Plausible mechanisms for improvement in exercise economy after a period of altitude exposure include a decreased cost of ventilation, greater CHO use for oxidative phosphorylation, and/or an increased ability of the excitation and contraction process to perform work at lower energy costs (25). Work from our research group suggest that the physiological mechanisms eliciting an improved economy after hypoxic exposure appear unrelated to decreased ventilation or a substantial shift in substrate use (70). Therefore, it is possible that the main mechanisms responsible for improved economy at sea level after a period of altitude exposure are either an increase in the ATP production per mole of oxygen used (31) and/or a decrease in the ATP cost of muscle contraction (60). A reduced energy requirement of one or more processes involved in excitation and contraction of the working muscles has been previously postulated by Green et al. (25), possibly as a result of a reduction in by-product accumulation, such as ADP, inorganic phosphate and H+, that occurs after altitude acclimatization, which increases the amount of free energy released from ATP hydrolysis and depresses the need to maintain hydrolysis rates at preacclimatized levels.
The concept of improved economy of exercise after hypoxic exposure being attributable to changes in the coupling of ATP demand and supply in the working muscles was first postulated by Hochachka (30). Performance in endurance events is defined as V˙O2max × V˙O2fracmax × efficiency, where V˙O2fracmax is the fractional use of V˙O2max that an athlete can attain during an event (18). Efficiency of physical work is an overall measure of how effective the body is at converting substrates into external work in the form of ATP (56). Explaining how economy might improve after altitude exposure requires an understanding of energy metabolism via oxidative phosphorylation, to determine the processes that may be altered after exposure to hypoxia and ameliorate energetic efficiency. The high ATP use required for endurance exercise can only be supported by mitochondrial oxidative phosphorylation, and, consequently, mitochondrial efficiency has a direct influence on whole-body efficiency (60).
It has also been established that low sensitivity to cytosolic ADP and the control of respiration by the creatine kinase (CK) system, is a hallmark of fatigue resistant oxidative muscles. At the local level, mitochondrial respiration is driven by the ratio of creatine (Cr) to creatine phosphate instead of cytosolic ADP, with mitochondrial CK being coupled to ADP production and translocation. Better coupling of energy production to energy utilization by the CK system may increase mitochondrial efficiency, by delaying anaerobic energy production because local ATP and ADP levels remain in relative homeostasis for longer (60). Another way of improving mitochondrial efficiency is by delivering the reducing equivalents of substrates into the mitochondrial respiratory chain at different steps. Oxidation of cytosolic NADH involves import of reducing equivalents into the mitochondria by the malate-aspartate shuttle or the glycerophosphate shuttle. The glycerophosphate shuttle omits the first phosphorylation step at complex I, yielding a lower amount of inorganic phosphate incorporated into ATP per mole of oxygen consumed (decreased efficiency), and accompanied by faster rates of respiration and increased thermogenesis (39). On the other hand, greater use of the malate-aspartate shuttle to oxidize NADH would produce more ATP per mole of oxygen used, leading to better muscle efficiency. In an animal model, it has been reported that 25-30 d of simulated altitude exposure equivalent to 5000 m via hypobaria for 5-6 h·d−1 resulted in improved mitochondrial efficiency (49). Lukyanova claims that the mechanisms responsible for this improved efficiency are related to the ability to maintain high coupling of oxidative phosphorylation and synthesis achieved by an increase in number of mitochondria in the cells accompanied by a reduced cytochrome content possessing a higher activity, new kinetic properties of NADH oxidation allowing maintenance of key enzyme activity in conditions of high NADH reduction under hypoxia, and reducing the role of the less efficient succinate oxidase pathway. In humans, 6 wk of simulated hypoxic training at 3000 m twice a week for 20 min resulted in adaptations of the athlete's skeletal muscle allowing better coupling between the energy use and production sites to promote more efficient oxidative pathways (60). Specifically, mitochondrial sensitivity to ADP was depressed by 57% in the group exposed to hypoxia compared with the control group, represented by a higher half-maximal velocity (Km) for ADP. After hypoxic training, the Km/(Km + Cr) ratio increased twice as much (124 vs 66%) in the hypoxic training group compared with the control group. This ratio reflects improved efficiency of mitochondrial CK and oxidative phosphorylation coupling and, taken together with reduced ADP sensitivity, indicates more efficient energy metabolism in the mitochondria (60).
