Lactate accumulation, proton buffering, and pH change in ischemically exercising muscle

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Abstract
The following is the abstract of the article discussed in the subsequent letter: 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. By reviewing theory ([6][1], [11][2], [12][3], [14][4]) and reanalyzing data ([3][5], [15][6], [19][7], [24][8], [25][9]), Robergs and colleagues argue ([21][10]), among other things, for a particular approach to the generation and disposal of protons in exercising skeletal muscle. They rightly insist that interpreting muscle cell pH changes requires an appropriate analysis of proton stoichiometry. I would add two points. First, one may be misled by neglecting, even for illustrative purposes, the pH dependence of this stoichiometry. Second, careful accounting is needed to assess how physicochemical buffering contributes to cellular acid-base balance. To argue this, I will consider only ischemic exercise (exercise without blood flow), which has the simplifying advantages that mitochondrial proton uptake and cellular proton efflux ([21][10]) are negligible, and the only glycolytic substrate is glycogen (although for completeness, results for glucose will also be given). What might be called the traditional analysis criticized by Robergs et al. takes the increase in cytosolic lactate concentration as a measure of the proton load arising from glycogenolysis, which is disposed of in two ways ([14][4], [16][11]). The first is physicochemical buffering [also called static ([23][12]) or structural ([21][10]) buffering], predominantly by cytosolic imidazole groups and inorganic phosphate ([1][13], [2][14], [16][11], [23][12], [26][15]). The second is the consumption of protons by the Lohmann reaction ([17][16]); this term refers to the hydrolysis of ATP and its simultaneous regeneration at the expense of phosphocreatine, catalyzed by creatine kinase ([7][17], [17][16], [21][10]) and is stoichiometrically equivalent to the splitting, or hydrolysis, of phosphocreatine to inorganic phosphate [all these terms can be found in the literature, but note that this reaction does not occur ([21][10]), being only a name for the sum of two enzyme-catalyzed processes]. This proton consumption is sometimes called dynamic ([23][12]) or metabolic ([21][10]) buffering. Taking the fall in cytosolic pH (to use a physical analogy) as the strain resulting from the glycolytic proton-load stress, the ratio of lactate increase to pH fall has been used as an apparent buffer capacity, a measure of both these components of proton handling ([23][12]) More properly, the true physicochemical buffer capacity is the ratio to the pH fall of the net proton load, that is, the total glycogenolytic proton load less that consumed by the Lohmann reaction ([16][11]). In criticizing this approach, Robergs et al. ([21][10]) note that the glycogenolytic proton load is generated by the hydrolysis of ATP rather than ionization of lactic acid ([6][1], [12][3], [14][4]), while the reduction of pyruvate to lactate actually consumes protons, mitigating acidification rather than causing it. Thus the naïve notion that glycolysis adds lactic acid to the cell is untenable ([21][10]). Robergs et al. develop this criticism to argue for a different understanding of acid-base balance, one implication of which is that for biopsy and 31P MRS studies of muscle energetics, the traditional approach yields gross underestimations of the true muscle buffer capacity ([21][10]). I will argue that while this analysis of proton generation is broadly correct at resting pH, it is much less so at low pH values commonly found in exercising muscle. Furthermore, because this analysis of muscle cell buffering capacity adds together components of proton generation that are partially cancelled by processes of proton consumption, it may be physiologically misleading. To understand this, we must consider the stoichiometry ([Table...

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