as in the heart (Dalsgaard et al 2003).

Musculature, for example:

In the past, two key assumptions have shaped our image of lactate:

1. The formation of lactate from pyruvate is a metabolic process that takes place without oxygen consumption, i.e. anaerobically. It was therefore assumed that the formation of lactate indicated an incipient deficiency in the supply of oxygen to the cell (aerobic threshold) or that there was a lack of oxygen and that energy was essentially obtained anaerobically (from the anaerobic threshold).
2. The formation of lactate from pyruvate can only take place in the cytosol of the cell under the mediation of lactate dehydrogenase. Its balance is very far from that of lactate. Lactate in the muscle cell was therefore regarded as a “waste product” of anaerobic metabolism.

Regarding point 1: However, it is now clear that the production of lactate from pyruvate takes place in cells that are sufficiently supplied with oxygen; even at rest, where an oxygen partial pressure of 40 mm Hg can be assumed at the mitochondria. (An oxygen deficiency is assumed today if the _O2 partial pressure in the mitochondria falls below 1 – 2 mm Hg). Even with a _VO2max of 65 %, a sufficiently high O2 partial _pressure in the mitochondria of 3 – 4 mm Hg can be assumed; there is no oxygen deficiency! It follows from this:

The production of lactate, including the increase in lactate concentration in the blood during physical exertion, is not an indication of a lack of oxygen in the muscle cells!

Regarding point 2: it remains true that the lactate dehydrogenase in the cytoplasm of muscle cells is practically unable to convert lactate into pyruvate. However, just like the heart, the muscle cell also has an enzyme complex that has a mitochondrial lactate dehydrogenase (mLDH) and a monocarboxylase transporter (_MTC1) in the inner mitochondrial membrane; the lactate docks onto this complex.

Inside the mitochondria, the reaction product of the enzyme-lactate complex, pyruvate, is released, which is then oxidized in the citric acid cycle (also known as the TCA cycle). The long-standing assumption that mitochondria have no lactate dehydrogenase and no _MTC1 transporter can now be regarded as refuted. (For details see Brooks, 2020). It is now assumed that muscle cells obtain around 50 % of their glucose-dependent energy requirements via the lactate pathway at rest and more than 75 % during exercise. The ratio of lactate/pyruvate concentrations increases from 10/1 at rest to > 500/1 during exercise!

Lactate is also an important source of energy in the muscle cells, both at rest and especially under stress!

Why the “detour via the lactate” in the delivery of pyruvate from glucose into the mitochondria? And what mechanisms trigger this?

While the answers to the second question are still awaited, the first question seems to be closer to an answer: Intracellular lactate is obviously an important messenger substance. intracellularly, lactate is obviously an important messenger substancewhich is likely to play a central role in the adaptation to more intensive stress!

Example: Cell to cell shuttle

In addition to the utilization of lactate in the lactate-producing cell, a shuttle of lactate to other cells also takes place without it appearing in the circulation in the meantime. Examples of this are

• The shuttle between muscle cells (type II to type I muscle cells)
• Astrocyt to Neuron lactate shuttle

In addition, lactate is transported from the muscle cell to other organs, e.g.

• Muscle cell to heart cell
• muscle cells to liver cells (gluconeogenesis)

Lactate as a messenger substance, hormone

Everything indicates that lactate – in addition to its function as an energy source – has an important signaling function, that lactate is an important messenger substance.

• Active muscle cell

In no cell of the organism are higher lactate concentrations found than in the stressed muscle cell. The trainability of muscle cells and their organelles, especially the mitochondria, has been proven time and again. A distinction can be made between complex short-term and long-term adaptation processes.

It is now assumed that lactate has direct effects on various gene expressions, but also has an influence on the amount of mitochondrial proteins via the induction of other mediators (reactive oxygen species (ROS, oxygen radicals) Ca++, etc.).

• Vascularization

Even a slight increase in lactate is said to trigger a wide variety of effects: From the formation of new blood vessels (angioneogenesis) in the stressed muscle to the assumption,

• Brain

that the positive effect of physical activity on the brain is caused by lactate receptors in the brain. Bergersen: Lactate transport and signaling in the brain: potential therapeutic targets and roles in body-brain interaction (2015).

We usually call a messenger substance that also has specific receptors a hormone!

As endocrinologists, we are naturally pleased that everything points to lactate being understood as a messenger substance, also as a hormone, in addition to its role in the provision of energy, especially for the stressed muscle during exercise.

A good article – also in German – on the subject of lactate as a hormone can be found in Wahl P; Bloch W; Mester J: Moderne Betrachtungsweisen des Laktats: Laktat ein überschätztes und gleichzeitig unter- schätztes Molekül (2009).

So get moving, the higher the lactate, the better for the brain? Certainly not!

Quote (no longer online) from the Süddeutsche Zeitung of 14.1.17: “In the finish area of a cross-country skiing competition, it sounds like a hospital ward. When the skiers have finished their race, the big coughing begins. Asthmatic problems are common in endurance sports, especially in winter.”

Extensive research into lactate by sports scientists has shown that lactate values above the IANS (the term “anaerobic threshold” is no longer a household word) of _LT2, the second lactate threshold, indicate an incipient over-acidification of the organism with all the associated problems. At the same time, the level of the hormone cortisol, which promotes protein breakdown, rises with an intensification of protein consumption to provide energy.

We are therefore looking for a target corridor for a reasonable lactate increase. As always:

It’s the dose that counts, even with exercise!

As long as we know nothing better: For “health athletes” training between _LT1 and _LT2!

Lactate resistance?

However, if we look at lactate and its great effects in mediating the blessings of our organism through sport, then we must also look for an answer to the following phenomenon: The worse a person’s physical performance, even the more overweight they are, the more often we see high lactate levels even at rest! However, the lifespan of the ever-growing population group just described is lower than that of those with a low basal lactate! Is this paradox possibly due to lactate resistance in the affected group? – I feel so strongly reminded of insulin resistance that I almost wrote insulin resistance instead of lactate resistance!

In a study from this year (Chondronikola et al, 2018) pointed out the connection between insulin resistance and high fasting lactate.

There is still a lot of research to be done!