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

Authors

Bruno Grassi

Published in

Experimental physiology. Sep 28, 2026. Epub Sep 28, 2026.

Abstract

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.

PMID:
42803361
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.

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