Biochemistry of exercise-induced metabolic acidosis

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Invited ReviewR512Table 5. Causes of acidosis and proton bufferingin skeletal muscleCauses of ProtonReleaseBlood andventilatorybufferingH Buffering and RemovalIntracellular H bufferingH removalGlycolysis H HCO 3Proteins Mitochondrial transportAmino acidsH 2CO 3 CrP hydrolysis Lactate /H SymportATP hydrolysisH 2O CO 2Lactate production Sarcolemmal Na /H exchangeIMP formationHCO 3HCO 3 /Cl ExchangeSIDP iHCO 3, bicarbonate; H 2CO 3, carbonic acid; CrP, creatine phosphate; SID,strong ion differenceand efflux from working muscles is more a consequence thana cause of acidosis.Noakes (34) recognized and supported the opinions ofGevers (10, 11) by stating that the protons released from thehydrolysis of ATP are not needed for the resynthesis of ATP bythe glycolytic pathway. He also suggested that at first some ofthe protons generated by high rates of glycolytic ATP breakdownare taken into the mitochondria with pyruvate. Some areused in the reduction of pyruvate to lactate and some arebuffered by intracellular histidine residues and P i . Consequently,unbuffered intracellular protons leave the cell via thesarcolemmal Na /H exchangers and H lactate symportersand can alter blood pH, which coincides with an increase inthe blood lactate concentration.COMPONENTS OF CELLULAR PROTON PRODUCTION,BUFFERING, AND REMOVALThe cause of metabolic acidosis is not merely proton release,but an imbalance between the rate of proton release and the rateof proton buffering and removal. As previously shown fromfundamental biochemistry, proton release occurs from glycolysisand ATP hydrolysis. However, there is not an immediatedecrease in cellular pH due to the capacity and multiplecomponents of cell proton buffering and removal (Table 5).The intracellular buffering system, which includes amino acids,proteins, P i , HCO 3 , creatine phosphate (CrP) hydrolysis,and lactate production, binds or consumes H to protect thecell against intracellular proton accumulation. Protons are alsoremoved from the cytosol via mitochondrial transport, sarcolemmaltransport (lactate /H symporters, Na /H exchangers),and a bicarbonate-dependent exchanger (HCO 3 /Cl )(Fig. 13). Such membrane exchange systems are crucial for theinfluence of the strong ion difference approach at understandingacid-base regulation during metabolic acidosis (5, 26).However, when the rate of H production exceeds the rate orthe capacity to buffer or remove protons from skeletal muscle,metabolic acidosis ensues. It is important to note that lactateproduction 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.BIOCHEMISTRY OF METABOLIC ACIDOSISTHE STOICHIOMETRY OF LACTATE PRODUCTIONAND PROTON ACCUMULATION IN CONTRACTINGSKELETAL MUSCLEApart from biochemical facts, the most compelling additionalevidence for the acidosis of nonmitochondrial ATPturnover in contracting skeletal muscle comes from a compilationof research that enables calculations of the componentsof proton release, buffering, and removal presented in Table 5.Juel et al. (19) quantified lactate and proton release fromcontracting skeletal muscle during one-legged knee extensorexercise. The data of Fig. 15 were obtained from data of lactateand proton release during incremental exercise to fatigue anddrawn as this original presentation. Clearly, muscle protonrelease was greater than lactate release, with the differenceincreasing with increases in exercise intensity with an almosttwofold greater proton to lactate release at exhaustion.When concerned with intracellular nonmitochondrial ATPturnover and proton and lactate balance, the best exercise andresearch model to use is the quadriceps occluded blood flowmodel (50), as this minimizes the effect of blood flow onproton and lactate removal from the active muscle. However,the highest calculations for nonmitochondrial ATP turnover(370 mmol/kg dry wt) come from Bangsbo et al. (1), whoquantified muscle metabolites and blood lactate efflux from thequadriceps muscles during one-legged dynamic knee extensorexercise to exhaustion. Bangsbo and colleagues (1, 2) arguedthat when totally accounting for all muscle lactate production(accumulation, removal, and oxidation), a more valid estimateof nonmitochondrial ATP turnover (ATP-NM) is obtained. Thegenerally accepted equation (2) for this calculation is presentedin Eq. 7.ATP-NM CrP ATP*1.5*La (7)When combining data from multiple studies (1, 33, 50, 51),with the data from Spriet and colleagues (50, 51) used formuscle metabolite accumulation during intense exercise tofatigue and the data from Bangsbo et al. (1) for ATP-NM, thedata totally support the biochemically proven nonmitochondrialturnover origin of exercise-induced skeletal muscle metabolicacidosis. For example, Fig. 16 represents the biochemicalbalance of protons if you assume that lactate productioncauses acidosis. The published data reveal that the musclebuffer capacity (structural and metabolic) is almost double thatFig. 15. Data for proton and lactate removal from contracting skeletal muscle.Figure is an original presentation of data from Juel et al. (19).Downloaded from ajpregu.physiology.org on October 31, 2008AJP-Regul Integr Comp Physiol • VOL 287 • SEPTEMBER 2004 • www.ajpregu.org
