Dette er en ekstremt viktig studie på hvorfor melkesyre er så misforstått og hva det er som egentlig skaper syreoverskudd i musklene.
Det viser seg at melkesyre faktisk er en beskyttende faktor og reduserer syreoverskudd ved at 2 H+ ioner brukes i prosessen til å skape ett melkesyremolekyl (som kan avgi 1 H+).
Melkesyreterskel er fortsatt en indikasjon på når syreoverskuddet tar overhånd i musklene, men problemene man kjenner har svært lite med melkesyre å gjøre.
Metabolsk acidose oppstår når ATP behovet blir større enn mitokondrienes hastighet i ATP-produksjonen.
Mitokondriene ikke får skapt nok ATP (energi) raskt nok, og produseres det utenfor mitokondriene i en prosess som produserer mye syre (H+ ioner). Utenfor mitokondriene er det mye dårligere forsvar mot syre (H+) og det blir lettere syreoverskudd.
Melkesyre (og CO2) er to faktorer som faktisk beskytter mot syreoverskudd.
The development of acidosis during intense exercise has traditionally been explained by the increased production of lactic acid, causing the release of a proton and the formation of the acid salt sodium lactate. On the basis of this explanation, if the rate of lactate production is high enough, the cellular proton buffering capacity can be exceeded, resulting in a decrease in cellular pH. These biochemical events have been termed lactic acidosis. The lactic acidosis of exercise has been a classic explanation of the biochemistry of acidosis for more than 80 years. This belief has led to the interpretation that lactate production causes acidosis and, in turn, that increased lactate production is one of the several causes of muscle fatigue during intense exercise. This review presents clear evidence that there is no biochemical support for lactate production causing acidosis. Lactate production retards, not causes, acidosis. Similarly, there is a wealth of research evidence to show that acidosis is caused by reactions other than lactate production. Every time ATP is broken down to ADP and Pi, a proton is released. When the ATP demand of muscle contraction is met by mitochondrial respiration, there is no proton accumulation in the cell, as protons are used by the mitochondria for oxidative phosphorylation and to maintain the proton gradient in the intermembranous space. It is only when the exercise intensity increases beyond steady state that there is a need for greater reliance on ATP regeneration from glycolysis and the phosphagen system. The ATP that is supplied from these nonmitochondrial sources and is eventually used to fuel muscle contraction increases proton release and causes the acidosis of intense exercise. Lactate production increases under these cellular conditions to prevent pyruvate accumulation and supply the NAD+ needed for phase 2 of glycolysis. Thus increased lactate production coincides with cellular acidosis and remains a good indirect marker for cell metabolic conditions that induce metabolic acidosis. If muscle did not produce lactate, acidosis and muscle fatigue would occur more quickly and exercise performance would be severely impaired.
Although metabolic acidosis is caused by cytosolic (nonmitochondrial) catabolism, an understanding of why and when metabolic acidosis occurs in contracting skeletal muscle is partly explained by knowing how and why mitochondrial function can be rate limiting to ATP regeneration.
The proton transport systems between the cytosol and mitochondria are revealing of the power of mitochondrial respiration in contributing to the control over the balance of protons within the cell during conditions of muscle contraction that rely on mitochondrial respiration for ATP turnover.
A summary of the main reactions of mitochondrial respiration that support ATP regeneration. Note that each of cytosolic ADP, Pi, electrons (e−), and protons (H+) can enter the mitochondria (whether directly or indirectly) and function as substrates for oxidative phosphorylation.
Figure 14, A and B, present two scenarios of metabolism pertinent to the study of acidosis. Figure 14A depicts the movement of carbon substrate, electrons, protons, and phosphate molecules within and between the cytosol and mitochondria during moderate intensity steady-state exercise where the rate of glycolysis and subsequent pyruvate entry into the mitochondria for complete oxidation and mitochondrial ATP regeneration meet the rate of cytosolic ATP demand. Conversely, Fig. 14Bpertains to non-steady-state exercise as is typified by intense exercise to volitional fatigue within a time frame of 2–3 min. In each figure example, the magnitude of the arrows is proportionate to substrate flux through that reaction or pathway.
