The 'lactate paradox' revisited after 35 years: In memoriam Paolo Cerretelli

Some decades ago significant scientific interest was raised by the concept of the 'lactate paradox' occurring during altitude acclimatization. In short, in acute hypoxia blood lactate^- concentration ([La]_b) is higher, compared to normoxia, at any given submaximal work rate, whereas peak [La]_b at exhausting exercise is unchanged. During altitude acclimatization the [La]_b vs. submaximal work rate relationship falls towards the original sea-level curve, whereas peak [La]_b progressively falls with increasing altitude. Upon the premise that lactate^- accumulation derives from lack of O₂ and anaerobic glycolysis, the lowered [La]_b at altitude was considered 'paradoxical'. After decades of research on the 'lactate shuttle' and lactate metabolism the issue should be revisited. A new scenario could be summarized as follows. Muscle and blood lactate^- accumulation during increasing intensity exercise reflect a mismatch between a faster 'speed' of glycolysis and a relatively slower speed of oxidative phosphorylation, possibly aimed at accumulating lactate^- in blood, to be distributed for different purposes throughout the body. Acute hypoxia further accelerates glycolysis through an enhanced sympatho-adrenergic stimulation, worsens intracellular hypoxia and increases [ADP]∙[P_i]/[ATP], resulting in a greater [La]_b for the same absolute work rate. During altitude acclimatization the sympatho-adrenergic stimulation falls, intracellular hypoxia is attenuated (mainly through a reduced O₂ demand), the [ADP]∙[P_i]/[ATP] increase subsides, and a tighter coupling between lactate^- production and utilization ensues, with the end result of decreased [La]_b for the same absolute work rate and lower peak [La]_b. Although the perspective is radically changed, this remarkable series of metabolic adaptations appears of interest also today.