The key for an animal to survive prolonged hypoxia is to avoid rapid decline in ATP levels in vital organs such as the brain. This can be well achieved by a very few of hypoxia-tolerant animals such as freshwater turtles and newborn animals, since these animals can substantially suppress their metabolic levels by coordinated regulation of ATP-producing and ATP-demanding pathways. However, most animals, especially adult mammals, can only tolerate a short period of hypoxia since they are unable to maintain constant ATP levels and energy charge in vital organs during prolonged hypoxic exposure. Here, we described a special mouse model, in which a hypoxia intolerant adult mouse gradually built up an ability to survive prolonged hypoxia after intermittent hypoxic exposures. This increased ability was accompanied by reductions in body temperature and O-2 consumption as well as transient variations in blood pCO(2), pO(2) and pH. The glucose and energy metabolism in the brain of the mouse altered similarly to those reported in the brain of hypoxic turtles. Activities of phosphofructokinase and pyruvate kinase, the two rate-limiting enzymes controlling the rate of glycolysis decreased to baseline levels after a short period of increase. In contrast, the activity of complex I, the major enzyme complex controlling oxidative phosphorylation, was kept inhibited. These alterations in the ATP-producing pathway suggest the occurrence of reverse Pasteur effect, indicating that the animal had entered a hypometabolic state favoring maintenance of ATP level and energy charge in hypoxic conditions. In supporting this idea, the ATP levels and energy charge as well as neuronal structures in the brain were well preserved. This study provides evidence for a possibility that a hypoxic intolerant animal can build up an ability to survive prolonged hypoxia through regulation of its glucose and energy metabolism after an appropriate hypoxic training, which deserves further investigation. (C) 2011 Elsevier B.V. All rights reserved.