Lactate Paradox: High Altitude and Exercise

Also see:
Protective Altitude
Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide
Carbon Dioxide as an Antioxidant
Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
Protective Carbon Dioxide, Exercise, and Performance
Exercise and Effect on Thyroid Hormone
Altitude Improves T3 Levels
Synergistic Effect of Creatine and Baking Soda on Performance
Exercise Induced Stress
Ray Peat, PhD: Quotes Relating to Exercise


Quotes by Ray Peat, PhD:
“Fatigued cells take up water, and become heavier. They also become more permeable, and leak. When more oxygen is made available, they are less resistant to fatigue, and when the organism is made slightly hypoxic, as at high altitude, muscles have more endurance, and are stronger, and nerves conduct more quickly.”

“K. P. Buteiko believed that increased carbon dioxide in the body fluids sometimes caused cancers to disappear. In many studies over the last 40 years (and the trend can also be seen in insurance statistics published in 1912), it is clear that cancer mortality is much lower at high altitude. Under all conditions studied, the characteristic lactic acid metabolism of stress and cancer is suppressed at high altitude, as respiration is made more efficient. The Haldane effect shows that carbon dioxide retention is increased at high altitude.

Studying athletes at sea level and at high altitude, it was seen that less lactic acid is produced by maximal exercise at high altitude than at sea level. Since oxygen deficiency in itself tends to cause the formation of lactic acid, this has been called the “lactate paradox”; the expectation was that more lactic acid would be formed, yet less was produced. Something was turning off the production of lactic acid. Normally, it is oxidative respiration that turns off glycolysis and lactic acid production, so that in exercise beyond the ability of the body to deliver oxygen, and in cancer with its respiratory defect, glycolysis produces lactic acid. So, something is happening at high altitude which turns off glycolysis.

The Haldane effect is a term for the fact that hemoglobin gives up oxygen in the presence of carbon dioxide, and releases carbon dioxide in the presence of oxygen. It is the increased retention of carbon dioxide that accounts for the “lactate paradox.” Carbon dioxide activates the Krebs cycle, but it also combines with ammonium, and in doing so, deactivates glycolysis because ammonium activates a regulatory enzyme. At high elevation, carbon dioxide is retained, and lactic acid formation is suppressed. (This is called the Pasteur effect, but altitude physiologists haven’t begun thinking in these directions.) Comparing very low altitude (Jordan valley, over 1000 feet below sea level) with moderate altitude (620 meters above sea level), ACTH was increased in runners after a race only at the low altitude, indicating that the stress reaction was prevented by a moderate increase of altitude. (el-Migdadi, et aI., 1996.)

The perspective we get on cancer, from the high altitude studies, allows us to go beyond the specific issue of cancer, to the more general issue of stress and regeneration. In outline, stress alters the physical nature of the cellular substance in a way that activates the cell, in which case it will either die from exhaustion, or grow into new cells. The replacement of injured cells means that mutations need not accumulate, and this renewal with elimination of mutant cells has been observed in sun-damaged skin. Among the many layers of form-generating and form-sustaining systems, the balance of electrical fields has a basic place.”

“The production of lactic acid during lactic acid during intense muscle activity led some people to suggest that fatigue occurred when the muscle wasn’t getting enough oxygen, but experiments show that fatigue sets in while adequate oxygen is being delivered to the muscle. Underwater divers sometimes get an excess of oxygen, and that often causes muscle fatigue and soreness. At high altitudes, where there is relatively little oxygen, strength and endurance can increase.”

“The idea of the “oxygen debt” produced by exercise or stress as being equivalent to the accumulation of lactic acid is far from accurate, but it’s true that activity increases the need for oxygen, and also increases the tendency to accumulate lactic acid, which can then be disposed of over an extended time, with the consumption of oxygen. This relationship between work and lactic acidemia and oxygen deficit led to the term “lactate paradox” to describe the lower production of lactic acid during maximal work at high altitude when people are adapted to the altitude. Carbon dioxide, retained through the Haldane effect, accounts for the lactate paradox, by inhibiting cellular excitation and sustaining oxidative metabolism to consume lactate efficiently.”