BIOCHEMISTRY OF METABOLIC ACIDOSISInvited Reviewcomputations of the stoichiometry of proton and lactate balancein contracting skeletal muscle, prove that metabolic acidosisis caused by an increased reliance on nonmitochondrialATP turnover and not lactate production.IS THE DIFFERENTIATION BETWEEN LACTATEPRODUCTION AND THE TRUE BIOCHEMICAL CAUSEOF ACIDOSIS REALLY THAT IMPORTANT?R513Fig. 16. Comparison between the theoretical proton release from lactateproduction to the known skeletal muscle buffer capacity (structural andmetabolic). For example, if lactate production released protons, then themagnitude of the 2 columns of data should equal each other. Data for musclelactate, CrP and P i 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 7.0to 6.4.of lactate production. There is no stoichiometry to the assertionthat lactate production directly releases protons and causes alactic acidosis.When evaluating past research for evidence in support of thenonmitochondrial ATP turnover cause of metabolic acidosis,the stoichiometry is far more impressive. These data arepresented in Fig. 17. When the main consumers of protons arecombined, there is a near equality between proton release(ATP-NM and glycolysis) and proton consumption. A slightdiscrepancy is presented here, but in reality additional protonconsumption occurs via the muscle bicarbonate stores, a smallproton efflux that occurs regardless of exercise models havingzero blood flow, and the influence of the strong ion differenceacross the sarcolemma of the contracting muscle fibers (5, 12,26). Furthermore, we presented data assuming complete ionizationof key metabolites such as ATP, ADP, and P i . This isnot entirely accurate, yet adjustments based on proton balancesfrom fractional ionization provide unnecessary complicationsto the proton balance, do not change the relative depiction ofdata, and therefore do not alter the cause of metabolic acidosis.The data from Figs. 16 and 17 are very important as theyshow that nonmitochondrial ATP turnover is not just a theoreticalexplanation of metabolic acidosis, as is argued by manydue to Eq. 5. The fact is that research clearly supports thestoichiometry of the nonmitochondrial ATP turnover cause ofmetabolic acidosis. In so doing, research also clearly discreditsthe interpretation of acidosis as being caused by lactate production.Consequently, we showed that the biochemistry ofmetabolism supports nonmitochondrial ATP turnover as thecause of acidosis. Furthermore, we present data from experimentalresearch that through direct measurement and indirectThis is the crucial question that all physiologists must beable to answer. There are several examples of why the correctcause of metabolic acidosis needs to be accepted, communicatedin education, and used in research interpretation andpublication.Scientific validity. The most important reason to discard thelactic acidosis concept is that it is invalid. It has no biochemicaljustification and, to no surprise, no research support. We havebeen criticized for our stance on the need to change howto teach and interpret metabolic acidosis based on Eq. 5(glucose 3 2 lactate 2H ). However, this is a summaryequation that does not represent cause and effect, as previouslydescribed and illustrated in Fig. 10. As such, the concept of alactic acidosis remains evidence of 1920s academic and scientificinertia that, out of simple convenience and apathy, stillremains today. We would hope that the academics and professionalsfrom the basic and applied fields that continue to acceptthe lactic acidosis construct immediately change the way theyteach and interpret this topic.Education. Education is a powerful force that can inducechange or reinforce error. Rather than continuing to reinforceerror, educators need to recognize their power in reshapingFig. 17. Balance between intramuscular proton release and consumption basedon fundamental biochemistry, as explained in the text. Data for nonmitochondrialATP 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 drywt. Data for muscle lactate, CrP, P i, and buffer capacity as for Fig. 16.Downloaded from ajpregu.physiology.org on October 31, 2008AJP-Regul Integr Comp Physiol • VOL 287 • SEPTEMBER 2004 • www.ajpregu.org
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Biochemistry of exercise-induced metabolic acidosis

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