Muscular adaptation to middle altitude: practical issues for training

Muscular adaptation to middle altitude: practical issues for training

This brief review is aimed at providing support to the hypothesis that hypoxia may induce muscular adaptations affecting sea-level performance, depending an still unknown factors, mainly related to individual and environmental characteristics. Among them, this review will focus on the role of ethnicity and duration of exposure to and severity of hypoxia. Caucasian sea-level natives. It is well known that maximal mechanical (Margaria 1929) and aerobic power of Caucasians acutely or chronically exposed to hypoxia decreases with altitude. In addition, more than 50 years ago Balke et al. (1956) addressed first the issue as to the effects of altitude acclimatization on work capacity of lowlanders upon return to sea level. They showed that immediately after return from 6 weeks at about 4300 m physical performance was improved compared to pre-expedition. 10 years later, Grover and Reeves (1966) found no change in sea-level performance after 20 days at 3100 m as did Buskirk et al. (1967) in well-conditioned runners after 20 days at 4000 m.

On the contrary, Faulkner et al. (1968) found that the average 1-mile running time of 6 athletes improved significantly by 1% (from 282 ± 41 to 279 ± 41 s) after 40 days at 2300-3100 m altitude. Following those seminal but conflicting studies, many endurance athletes started training at altitude or adopting more complex procedures, such as the “living high-training low” paradigm (Levine and Stray-Gundersen, 1997), sharing their time between hypoxia and normoxia to improve sea-level performance. For many years it has been suggested that the main mechanism underlying such improvement is the hypoxia-induced increase in blood red cell mass, and haemoglobin concentration. The latter leads to an increase in oxygen-carrying capacity of the blood at sea level, and, consequently, of maximal oxygen consumption (VO2max) by muscles. However, in some conditions it appears that the sea-level performance is independent of increased oxygen delivery (Levine et al., 2005). This is particularly evident after prolonged sojourn above 5000 m altitude. In such a condition, acclimatised Caucasian climbers acutely breathing a normoxic gas mixture recovered only 90% of their sea-level VO2max, despite a great increase in oxygen carrying capacity (haemoglobin concentration above 20 g/dl) (Cerretelli 1973).

This finding was attributed to a likely reduction in maximal capillary blood flow in exercising muscles. About 20 years later, a much more relevant explanation for that finding was found, i.e. a muscle deterioration with severe ultrastructural changes. Muscle mass atrophy, reduction in mitochondrial volume density and oxidative enzyme activity (Howald et al., 1990) and increased content of muscle lipofuscin (Martinelli et al., 1990) were found in the vastus lateralis muscle of acclimatised climbers after 8-10 weeks at above 5000 m altitude. Lipofuscin is a granular yellow brown pigment composed of lipidcontaining residues of lysosomal digestion. It is a product of the peroxidation of unsaturated fatty acids by reactive oxygen species (ROS) and other free radicals. In fact, although it may appear a paradox, lowlanders sojourning at altitude are at an increased risk of oxidative stress, leading to the formation of altered molecules, including DNA, proteins and lipids. However, it is to note that during a prolonged sojourn at 4100 m, oxidative DNA damage has been found only in the first 2 weeks of exposure to hypoxia, being completely repaired by the 8th week (Lundby et al., 2003). Hypoxia and accumulation of ROS may also play a role in reducing protein synthesis followed by a downregulation of many ATP-dependent processes, like ion pumps. This would lead to cut down non-primary energy expenses to spare ATP for muscle contraction. Indeed, sometimes a decreased activity mainly of the Na+-K+-ATPase and to a lesser extent also of the sarcoplasmic reticulum Ca2+-ATPase has been found along with increased sealevel performance (for a review, see Marconi et al, 2006).