“Mild hypoxia, as at high altitude, suppresses lactic acid production (“the lactate paradox”), and increases the amount of carbon dioxide in tissues.”

Clin Physiol. 1990 May;10(3):265-72.
Limiting factors for exercise at extreme altitudes.
West JB.
Man can only survive and do work in the severe oxygen deprivation of great altitudes by an enormous increase in ventilation which has the advantage of defending the alveolar PO2 against the reduced inspired PO2. Nevertheless the arterial PO2 on the summit of Mt Everest at rest is less than 30 Torr, and it decreases with exercise because of diffusion limitation within the lung. One of the consequences of the hyperventilation is that the marked respiratory alkalosis increases the oxygen affinity of the haemoglobin and assists in loading of oxygen by the pulmonary capillary. Although ventilation is greatly increased, it is a paradox that cardiac output for a given work level is the same in acclimatized subjects at high altitude as at sea level. Stroke volume is reduced but not because of impaired myocardial contractility because this is preserved up to extreme altitudes. Indeed the normal myocardium is one of the few tissues whose function is unimpaired by the very severe hypoxia. There is evidence that oxygen delivery to exercising muscle is diffusion limited along the pathway between the peripheral capillary and the mitochondria. At the altitude of Mt Everest, maximal oxygen uptake is reduced to 20-25% of its sea level value, and it is exquisitely sensitive to barometric pressure. Seasonal variations of barometric pressure affect the ability of man to reach the summit without supplementary oxygen. In spite of the greatly reduced aerobic capacity, anaerobiosis is greatly curtailed, and it is predicted that above 7500 m, there is no rise in blood lactate on exercise. The paradoxically low lactate is possibly related to plasma bicarbonate depletion.

Eur J Appl Physiol Occup Physiol. 1996;74(3):195-205.
Lactate during exercise at high altitude.
Kayser B.
In acclimatized humans at high altitude the reduction, compared to acute hypoxia, of the blood lactate concentration (la) at any absolute oxygen uptake (VO2), as well as the reduction of maximum la (lamax) after exhaustive exercise, compared to both acute hypoxia or normoxia, have been considered paradoxical, and these phenomena have therefore become known as the “lactate paradox”. Since, at any given power output and VO2, mass oxygen transport to the contracting locomotor muscles is not altered by the process of acclimatization to high altitude, the gradual reduction in [la-]max in lowlanders exposed to chronic hypoxia seems not to be due to changes in oxygen availability at the tissue level. At present, it appears that the acclimatization-induced changes in [la-] during exercise are the result of at least two mechanisms: (1) a decrease in maximum substrate flux through aerobic glycolysis due to the reduced VO2max in hypoxia; and (2) alterations in the metabolic control of glycogenolysis and glycolysis at the cellular level, largely because of the changes in adrenergic drive of glycogenolysis that ensue during acclimatization, although effects of changes in peripheral oxygen transfer and the cellular redox state cannot be ruled out. With regard to the differences in lactate accumulation during exercise that have been reported to occur between lowlanders and highlanders, both groups either being acclimatized or not, these do not seem to be based upon fundamentally different metabolic features. Instead, they seem merely to reflect points along the same continuum of phenotypic adaptation of which the location depends on the time spent at high altitude.

Eur J Appl Physiol Occup Physiol. 1991;63(5):315-22.
Effect of beta-adrenergic blockade on plasma lactate concentration during exercise at high altitude.
Young AJ, Young PM, McCullough RE, Moore LG, Cymerman A, Reeves JT.
When unacclimatized lowlanders exercise at high altitude, blood lactate concentration rises higher than at sea level, but lactate accumulation is attenuated after acclimatization. These responses could result from the effects of acute and chronic hypoxia on beta-adrenergic stimulation. In this investigation, the effects of beta-adrenergic blockade on blood lactate and other metabolites were studied in lowland residents during 30 min of steady-state exercise at sea level and on days 3, 8, and 20 of residence at 4300 m. Starting 3 days before ascent and through day 15 at high altitude, six men received propranolol (80 mg three times daily) and six received placebo. Plasma lactate accumulation was reduced in propranolol- but not placebo-treated subjects during exercise on day 3 at high altitude compared to sea-level exercise of the same percentage maximal oxygen uptake (VO2max). Plasma lactate accumulation exercise on day 20 at high altitude was reduced in both placebo- and propranolol-treated subjects compared to exercise of the same percentage VO2max performed at sea level. The blunted lactate accumulation during exercise on day 20 at high altitude was associated with reduced muscle glycogen utilization. Thus, increased plasma lactate accumulation in unacclimatized lowlanders exercising at high altitude appears to be due to increased beta-adrenergic stimulation. However, acclimatization-induced changes in muscle glycogen utilization and plasma lactate accumulation are not adaptations to chronically increased beta-adrenergic activity.

