To the Editor: We thank Drs. Kemp et al. (3) for the opportunity to once again comment on the biochemistry of metabolic acidosis. However, we remain convinced that this continued interchange is not sufficiently based on science to contribute to an increased understanding of the biochemistry of metabolic acidosis. In addition, we are concerned that the letter by Kemp et al. (3) may further confuse the purpose and accomplishments of our original manuscript (5).
Let us return to why we wrote our manuscript. Historically speaking, the scientific community has largely been accepting of the assumption that exercise-induced metabolic acidosis is caused by the production of lactic acid and, therefore, that the quantification of lactate production indirectly quantifies the proton load of metabolic acidosis. We argued that such an assumption opposed the factual organic chemistry of the key reactions of muscle energy metabolism. The facts are that
1) Lactate production consumes, not produces, a proton (Fig. 9, p. R509, Ref. 5).
2) On the basis of fact 1, lactate production needs to be accounted for in proton metabolic buffering.
3) ATP hydrolysis produces a proton, and even when accounting for the pH dependence of ATP and ADP ionization, this represents the proton load of muscle contraction-induced metabolic acidosis (Fig. 10, p. R509 and Fig. 11, p. R510, Ref. 5).
4) The organic chemistry of the reactions of glycolysis reveals that it is impossible for any carboxylic acid intermediate to release a proton into solution (Fig. 5, p. R507, Ref. 5).
5) During intense exercise, there is considerable accumulation of hexose- and triose-phosphate glycolytic intermediates, revealing that the proton load of glycolysis is not balanced by lactate production (Fig. 17, p. R513, Ref. 5).
6) The Eqs. 14 and 29 of our last letter response (p. 16 and 18, Ref. 6) that Kemp et al. (3) accept in totality are interesting academically, but fail in the reality of the bioenergetics of intense muscle contraction as explained in fact 5, above.
7) On the basis of facts 1–6 above, excess glycolytic protons are produced relative to lactate production. In addition, for every lactate produced, there is one proton metabolically buffered. When adding protein buffering, additional metabolic buffering, nonmitochondrial ATP turnover and regeneration not connected to glycolysis, proton transport out of the cell, reductions in blood pH and combined blood and pulmonary buffering through hyperventilation, the proton load of intense muscle contraction is far greater than the production of lactate.
Despite these facts, Kemp et al. (3) attempted to argue for lactic acid to be the cause of acidosis, and, as such, the presence of a 1:1 stoichiometry between lactate and proton production in contracting skeletal muscle. The only scientifically valid explanation of metabolic acidosis is one that accepts facts 1–7 as expressed above and uses them as a base from which to explore the science of metabolic acidosis and acid-base biochemistry.
In their latest letter, Kemp et al. (3) have wandered to a new argument against our explanation of the nonmitochondrial ATP turnover cause of exercise-induced metabolic acidosis. On the basis of the explanations of the strong ion difference concept, reinforced by the letter from Lindinger et al. (4), they once again ignore the implications of facts 1–7 above, and continue their criticism. The issue of the strong ion difference is irrelevant to the question: Where do the protons come from during metabolic acidosis? We do not want to diverge to a topic of explaining what contributes to the final cell pH from a confined electrochemical equilibrium perspective.
We think the key difference in our approaches is expressed by the following statement of Kemp et al., “Nevertheless, as one proton accompanies each lactate, it does not seem unreasonable to describe this as production of lactic acid” (p. 5, Ref. 3).
In our opinion, and in light of the seven key facts expressed above, this sentence and the view of metabolism that it reflects is not only unreasonable, but pseudoscientific! It is this unscientific approach to this topic that explains our “ad hominem” (2) response (6) to this entire interchange.
The superficial approach of Kemp et al. (3) at understanding muscle metabolic biochemistry is further expressed by another statement in their latest letter, “Additionally, we can neglect ADP and AMP, because their concentrations are very low, . …” (see “Coupling” page R236).
We are in disbelief of this statement when research shows that during intense exercise to volitional fatigue, muscle AMP and IMP increase to a sum total of ∼2 mmol/kg wet wt. This represents a capacity for ATP regeneration amounting to at least ∼10% of muscle creatine phosphate (1, 7). How can this be ignored? It is irrelevant that ADP remains low in concentration. The reactions of intermediary metabolism, within which the adenylate kinase reaction is included, function to maintain an adequately high ATP concentration and a relatively low ADP concentration. Such an ATP-to-ADP stoichiometry is a necessity for sustaining an adequate free energy release from ATP hydrolysis and cellular life, in general.
We see no reason to extend this interchange, which is far from a scientific debate, any further. As we stated in our last letter, we are impatient for the scientific community to accept the nonmitochondrial ATP hydrolysis cause of skeletal muscle acidosis, disregard past and present acceptance of a lactic acidosis, and pave the way for allowing more valid research and learning of the intricacies of muscle metabolic regulation and proton balance.
- Copyright © 2006 the American Physiological Society