However, a downregulation of Na+-K+-ATPase should contribute to decline muscle excitability and accelerate fatigue and induce a further production of ROS and accumulation of intramitochondrial nitric oxide (NO). The latter may compete with oxygen for cytochrome c oxidase (COX). It is to note that downregulation of ATPase activity seems to occur very early, i.e. within the first 5 nights of exposure to hypoxia (“living high-training low”), been followed by a compensatory increase (Aughey et al, 2006). Recently, the improved sea-level performance of elite runners after normobaric hypoxia has been related to a better coupling between ATP demand and supply, due to a decreased activity in uncoupling protein 3 (UCP3) or decreased sensitivity of mitochondrial respiration to ADP (Ponsot et al., 2006). High altitude natives. Hurtado showed first that the endurance time of Andean natives at Morococha (4540 m) was longer than that of lowlanders running at sea level at the same speed and incline of the treadmill. In addition, altitude natives were characterized by greater pulmonary ventilation, lower heart rate and less oxygen consumption per unit of mechanical power output than lowlanders. The average “net” efficiency of treadmill running was 22.2% and 19.9% for altitude natives and lowlanders, respectively. Based on the above findings Hurtado (1964) concluded that “a high degree of physical efficiency is one of the most important characteristics of the native residents and possibly the best index of their acclimatization”.

Unfortunately, this important conclusion fell into oblivion in the subsequent 30 years. Since then, only few studies have compared submaximal exercise VO2 of highland natives (mainly Tibetans) with that of acclimatised lowlanders permanently living at the same altitude. From these studies, it appears that Tibetans have a greater economy of locomotion (defined as oxygen consumption at a given mechanical power output) than acclimatised lowlanders. Interestingly, during an identical incremental exercise protocol carried out at Lhasa (3658 m), Tibetans from a higher settlement (4400 m) have a lower VO2 of than local subjects irrespective of the workload. The above findings allow to conclude that Tibetans are characterized by a more efficient aerobic metabolism compared to acclimatized lowlanders and maybe also highland Andeans (Brutsaert et al., 2004), who have up to 10% European admixture. Strong evidence that high-altitude Tibetans are characterized by a greater economy of locomotion has been recently provided by the author of this review (Marconi et al., 2005), showing at 1300 m that altitude Tibetans walking and running at constant speed and inclines had a lower VO2 than Nepali controls. The greater economy of locomotion of Tibetans compared to Nepali has no evident explanation. In fact, it is not accounted for by a greater compensatory reliance on anaerobic energy sources nor by lower energy expenditure to sustain the ventilatory and cardiac work at a given load. Interestingly, recent unpublished yet experiments carried out at 4300 m altitude in Tibet reveal that economy of locomotion of Tibetans increases with severity of hypoxia.

Metabolic adaptations in high-altitude Tibetans. Analysis of the most expressed proteins has been carried out on muscle biopsy obtained from a number of the same Tibetan and Nepali subjects, who underwent experiments at 1300 m. Compared to Nepali lowlanders, Tibetans exhibit a greater expression of a limited number of muscle proteins influencing directly and indirectly cellular respiratory function, such as a 4-fold increase in Glutathione- S-Transpherase P1-1 (GST P1-1), and a 100% overexpression of 1 out of 3 myoglobin isoforms, i.e. that with pI = 7.29 (Gelfi et al., 2004). Based on the above results it has been hypothesised that muscle cells of Tibetans have a greater antioxidant protection against ROS accumulation preventing from mitochondrial damage. The found increase in myoglobin may play a relevant role in controlling mitochondrial respiration. In fact, it has been suggested that particularly in hypoxia, reduced and oxygenated myoglobin, NO, and COX are tied to each other by complex relationships with implications for the efficiency of the oxidative phosphorylation-electron transfer coupling. In fact, myoglobin may be involved in the regulation of NO concentration at the microvascular and tissue level and may relieve NOinduced inhibition of COX (see Marconi et al., 2006), optimising the rate of oxygen inflow and consumption by the muscles. Conclusions.

Exposure to hypoxia induces molecular adaptations in the muscle cells, which at least in part may be due to increased oxidative stress and may (or may not) increase the efficiency of the metabolic machinery, depending on severity of hypoxia, duration of exposure and ethnic or individual characteristics. So far it seems quite difficult to define an optimal protocol of altitude sojourn and the proper time interval upon return to normoxia to obtain the greater increase in sea-level endurance performance. In addition, evaluation of blood oxidative stress markers and, if necessary, administration of antioxidants supplementation should be highly advisable. Finally, it is to be hoped that the improving knowledge as to muscle adaptation to hypoxia in athletes or high altitude natives will be useful for the treatment of sea-level chronically hypoxic patients.