High Alt Med Biol. 2003 Winter;4(4):431-43.
Persistence of the lactate paradox over 8 weeks at 3,800 m.
Pronk M, Tiemessen I, Hupperets MD, Kennedy BP, Powell FL, Hopkins SR, Wagner PD.
The arterial blood lactate [La] response to exercise increases in acute hypoxia, but returns to near the normoxic (sea level, SL) response after 2 to 5 weeks of altitude acclimatization. Recently, it has been suggested that this gradual return to the SL response in [La], known as the lactate paradox (LP), unexpectedly disappears after 8 to 9 weeks at altitude. We tested this idea by recording the [La] response to exercise every 2 weeks over 8 weeks at altitude. Five normal, fit SL-residents were studied at SL and 3,800 m (Pbar = 485 torr) in both normoxia (PIO2 = 150 torr) and hypoxia (PIO2 = 91 torr approximately air at 3,800 m). Arterial [La] and blood gas values were determined at rest and during cycle exercise at the same absolute workloads (0, 25, 50, 75, 90, and 100% of initial SL-VO2Max) and exercise duration (4, 4, 4, 2, 1.5, and 0.75 min, respectively) at each time point. [La] curves were elevated in acute hypoxia at SL (p < 0.01) and at 3,800 m fell progressively toward the SL-normoxic curve (p < 0.01). On the same days, [La] responses in acute normoxia showed essentially no changes over time and were similar to initial SL normoxic responses. We also measured arterial catecholamine levels at each load and found a close relationship to [La] over time, supporting a role for adrenergic influence on [La]. In summary, extending the time at this altitude to 8 weeks produced no evidence for reversal of the LP, consistent with prior data obtained over shorter periods of altitude residence.

Fed Proc. 1986 Dec;45(13):2953-7.
Lactate during exercise at extreme altitude.
West JB.
Maximal exercise at extreme altitude results in profound arterial hypoxemia and, presumably, extreme tissue hypoxia. The best evidence available indicates that the resting arterial PO2 on the summit of Mount Everest is about 28 torr and that it falls even further during exercise. Nevertheless, some 10 climbers have now reached the summit without supplementary oxygen. Paradoxically, blood lactate for a given work rate at high altitude in acclimatized subjects is essentially the same as at sea level. Because work capacity decreases markedly with increasing altitude, maximal blood lactate also falls. Extrapolation of available data up to 6300 m indicates that a climber who reaches the Everest summit will have no increase in blood lactate. The cause of the low blood lactate during exercise at extreme altitude is not fully understood. One possibility is depletion of plasma bicarbonate in acclimatized subjects, which reduces buffering and results in large increases in H+ concentration for a given release of lactate. The consequent local fall in pH may inhibit enzymes, e.g., phosphofructokinase (EC, in the glycolytic pathway.

