Altitude Exercise and Skeletal Muscle Angio Adaptive Responses to Hypoxia

Written by Ben Bunting: BA(Hons), PGCert. Sport & Exercise Nutrition. British Army Physical Training Instructor.  


Several studies have shown that hypoxia can have a profound effect on the skeletal muscle's ability to angiogenesis, especially at high altitude.

This is the process by which blood vessels are formed in the muscles. The expression of the vascular endothelial growth factor (VEGF) gene is important for the skeletal muscle's ability to angiogenesis.

It is also possible that barometric pressure can affect the ability of the skeletal muscle to respond to hypoxia.

ATP production occurs via mitochondrial oxidative phosphorylation of reduced intermediates

ATP production occurs through oxidative phosphorylation at the inner mitochondrial membrane.

This is a complex process involving a number of interacting bioenergetic pathways.

Some of the pathways that contribute to mitochondrial energy metabolism are glycolysis, the tricarboxylic acid cycle, and the oxidative phosphorylation of reduced intermediates.

In normal cardiac tissue, the tricarboxylic acid (TCA) cycle is important for fatty acid oxidation.

However, in oxygen-deprived heart tissues, the b-oxidation of fatty acids is diminished, possibly because of an increased concentration of lipofuscin, a lipid peroxidation product.

The TCA cycle is involved in the generation of a substantial portion of intramitochondrial fatty acids (FADH).

The b-oxidation of fatty acids and its contribution to cellular ATP generation are critical for maintaining myocardial contractility.

In the fetal heart, there is a reduction in the activities of the TCA cycle and the production of FADH.

The fetal heart also exhibits decreased mitochondrial volume density. This is likely a compensatory response to an environment that is relatively hypoxic.

This adaptation may reduce O2 diffusion gradients, increase ATP synthesis, and improve local O2 delivery.

Nevertheless, further research is needed to fully characterize the physiological role of mitochondrial efficiency.

The oxidative phosphorylation of reduced acetyl coenzyme A and pyruvate is an important mitochondrial mechanism for cellular energy production.

This is accomplished by AMP-activated serine/threonine protein kinase, a molecular energy sensor. The serine/threonine kinase is activated when cellular ATP levels decline.

ATP synthesis is not complete before or after the opening of the mitochondrial permeability transition pore (MPTP).

The MPTP opens when Ca2+ concentration is high in isolated mitochondria. The MPTP cannot open when the Ca2+ concentration is high in vivo.

HIF-1a is degraded

Despite the many studies conducted to investigate the effects of hypoxia on the skeletal muscle, the molecular basis of the angio-adaptive response to hypoxia is still unclear.

This review aims to describe the key facets of this adaptive response and highlight some of the recent controversy in the field.

In skeletal muscle, angio-adaptive responses are essential for maintaining optimal oxygen supply to myofibers. VEGF and HIF transcription factors play important roles in this response.

However, controversies remain about how much hypoxia actually occurs and how it affects the expression of these genes.

Several studies have looked at the mRNA levels of VEGF-A. However, most have focused on measuring the protein level in ELISAs. Other research has studied the expression of VEGF-A in the muscle tissue.

In normoxia, mRNA levels of the genes associated with the VEGF pathway are not found in the muscle fibres.

This suggests that the effects of hypoxia on the gene expression are mediated post-transcriptionally. During exercise, HIF-1a accumulates in the nucleus and is degraded. This is thought to regulate ROS production.

In addition, several studies have shown that aerobic exercise induces the expression of numerous molecular regulators of insulin sensitivity. AMP-activated serine/threonine protein kinase (AMPK) is one of these pathways.

When AMPK activity is increased, multiple pathways are activated, including suppression of cell growth, ATP synthesis, and modulation of the transcription of a number of genes.

In contrast, mTOR was downregulated in the vastus lateralis. This is likely due to a decreased level of protein synthesis.

Similarly, PDK1 inhibition was also downregulated in the vastus lateralis. These results suggest that biogenesis may be impaired in the muscle fibres of the vastus lateralis in hypoxia.

VEGF gene expression is critical for skeletal muscle angiogenesis

VEGF is an important factor in angiogenesis. Studies have shown that VEGF increases the proliferation of vascular endothelial cells and promotes splitting angiogenesis. It also increases the number of capillaries in skeletal muscle.

VEGF gene expression is highly sensitive to hypoxia. In this study, the abundance of VEGF mRNA increased significantly with exercise in hypoxic conditions.

However, this was not accompanied by an increase in bFGF mRNA. Moreover, there was no correlation between the abundance of VEGF mRNA and the intracellular PO2 during exercise.

The relationship between the mRNA level of VEGF and the intracellular PO2 during exercise was tested with regression analysis.

The relationship was not statistically significant. The magnitude of the difference was less than 10% in the dynamic range of the assay.

The abundance of VEGF mRNA was found to be elevated in the foot skin bordering gangrene. This may be due to the relative cellular hypoxia induced by exercise.

The study suggests that vascular endothelial growth factor is an important mediator of skeletal muscle angiogenesis in response to hypoxia.

