Intermittent Hypoxia Erythropoiesis Mitochondrial Biogenesis Effects on Behavior Including Endurance in Athletics

Intermittent Hypoxia, Erythropoiesis, Mitochondrial Biogenesis, Effects on Behavior (including Endurance in Athletics

A test of fourteen senior male national squad rowers was conducted by Telford and co-workers (1994) in order to ascertain whole blood viscosity at higher 100 s-1 (WBVH) shear rate and low 0.1 s-1 (WBVL), red blood cell mean cell volume, white and red blood cell count, blood parameters of haemoglobin concentration. In order to evaluate the performance of rower, rowing ergometer was used for the 2500 m continuous effort. The results of rowers included Hb 15.5 g.dL-1, Hct 45.5%, WBVL 64.1 cP, WBVH 4.2 cP, and a BMI (Body Mass Index) of 24.6. WBVH demonstrated by the rowers was significantly (p

Significant correlation was found of WBVH in rowers with rowing performance (p

Considering that WBVH is greatly influenced by haematocrit, plasma viscosity, and erythrocyte deformability then rowers' better performance can be attributed to decreased plasma viscosity and increased "red blood cell deformability." Viscosity is increased when the red blood cell aggregation is increased, which dampens the effect of haematocrit, plasma viscosity, and "red blood cell deformability" on the whole body, particularly at lower shear rates (Telford et al., 1994). Hence this paper will not only look at the aforementioned aspects but also pay primary attention at the influential aspects of intermittent hypoxia, erythropoiesis, mitochondrial biogenesis and RBC production on the athlete's overall performance and endurance.

Living High-Training Low

Levine et al. (1991) in their study, as well as Levine and Stray-Gundersen (1992) in their respective study, initiated an innovative path to training at altitudes for athletes to increase their endurance or performance. Levine and his colleagues suggested that the 'most effective' plan in training could be to live at some altitude, either by living at that height or by using a simulator of height resembling the altitude of around 2500 meters, and to minimize the training at sea-level. The plus points of normally living in an environment comparatively low in oxygen are increase in the density and count of RBCs, without really giving up an increase in VO2 max and recovery time. But one negative point in training at heights is decrease in the excellence and power of training because of living and doing training at such elevated heights. Intermittent Hypoxic Exposure or IHE is the rule of training of 'living high' at the altitude of 2500 meters and at sea-level ie. 'training low.'

The presumptive theory of "living at high altitude and training at low altitude (high-low)" was applied on nine aggressive and able runners in an experimental period of training for four weeks to see its impact on their endurance and performance. The high-low group was made to live at 2500 m but both the groups, control ("low-low") and the "high-low," were trained at 1300 m. In the "high-low" group there was a noteworthy increase of 5% in VO2max. "High-low" group was also able to enhance their running time trial of 5 km at normal sea-level radically, by 30 seconds. No particular alterations were seen in running time trial of 5 km in low-low group. There was an increase of 500ml of total volume of blood in "high-low" group as compared to "low-low" group. Problems associated with decrease in excellence and power of training normally seen at elevated heights, were somewhat circumvented by training of both groups at decreased altitude i.e. 1300 m.

Stray-Gundersen and Levin (1994), and Stray-Gundersen et al. (1995) initiated their role as training supervisors by supervising 6 weeks of continuous training at sea level after subsequent studies had been done on subjects like 'living high' and 'training low'. The athletes then underwent a 4-week training on subjects - 'high-low' (2500/1300) and 'high-high' (2500). On the other hand a focus group underwent the same training to improve endurance and performance but at sea level. Groups which underwent training on 2 subjects, 'high-high' and 'high-low', recorded an increase in serum EPO at altitude and a substantial increase in RBC mass and sea-level VO2 max. The serum EPO, sea level VO2 max and RBC mass remained the same for the focused group sea level. 'High-high', high-low' and low-low groups did not record a substantial statistical difference in the sea level performance of 5 km running time on the running track.