There have been relatively few studies that have investigated changes in membrane transport proteins in response to altitude exposure. It has been demonstrated in rats that hypoxia stimulates glucose transport by via translocation of Glut-4 from the intracellular compartments to the plasma membrane of skeletal muscle. It has also been shown that the major signaling agents for the hypoxia-mediated glucose transport in skeletal muscle is dependent on the presence of AMP-activated protein kinase and may also be effected by reactive oxygen species (43). Clark et al. (16) measured MCT1 and MCT4 protein content in skeletal muscle of well-trained individuals after 20 nights of simulated moderate LHTL. Although this study reported a decrease in lactate rate of appearance, there was no change in MCT1 and MCT4 protein abundance. Because the lactate/H+ transport system is thought to be more active during exercise than at rest (37), it may be that only sleeping under hypoxic conditions is not an adequate stimulus to increase MCT1 and MCT4 protein expression. On the other hand, Juel et al. (37) have reported a fivefold increase in MCT1 proteins in the erythrocytes after 8 wk of acclimatization to 4100 m in untrained humans. The authors of this study suggest that if the increase in the MCT1 in erythrocytes is functional then it could be expected to enhance the lactate/H+ transport across the erythrocyte membrane and may act as an important dilution space during intense exercise when there are fast changes in plasma lactate and pH (37). Interestingly, it was reported that there was no change in the skeletal muscle MCT1 and MCT4 transporters (37). These results are similar to those of Clark et al. (16), and in both studies the subjects performed no vigorous exercise under hypoxia. In contrast, Zoll et al. (86) reported an increase in the muscle mRNA concentration of MCT1 (44%) in nine well-trained runners after 6 wk of training (12× 24- to 40-min sessions) under hypoxic conditions (3000-m simulated altitude) compared with a control group. Run time to exhaustion at V˙O2max was increased in the hypoxic trained group with no change in the maximal lactate accumulation. The authors concluded that the increase in MCT1 mRNA allowed an improvement of lactate exchange and removal that may lead to the slower decline in pH at a given running velocity, thereby allowing the athletes to run longer (86). The capacities of the pH-regulating transport systems are not only dependent on the protein density and activation of the individual transport proteins but also on the carbonic anhydrases (CA) (37). The reactions catalyzed by CA function as H+ acceptors or donors and thereby influence the rate of H+ and HCO3− transport (21). An increase in CA IV isoforms in glycolytic muscle fibers was reported after 8 wk of acclimation to altitude (37). Furthermore, it has been demonstrated that the muscle mRNA of CA IV has been increased after 6 wk of training in hypoxic conditions (86). Collectively, these few studies indicate that altitude acclimatization may alter the transport systems that are involved with changes in dynamic buffering capacity.
A balanced review of the effects of hypoxia on sea-level performance is incomplete without some consideration of its potentially unfavorable effects, which include hypoxia's impact on cardiac function, anaerobic metabolism, muscle function, sleep and immune function. At high altitude, there is a depression of cardiac output caused mainly by a reduction in stroke volume and possibly lower myocardial contractility (27) and even after more moderate altitude (4 wk of LHTL at 2500 m) there was a trend toward a lower cardiac output and a significantly larger arteriovenous difference during treadmill running at race pace at sea level (46). On the other hand, at a low altitude (1980 m), LHTL for 2 wk was associated with improved left ventricular contractility (48).
Sleep is essential for athlete recovery, but even at moderate altitudes (2650 m) there is sleep disturbance and even periodic breathing among some susceptible athletes (44). A further consideration for athletes that have to travel abroad to access suitable altitudes is the increased propensity to illness (7) as evidenced by a suppressed immune function (54). Overall, the negative effects of hypoxia seem more pronounced at high to extreme altitude, albeit that sleep and immune function of some athletes are likely compromised even at moderate altitude.
In summary, this brief review has detailed the large body of literature that demonstrates improvements in sea-level performance after a period of altitude exposure/training may have a multifactorial etiology and are not solely dependent on increasing red cell volume via erythropoiesis. Mechanisms responsible for this observed improvement in performance after exposure to hypoxia appear to be a HIF-1 driven response at a molecular level and are likely to include improved exercise efficiency related to tighter coupling of muscular intracellular bioenergetics and mitochondrial function leading to improved mitochondrial efficiency, and/or improved muscle pH regulation and βm. Another novel mechanism may be related to changes in UCP3 content within the skeletal muscle to attenuate proton leakage across the mitochondrial membrane and improve efficiency of metabolic oxidation. Finally, with quite small performance benefits (1-2%) associated with LHTL it is possible that type II errors (false negatives) may be present in our search for mechanisms to explain an improvement in athletes' sea-level performance subsequent to altitude exposure. For instance, with a P value of 0.05 and power of 80%, a sample size of 64 athletes would be required for fully controlled study to detect a 1% improvement in performance if the within subject variation in performance is also 1% (http://sportsci.org/resource/stats/ssdetermine.html).
We are indebted to our colleagues at the Australian Institute of Sport who over 12 years have contributed to our research. We would particularly like to thank Prof Allan Hahn, Dr Michael Ashenden, Dr David Martin, Assoc Prof David Pyne, and Dr Nathan Townsend from the AIS as well as affiliated researchers Dr Rob Aughey, Dr Chin-Moi Chow, Prof John Hawley, Dr Tahnee Kinsman, Prof Michael McKenna and Prof Richard Telford. The support of the Applied Research Centre of the Australian Institute of Sport is also gratefully acknowledged.
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