These findings are consistent with recent studies indicating that EC metabolic reprogramming is a key factor for exercise-induced angiogenesis.

The increased abundance of VEGF mRNA in response to hypoxia could be an important mechanism for promoting adaptation to exercise.

The study is not the first to examine VEGF gene expression in response to hypoxia.

Other studies have examined the effect of VEGF on skeletal muscle angiogenesis in intact rats. A similar result was obtained in electrically stimulated rat skeletal muscle.

The increased VEGF mRNA may promote the intussusception of skeletal muscle cells and increase the number of capillaries. VEGF is secreted by myoblasts in skeletal muscle.

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Effect of barometric pressure on responses to hypoxia

Several studies have been conducted to determine how barometric pressure affects physiological responses.

In particular, how does reduced barometric pressure modulate pulmonary ventilation, metabolic functions, and other responses to hypoxia.

One study looked at the effects of reduced barometric pressure on endurance exercise performance in humans. 11 young men performed a treadmill running test to exhaustion under three different conditions.

The results showed that maximal oxygen uptake decreased with elevation, but no discernable difference was found between groups. However, the study did find that there were some notable differences in the relative efficacy of the various modes of ventilation.

The highest performing group was the one breathing non-He-O2 and performed a slightly longer test than the He-O2 group.

Another study examined the effects of reduced barometric pressure on a fire hazard simulation in an oxygen-enriched room. The study found that a higher air column produced a larger column of heated air.

The effect was most noticeable during warm summer days. The researchers concluded that the increase in pressure caused an increase in the mass of the heated air, thus making the process less efficient.

There are many possible explanations for why a given stimulus may be more effective at one altitude compared to another.

These include increased partial pressure of gases, greater air resistance, and a greater air density. These are not a substitute for physiological response to hypoxia.

The best evidence suggests that the effect of barometric pressure is only minor. For example, in an oxygen-enriched room, the equilibrium constant of chemical relationships is reduced to an impressive degree.

The resulting increase in alveolar pressure can be countered by an increase in pulmonary ventilation.


Several studies have investigated individual differences in response to altitude training. They have shown that muscle metabolism is altered during intensive exercise in hypoxia, but the magnitude of these changes is unknown.

Angio-adaptive mechanisms involve an increased VEGF pathway, which may result in improved tissue oxygenation. The pro-angiogenic protein TSP-1 is involved in this process.

Increasing capillary density can increase oxygen transport and improve exercise performance. However, less is known about the role of mitochondrial efficiency. The mTOR pathway is likely to be suppressed during chronic hypoxia.

The erythropoietic response is determined by the level of altitude exposure and duration of the acclimatization period. It is important to evaluate erythropoietin levels and Epo receptor expression before hypoxic exposure.

Molecular pathways regulating skeletal muscle angio-adaptation to pathological conditions are complex. This review outlines the key players and discusses the current controversies.

Ultimately, coordinated metabolic adaptation studies may help resolve these controversies and lead to improved understanding of how tissues respond to hypoxia in disease states.

Many facets of hypoxic adaptation have been studied in both cultured cells and animal models. There are also controversies about the degree of hypoxia, the timing of adaptations, and the specificity of gene expression.

Several studies have shown that exercise at high altitude is associated with decreased VO2 during submaximal exercise.

This is consistent with findings from patients with chronic obstructive pulmonary disease (COPD). It is unclear how these changes influence endurance athletic performance.

Similarly, studies have shown that intermittent hypoxia increases tidal volume and lung diffusion capacity. While the mechanisms of these adaptations are still unclear, it appears that they may have synergistic effects.

The angio-adaptive response is also influenced by a number of other factors. These include TSP-1, VEGF-A, and thrombospondin. These molecules are released as myokines, which can act on distant tissues.


Several facets of hypoxic adaptation have been studied in animal models and in human cultured cells.

However, understanding the integrated response to hypoxic challenge in man is still limited. There is an incomplete understanding of homeostatic adjustments, and it is difficult to differentiate adaptive from maladaptive responses.

Altitude-acclimatized healthy human subjects can be used to study hypoxic adaptation. However, controversies exist regarding the degree of hypoxia, the timing of adaptations, and the effects of pre-acclimatization.

These issues can be addressed by future well-controlled experiments that use different hypoxia-exposure protocols. They should also include broad age categories for both sexes.

Hypoxic adaptation in skeletal muscle involves complex angio-adaptive responses, which involve changes in the capillary-to-myofiber interface. The key signaling pathways involved in these processes are not fully understood.

In particular, the AMP kinase (AMPK) is activated by a decline in cellular ATP levels, leading to modulation of multiple pathways.

These pathways may play a role in training efficiency, pre-acclimatization, and improved exercise tolerance.

A number of cellular mechanisms have been proposed to contribute to hypoxic adaptation. These include increased ventilation rate, erythropoiesis, and possible enhanced vascularization of tissues.

In addition, protein synthesis has been downregulated in response to energy deprivation. These changes may lead to a reduction in skeletal muscle oxidative capacity.

A number of studies have been performed to examine the effects of acclimatization on the respiratory system.

These studies suggest that acclimatization may reduce the incidence of acute AMS.

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