From the time of these studies, Finnish researchers like Rusko et al. 1995 built a peculiar 'altitude house' in which with the use of normobaric displacement of nitrogen and the content of oxygen in the air could be brought down. These 'altitude houses' had a distinguishing feature that it permitted the athletes to sleep and 'live' under normobaric hypoxic conditions of simulated altitude, however, simultaneously train them with their standard sea level regime. This was again done in effort to improve athlete's endurance and performance. Impressed with these houses, Australia with the help of Australian Institute of Sport built up a similar structure of an altitude house.

The consequences of a hypoxic normobaric environment and normoxic mormobaric environment were looked into at the two studies that were done at the Australian Institute of Sport by Ashenden (1999a and 1999b) on chosen dependant variables. Under this study, the majorly trained cyclists, female (Ashenden 1999a) and majorly trained runners, male (Ashenden 1999b), slept in normobaric hypoxia simulating a 2650 m altitude. A focus group of athletes was included in every study that underwent the same training but slept at 600m. No change in Hbmass or VO2 max was observed in an exercise that lasted 4 minutes.

The group of highly trained runners - 400 m was disclosed to a normobaric hypoxia environment (~2200m) in a Live-High Train-Low rule for ten days and beneficial results of performance were observed (Nummela and Rusko 2000). The control group as compared to the runners who were disclosed to the hypoxia did not show any change however the time for such runners fell in 400 m race time.

For more knowledge on the prevailing trends in altitude training, read the follow-ups done by Wilber (2001) and Levine (2002). To sum it up, according to Levine et al. 1991, as well as other researchers like Nummela and Rusko 2000, and Stray-Gunderson and Levine 1994, the Live High Train Low rule is more of an advantage to sea level VO2man and time trial performance of the athletes. On the other hand Stray-Gundersen and Levine (1994) and Stray-Gundersen et al. (1995) think of the same rules as a disadvantage.

Significant individual behavior variability exists in the magnitude of betterment in spite of the favorable position of the live-high train-low over traditional altitude or sea level training (Levine 2002). According to him the reason behind the variability of studies is because of the lack of iron. He also said that a major reason for the decline in iron stones in bone marrows in 40% distance runners which comprises of 20% male and 60% female runners is only due to the existence of serum ferritin. Such athletes do not grow and increase erythrocyte volume, RBC volume or VO2nab whenever they seek altitude training.

Mechanisms IHE

There is no available resource which explains about the reticulocyte counts, the plasma concentration of transferrin receptors and erythroprotein as the RBC count was never calculated in any study (Julian et al., 2004; Hinckson et al., 2007) and that IHE increases the red cell mass. Economy cannot be changed by IHE (Julian et al., 2004; Tadibi et al., 2007), and the buffering property cannot be changed by unaltered anaerobic performance (Tadibi et a., 2007).

After passing seven days, an increase in hypoxic ventilatory response is not possible (Fagenholz et al., 2007) and fourteen days of IHE (Serebrovskaya et al., 1999) observed in untrained athletes as advancement of performance is also highly unlikely. It can be stated, that intermittent hypoxic exposure cannot affect any mechanism which are responsible for improvement of athlete performance by height or hypoxia (Bartsch, 2008).

An advanced peek in the writings shows no proof of any studies on association between total blood viscosity, RBC colume and ability to function. However, the facts point towards the suggestion that "fitness level" and resting WBV have an inverse relationship (Brun et al. 1994 and Ernst et al. 1985c). As mentioned by Letcher et al. 1981, there are various rationales for this inverse relationship which include a change in deformation of red blood cell. The definite solution lies in spreading up of plasma volume with ongoing exercise.

The process behind increase in plasma volume due to training is considered to engage the concentrations of vasopressin, renin, albumin and aldesterone in plasma with increase in plasma volume to pay off for the reduction in plasma volume related to every training session (Rocker et al. 1989). A total of 14 senior rowers of national squad of males were observed by Telford and co-workers (1994) for the blood factors of RBCC, WBCC, MCV, Hb and WBV. It is necessary that another research do the same as done by Telford et al. study and put in the results of these factors to WBV and so figure out where does the change take place.

The normal changes that take place in reaction to the stamina running training, like decrease in plasma viscosity, raise in plasma volume, as well as decrease in the viscosity of total body and raise in deformability of red blood cell are different adaptations than can be seen during hypoxia. The very first exposure to hypoxia and to increased altitude resulted in the decrease in the plasma volume. The result of this decrease causes a simultaneous raise in Hct and consequent decrease in the volume of total blood. This reaction starts on the very day of reaching at that height and Hct keeps on rising during primary days of adaptation (Jung et al. 1971).