J Appl Physiol. 1991 Apr;70(4):1720-30.
Metabolic and work efficiencies during exercise in Andean natives.
Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS.
Maximum O2 and CO2 fluxes during exercise were less perturbed by hypoxia in Quechua natives from the Andes than in lowlanders. In exploring how this was achieved, we found that, for a given work rate, Quechua highlanders at 4,200 m accumulated substantially less lactate than lowlanders at sea level normoxia (approximately 5-7 vs. 10-14 mM) despite hypobaric hypoxia. This phenomenon, known as the lactate paradox, was entirely refractory to normoxia-hypoxia transitions. In lowlanders, the lactate paradox is an acclimation; however, in Quechuas, the lactate paradox is an expression of metabolic organization that did not deacclimate, at least over the 6-wk period of our study. Thus it was concluded that this metabolic organization is a developmentally or genetically fixed characteristic selected because of the efficiency advantage of aerobic metabolism (high ATP yield per mol of substrate metabolized) compared with anaerobic glycolysis. Measurements of respiratory quotient indicated preferential use of carbohydrate as fuel for muscle work, which is also advantageous in hypoxia because it maximizes the yield of ATP per mol of O2 consumed. Finally, minimizing the cost of muscle work was also reflected in energetic efficiency as classically defined (power output per metabolic power input); this was evident at all work rates but was most pronounced at submaximal work rates (efficiency approximately 1.5 times higher than in lowlander athletes). Because plots of power output vs. metabolic power input did not extrapolate to the origin, it was concluded 1) that exercise in both groups sustained a significant ATP expenditure not convertible to mechanical work but 2) that this expenditure was downregulated in Andean natives by thus far unexplained mechanisms.

J Appl Physiol. 1991 May;70(5):1963-76.
Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders.
Matheson GO, Allen PS, Ellinger DC, Hanstock CC, Gheorghiu D, McKenzie DC, Stanley C, Parkhouse WS, Hochachka PW.
Two metabolic features of altitude-adapted humans are the maximal O2 consumption (VO2max) paradox (higher work rates following acclimatization without increases in VO2max) and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at increasing altitude). To assess underlying mechanisms, we studied six Andean Quechua Indians in La Raya, Peru (4,200 m) and at low altitude (less than 700 m) immediately upon arrival in Canada. The experimental strategy compared whole-body performance tests and single (calf) muscle work capacities in the Andeans with those in groups of sedentary, power-trained, and endurance-trained lowlanders. We used 31P nuclear magnetic resonance spectroscopy to monitor noninvasively changes in concentrations of phosphocreatine [( PCr]), [Pi], [ATP], [PCr]/[PCr] + creatine ([Cr]), [Pi]/[PCr] + [Cr], and pH in the gastrocnemius muscle of subjects exercising to fatigue. Our results indicate that the Andeans 1) are phenotypically unique with respect to measures of anaerobic and aerobic work capacity, 2) despite significantly lower anaerobic capacities, are capable of calf muscle work rates equal to those of highly trained power- and endurance-trained athletes, and 3) compared with endurance-trained athletes with significantly higher VO2max values and power-trained athletes with similar VO2max values, display, respectively, similar and reduced perturbation of all parameters related to the phosphorylation potential and to measurements of [Pi], [PCr], [ATP], and muscle pH derivable from nuclear magnetic resonance. Because the lactate paradox may be explained on the basis of tighter ATP demand-supplying coupling, we postulate that a similar mechanism may explain 1) the high calf muscle work capacities in the Andeans relative to measures of whole-body work capacity, 2) the VO2max paradox, and 3) anecdotal reports of exceptional work capacities in indigenous altitude natives.

High Alt Med Biol. 2006 Summer;7(2):105-15.
Work capacity of permanent residents of high altitude.
Marconi C, Marzorati M, Cerretelli P.
Tibetan and Andean natives at altitude have allegedly a greater work capacity and stand fatigue better than acclimatized lowlanders. The principal aim of the present review is to establish whether convincing experimental evidence supports this belief and, should this be the case, to analyze the possible underlying mechanisms. The superior work capacity of high altitude natives is not based on differences in maximum aerobic power (V(O2 peak)), mL kg(-1)min(-1)). In fact, average V (O2 peak) of both Tibetan and Andean natives at altitude is only slightly, although not significantly, higher than that of Asian or Caucasian lowlanders resident for more than 1 yr between 3400 and 4700 m (Tibetans, n = 152, vs. Chinese Hans, n = 116: 42.4 +/- 3.4 vs. 39.2 +/- 2.6 mL kg(-1)min(-1), mean +/- SE; Andeans, n = 116, vs. Caucasians, n = 70: 47.1 +/- 1.7 vs. 41.6 +/- 1.2 mL kg(-1)min(-1)). However, compared to acclimatized lowlanders, Tibetans appear to be characterized by a better economy of cycling, walking, and running on a treadmill. This is possibly due to metabolic adaptations, such as increased muscle myoglobin content and antioxidant defense. All together, the latter changes may enhance the efficiency of the muscle oxidative metabolic machinery, thereby supporting a better prolonged submaximal performance capacity compared to lowlanders, despite equal V(O2 peak). With regard to Andeans, data on exercise efficiency is scanty and controversial and, at present, no conclusion can be drawn as to the origin of their superior performance.