Two diagrams representing energy metabolism in skeletal muscle during two different exercise intensities. A: steady state at ∼60% V̇O2 max. Note that macronutrients are a mix of blood glucose, muscle glycogen, blood free fatty acids, and intramuscular lipid. Blood free fatty acids and intramuscular lipolysis eventually yield the activated fatty acid molecules (FA-CoA). Pyruvate, NADH, and protons produced from substrate flux through glycolysis are predominantly consumed by the mitochondria as substrates for mitochondrial respiration. The same is true for the products of ATP hydrolysis (ADP, Pi, H+). Such a metabolic scenario can be said to be pH neutral to the muscle cells. B: short-term intense exercise at ∼110% V̇O2 max, causing volitional fatigue in ∼2–3 min. Size of the arrows approximate relative dependence/involvement of that reaction and the predominant fate of the products. Note that Pi is also a substrate of glycogenolysis. In this scenario, cellular ATP hydrolysis is occurring at a rate that cannot be 100% supported by mitochondrial respiration. Thus there is increased reliance on using cellular ADP for ATP regeneration from glycolysis and creatine phosphate. For every ADP that is used in glycolysis and the creatine kinase reaction under these cellular conditions, a Pi and proton is released into the cytosol. However, the magnitude of proton release is greater than for Pidue to the need to recycle Pi as a substrate in glycolysis and glycogenolysis. As explained in the text, the final accumulation of protons is a balance between the reactions that consume and release protons, cell buffering, and proton transport out of the cell. This diagram also clearly shows that the biochemical cause of proton accumulation is not lactate production but ATP hydrolysis.
The additional underlying message of Fig. 14 is that the cellular mitochondrial capacity is pivotal in understanding metabolic acidosis. The mitochondrial capacity for acquiring cytosolic protons and electrons retards a dependence on glycolysis and the phosphagen system for ATP regeneration, essentially functioning as a depository for protons for use in oxidative phosphorylation. Metabolic acidosis occurs when the rate of ATP hydrolysis, and therefore the rate of ATP demand, exceeds the rate at which ATP is produced in the mitochondria.
The intracellular buffering system, which includes amino acids, proteins, Pi, HCO3−, creatine phosphate (CrP) hydrolysis, and lactate production, binds or consumes H+ to protect the cell against intracellular proton accumulation. Protons are also removed from the cytosol via mitochondrial transport, sarcolemmal transport (lactate−/H+ symporters, Na+/H+exchangers), and a bicarbonate-dependent exchanger (HCO3−/Cl−) (Fig. 13). Such membrane exchange systems are crucial for the influence of the strong ion difference approach at understanding acid-base regulation during metabolic acidosis (5, 26). It is important to note that lactate production acts as both a buffering system, by consuming H+, and a proton remover, by transporting H+ across the sarcolemma, to protect the cell against metabolic acidosis.
Comparison between the theoretical proton release from lactate production to the known skeletal muscle buffer capacity (structural and metabolic). For example, if lactate production released protons, then the magnitude of the 2 columns of data should equal each other. Data for muscle lactate, CrP and Pi from Spriet et al. (49, 50). Data for muscle buffer capacity (by titration) from Sahlin (38) at 42 slykes for a muscle pH decrease from 7.0 to 6.4.
Balance between intramuscular proton release and consumption based on fundamental biochemistry, as explained in the text. Data for nonmitochondrial ATP turnover (ATP-NM) from Bangsbo et al. (1) at 370 mmol/kg dry wt. Data for glycolysis from Spriet et al. (50) at 73.8 mmol glucosyl units/kg dry wt. Data for muscle lactate, CrP, Pi, and buffer capacity as for Fig. 16.
The data from Figs. 16 and 17 are very important as they show that nonmitochondrial ATP turnover is not just a theoretical explanation of metabolic acidosis, as is argued by many due to Eq. 5. The fact is that research clearly supports the stoichiometry of the nonmitochondrial ATP turnover cause of metabolic acidosis. In so doing, research also clearly discredits the interpretation of acidosis as being caused by lactate production.
The most important reason to discard the lactic acidosis concept is that it is invalid. It has no biochemical justification and, to no surprise, no research support. We have been criticized for our stance on the need to change how to teach and interpret metabolic acidosis based on Eq. 5(glucose → 2 lactate + 2 H+). However, this is a summary equation that does not represent cause and effect, as previously described and illustrated in Fig. 10. As such, the concept of a lactic acidosis remains evidence of 1920s academic and scientific inertia that, out of simple convenience and apathy, still remains today. We would hope that the academics and professionals from the basic and applied fields that continue to accept the lactic acidosis construct immediately change the way they teach and interpret this topic.