Adaptability of Metabolic Efficiencies Under Chronic Hypoxia in Man

128With potentially limiting O₂ availability, increasing efficiency of metabolism and cell work in principle can be achieved in at least three ways: (1) through maximizing the moles of ATP obtained per mole of fuel substrate metabolized; (2) through maximizing the moles of ATP obtained per mole of O₂ consumed; and (3) through maximizing work achieved per mole ATP utilized. In the first case, decreasing the contributions of anaerobic pathways (low ATP yield) relative to aerobic ones (high ATP yield) is favored. In the second strategy, glycogen (glucose) oxidation is favored over the oxidation of fats because it leads to fractionally more ATP per mole of O₂ consumed during complete oxidation. In the third case, increasing efficiency classically defined as ratio of mechanical power output to metabolic power input is favored. All three strategies for maximizing efficiency of muscle metabolism and work are utilized by high altitude natives during exercise to fatigue under normoxic and hypoxic conditions. Interestingly, the underlying metabolic adaptations behave like (genetically or developmentally) fixed characteristics, because they are expressed even after prolonged time periods at sea level. Of these three kinds of adaptive responses, the fractional gains achieved by increasing the ratio of aerobic/anaerobic metabolism, strategy (1) above, far exceed the possibilities in (2) and (3); thus underlying mechanisms are of special interest. Currently, it appears that a two-tiered regulation system is involved. A primary (coarse level) mechanism involves closer coupling of energy demand and energy supply so that intermediates such as the adenylates are less perturbed during work and thus less strongly activate glycogen carbon flux to pyruvate. Superimposed upon this is a finer tuning of enzymes at the pyruvate branchpoint (upregulation of pyruvate kinase and malate dehydrogenase activities; downregulation of total and muscle-type lactate dehydrogenase activity and of mitochondrial oxidative capacity) so as to minimize pyruvate flux to lactate while increasing the ratio of aerobic to anaerobic metabolism.