Cor Vasa. 1981;23(5):359-65.
Heart rhythm disturbances in the inhabitants of mountainous regions.
Mirrakhimov MM, Meimanaliev TS
The authors studied 513 males, permanently living in the high-mountain regions of Tian Shan and the Pamirs (2800 – 4000 m above sea level). A control group consisted of 404 males permanently living at low altitudes (780-900 m above sea level) in the Kemin District, Kirghiz SSR. The probands’ ages were 30-59 years. In all of them the resting electrocardiograms were recorded; 110 exercise tests were made in the high mountains, and 35 tests, at the low altitudes. The prevalence of heart rhythm disturbances was statistically significantly higher in the inhabitants of the high-mountain regions (12.1%) than in the low-altitude inhabitants (2.9%; p less than 0.0001). The most frequent disturbance was the 1st-degree a-v block (6 per cent). In the high mountains cardiac arrhythmias are usually associated with right ventricular hypertrophy, caused by high-altitude hypoxia. During exercise heart arrhythmias appeared conspicuously less frequently in the high mountain than in the low altitude inhabitants.

Acta Physiol Scand. 2000 Dec;170(4):265-9.
The ‘lactate paradox’, evidence for a transient change in the course of acclimatization to severe hypoxia in lowlanders.
Lundby C, Saltin B, van Hall G.
The metabolic response to exercise at high altitude is different from that at sea level, depending on the altitude, the rate of ascent and duration of acclimatization. One apparent metabolic difference that was described in the 1930s is the phenomenon referred to as the ‘lactate paradox’.Acute exposure to hypoxia results in higher blood lactate accumulation at submaximal workloads compared with sea level, but peak blood lactate remain the same. Following continued exposure to hypoxia or altitude, blood lactate accumulation at submaximal work and peak blood lactate levels are paradoxically reduced compared with those at sea level. It has recently been shown, however, that, if the exposure to altitude is sufficiently long, blood lactate responses return to those seen at sea level or during acute hypoxia. Thus, to evaluate the ‘lactate paradox’ phenomenon in relation to time spent at altitude, five Danish lowland climbers were studied at sea level, during acute exposure to hypoxia (10% O2 in N2) and 1, 4 and 6 weeks after arrival in the basecamp of Mt Everest (approximately 5400 m, Nepal). Basecamp was reached after 10 days of gradual ascent from 2800 m. Peak blood lactate levels were similar at sea level (11.0 +/- 0.7 mmol L-1) and during acute hypoxia (9.9 +/- 0.3 mmol L-1), but fell significantly after 1 week of acclimatization to 5400 m (5.6 +/- 0.5 mmol L-1) as predicted by the ‘lactate paradox’. After 4 weeks of acclimatization, peak lactate accumulation (7.8 +/- 1.0 mmol L-1) was still lower compared with acute hypoxia but higher than that seen after 1 week of acclimatization. After 6 weeks of acclimatization, 2 days after return to basecamp after reaching the summit or south summit of Mt Everest, peak lactate levels (10.4 +/- 1.1 mmol L-1) were similar to those seen during acute hypoxia. Therefore, these results suggest that the ‘lactate paradox’ is a transient metabolic phenomenon that is reversed during a prolonged period of exposure to severe hypoxia of more than 6 weeks.

“Many people experience exhilaration when they go to very high altitudes, and it is known that people generally burn calories faster at high altitude. It has been found that, during intense exercise (which always produces a lactic acid accumulation in the blood), a lower peak accumulation of lactate occurs at high altitude, and this seems to be caused by a reduction in the rate of glycolysis, or glucose consumption (B. Grassi, et al.)” –Ray Peat, PhD

J Appl Physiol. 1995 Jul;79(1):331-9.
Maximal rate of blood lactate accumulation during exercise at altitude in humans.
Grassi B, Ferretti G, Kayser B, Marzorati M, Colombini A, Marconi C, Cerretelli P.

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