The hypothesis is based on the observation that lactate is formed and utilized continuously in diverse cells under both anaerobic and aerobic conditions.
By this logic, lactate was traditionally considered a toxic metabolic byproduct that could give rise to fatigue and muscle pain during times of anaerobic respiration.
[10] This evidence is supported by an increased amount of MCT shuttle proteins in the heart and muscle in direct proportion to exertion as measured through muscular contraction.
[11] Furthermore, both neurons and astrocytes have been shown to express MCT proteins, suggesting that the lactate shuttle may be involved in brain metabolism.
Lactate is then shuttled out of the peroxisome via MCT2, where it is oxidized by cytoplasmic LDH (cLDH) to pyruvate, generating NADH for energy use and completing the cycle (see figure).
Baba and Sherma (1971) were the first to identify the enzyme lactate dehydrogenase (LDH) in the mitochondrial inner membrane and matrix of rat skeletal and cardiac muscle.
Brooks et al. confirmed this in 1999, when they found that lactate oxidation exceeded that of pyruvate by 10-40% in rat liver, skeletal, and cardiac muscle.
[6] It is suspected that this difference in isoenzyme is due to the predominant pathway the lactate will take – in liver it is more likely to be gluconeogenesis, whereas in the myocardium it is more likely to be oxidation.
Despite these differences, it is thought that the redox state of the mitochondria dictates the ability of the tissues to oxidize lactate, not the particular LDH isoform.
[1] Brooks demonstrated in his earlier studies that little difference in lactate production rates were seen in trained and untrained subjects at equivalent power outputs.
[23][24][25] In some tumor types, growth and metabolism relies on the exchange of lactate between glycolytic and rapidly respiring cells.
Other cells in the same tumor may have access to or recruit sources of oxygen (via angiogenesis), allowing it to undergo aerobic oxidation.
Thus a promising target of cancer therapy is the inhibition of lactate export, through MCT-1 blockers, depriving developing tumors of an oxygen source.