In reaction to long episodes of hypoxia, there are increasingly stable and permanent increases in the concentration of Hb, enzyme activity in presence of oxygen and capillary density. Consequently, after some weeks of practicing at modest height, the athletes are expected to make a huge quantity of energy in the presence of oxygen, devoid of any chief build up of lactate in blood and sustain their speed at a comparatively increased level.

When VO2 max tests were carried out right after coming down from height (Faulkner et al. 1968) and/or after two weeks from coming down (Buskirk et al. 1967), the results of these tests proved the fact that after returning to normal sea-level there is no particular enhancement in VO max regardless of the time duration spent at a certain altitude (Klausen et al. 1991, Jensen et al. 1993).

According to Levine et al. (1991), a new way of training at altitudes started by him could enhance the VO2 max performance on sea-level. The purported concept of Living High Training Low training plan seems to have revealed the mystery of how to gain higher performance in the VO2 max tests from exposure to height (Levine et al. 1991, Stray-Gunderson and Levine 1994). These and the rest of the researches on the topic, which were only tried by a group in Finland named Heikki Rusko and at the Australian Institute of Sport by the Department of Applied Nutrition and Physiology, have been inconclusive to point out the rationale of RBC, hypoxia and endurance development in athletes related to the theory of Live High- Train Low.

Red Blood Cells (RBC) and Human Behavior

Stray-Gunderson and Levine in 1991 presented the concept of training HiLo, "Living High, and Training Low." Athletes, training on low or sea level altitude while living at moderate height, should have, theoretically, been able to achieve positive results from acclimatization of altitudes, especially in the oxygen delivery system adoption, a raise in the body hemoglobin level to maximize the transport and usage of oxygen apart from training intensity. But, numerous elements of an athletes' state were unclear in HiLo, and thus, research on HiLo fell behind, for example the research of the athletes' immune function using HiLo. (Zhang et al., 2005).

Immune functions are also performed by the red blood cells, apart from respiratory function, as explained by Siegel et al. In 1981. Immune observance is one of the vital functions of the RBCs. Red blood cells tie themselves to antigen-complement complexes or the antigen-antibody-complement on the external through the use of complement receptor type 1 (CR1). The immunity role of the white blood cells and the red blood cells merge inside the body, i.e. boosting the body's defense functions in fight against the immune monitor of the malignant cells and against pathogens (Guo 1990; Siegel et al. 1981). An increase or a decrease, or at times, no change at all, in RBC's CR1 activity took place with some exercise programs, according to some studies (Huang et al. 1999; Thomsen 1992).

Various items of immunity functions were affected and modified through the exposure of environmental stressors, like altitude training and physical activities. Body challenged by the 2 incentives together, of increased diseases risk and immune dominance, were quickly caused by altitude training (Chang et al. 2002; Shephard 1998). Though a data scarcity of RBC's qualities or functions in the autoimmunity, it was expected that a RBC immune system would play a vital function to explain the modification within immune functions related to altitude training.

Mitochondrial biogenesis and its impact on Behavior

Originating from gene products of mitochondrial DNA and nuclear DNA (mtDNA and NDna), Mitochondria is created. Mitochondrial diseases can be the result of the changes taking place in either of the genome's genes. Oxidative phosphorylation is a typical characteristic of a mitochondrial disease, further taking it to an endangered ATP provision. Therefore, the disease first targets tissues requiring the most energy, such as the heart and the brain or the muscles.

Although, changes in nDNA are far less then in mtDNA, as mtDNA does not carry a defensive histone cover, while having scarce repair activity in DNA, and being near to the reactive oxygen species creation through the electron's transport chain (Adhihetty et al., 2003; Bohr et al., 2002). Only 1% of the mitochondrial proteins are converted by the mtDNA; oxidative phosphorylation crucially requires the gene products (Adhihetty et al., 2007).

Multiple copies of a DNA is found within Mitochondria, where patients having mtDNA problems show a rare situation, known as heteroplasmy, where a variable mixture of mutant and wild-type DNA are found in cells. Therefore, the mutant phenotype's level can flex between cells having same tissues or different ones. The symptom's seriousness in patients is determined through the ratio of mutant DNAs to wild-type DNA inside a particular tissue (Shoubridge, 1994).

Mitochondrial myopathy patients (MMPs) are those patients with mtDNA problems who display muscle dysfunction as the primary clinical appearance. Inflated leakage of sabsarcolemmal mitochondria is often exhibited by muscles of MMPs, resulting in histochemical staining with "ragged red fiber" phenotype (Huang et al., 2002). The restricted leakage of mitochondrial is possibly an adjusting response which attempts to control the shortage of ATP production. Mitochondrial content is found to be increased due to multiple motioning pathways, while reducing the ATP to ADP ratios, modifying the Ca2 homeostasis, and/or production of deregulated ROS (Biswas et al., 1999; Miranda et al., 1999; Winder et al., 2000; Wu et al., 1999). Various transcription factors are activated by motioning pathways, leading to an increase in the nuclear-encoded mitochondrial genes' expressions (Irrcher and Hood, 2004).

Gene expression and mtDNA replication takes place due to the important factor of nuclear-encoded mitochondrial transcription (Ekstrand et al., 2004; Gordon et al., 2001). Peroxisome proliferator-activated receptor, coactivator-1 (PGC-1), is also vital, which creates mitochondrial and nuclear gene expression (Lin et al., 2002; Wu et al., 1999). As nuclear encoded mitochondrial proteins showing promise are formed, they should be located across by a protein import machinery component to a preexisting mitochondrial reticulum, while a few of such import factors during an enhanced mitochondrial biogenesis are unregulated (Ornatsky et al., 1995; Takahashi et al., 1998; Joseph et al., 2004; Gordon et al., 2001). Such adaptations produced by the mitochondrial biogenesis regulatory proteins are not yet researched under MMPs (Adhihetty et al., 2007).

An increase in elevated ROS productions' biochemical marker indicators is exhibited by the muscles of MMPs (Di Giovanni et al., 2001; Kunishige et al., 2003; Rusanen et al., 2000). Manganese superoxide dismutase (MN SOD) and oxidative-induces lesions, are the antioxidant enzymes found within mitochondrion which helps to detoxify the ROS, where mtDNA can be cured through the enzyme 8-oxoguanine DNA glycolase -1 (OFF-1) of DNA repairs (Hamilton et al., 2001; Hudson et al., 1998; Shigenaga et al., 1994). MtDNA damage can be encouraged by a high ROS level, while it can also lead to an increased vulnerability to apoptosis of the muscles, as ROS increased the output of apoptosis-inducing factors (AIF) as well as cytochrome C. By enhancing the mtPTP or mitochondrial permeability transition pore's opening.

Bcl-2 protein's family made up of anti (Bcl -2) and pro-apoptotic (Bax) members found in the mitochondrion's outer structure controls the structure of the mtPTP (Sedlak et al., 1995). Thus, an enhanced mitochondrial ROS is most probably a vital issue of the mitochondrial disease pathogenesis (Adhihetty et al., 2007).

Mitochondrial biogenesis and hypoxia and its impact on Athlete Behavior and Endurance

Hypoxia can damage the brain of an athlete as it is sensitive and damage to neurons can be caused due to low density of capillaries, high levels of energy phosphates, high rate of oxygen metabolism (CMRO) and limited reserves of substrate. If hypoxia which is applied is not too extreme, the brain adopts a mechanism for its protection in which its high energy demands are managed by mitochondria (Semenza and Wang, 1992; Levy et al. 1995; Bunn and Poyton,1996).

If an athlete is exposed to hypoxia previously a state of neuro protection is achieved (Sharp et al., 2004) and so hypoxic preconditioning is not required. Adaptation to hypoxia by other aerobic tissues e.g. heart tissues, is achieved by various methods of increased respiratory capability and mitochondrial mass (Meerson et al., 1972, 1973; Eells et al., 2000).This proves that increase in bioenergetic capacity and production of new mitochondrial cells can support the capacity to bear the stress caused by Hypoxia (Gutsaeva, 2008).