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Oxygen pathway modeling estimates high reactive oxygen species production above the highest permanent human habitation.

Cano I, Selivanov V, Gomez-Cabrero D, Tegnér J, Roca J, Wagner PD, Cascante M - PLoS ONE (2014)

Bottom Line: However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery.This altitude roughly coincides with the highest location of permanent human habitation.Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the "death zone" in mountaineering.

View Article: PubMed Central - PubMed

Affiliation: Center for respiratory diagnoses, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES) and Universitat de Barcelona, Barcelona, Catalonia, Spain.

ABSTRACT
The production of reactive oxygen species (ROS) from the inner mitochondrial membrane is one of many fundamental processes governing the balance between health and disease. It is well known that ROS are necessary signaling molecules in gene expression, yet when expressed at high levels, ROS may cause oxidative stress and cell damage. Both hypoxia and hyperoxia may alter ROS production by changing mitochondrial Po2 (PmO2). Because PmO2 depends on the balance between O2 transport and utilization, we formulated an integrative mathematical model of O2 transport and utilization in skeletal muscle to predict conditions to cause abnormally high ROS generation. Simulations using data from healthy subjects during maximal exercise at sea level reveal little mitochondrial ROS production. However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. This altitude roughly coincides with the highest location of permanent human habitation. Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the "death zone" in mountaineering.

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Related in: MedlinePlus

Mitochondrial Po2 () as a function of regional ratios of metabolic capacity () to blood flow () at four altitudes.The lower  (supply) is in relation to  (demand), the lower is  at any altitude; also,  at any  ratio falls with increasing altitude. Vertical dashed lines mark the normal range of . Both panels show the same data, but the lower panel expands the y-axis in its lower range to show when ROS generation is high (i.e., when ). Below 17,000ft, ROS generation remains low, but above this altitude, regions of normal muscle with high  ratio generate high ROS levels, until at the Everest summit, almost the entire muscle generates high ROS levels.
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pone-0111068-g004: Mitochondrial Po2 () as a function of regional ratios of metabolic capacity () to blood flow () at four altitudes.The lower (supply) is in relation to (demand), the lower is at any altitude; also, at any ratio falls with increasing altitude. Vertical dashed lines mark the normal range of . Both panels show the same data, but the lower panel expands the y-axis in its lower range to show when ROS generation is high (i.e., when ). Below 17,000ft, ROS generation remains low, but above this altitude, regions of normal muscle with high ratio generate high ROS levels, until at the Everest summit, almost the entire muscle generates high ROS levels.

Mentions: When is high (metabolic capacity high in relation to O2 availability), mitochondrial Po2 will be low, and vice versa as shown in Figure 4 (simulated for several altitudes from sea level to 30,000 ft.). When expressed as the second moment of the distribution, on a log scale, the value is about 0.1. This can be compared to the identically computed and well-established index of ventilation/perfusion () inequality in the normal lung of 0.3–0.6 [31], which is generally regarded as small. Figure 4 also shows the range of ratios for a muscle with normal heterogeneity (i.e., dispersion of 0.1) as from about 0.15 to about 0.36, pointing out the large range of mitochondrial Po2 that this seemingly small amount of heterogeneity creates. Thus, muscle regions with a high ratio become susceptible to high ROS generation before those with lower ratio. With the critical switch from low to high ROS production occurring at a of about 0.1 mm Hg, Figure 4 shows that with normal heterogeneity, the muscle regions with highest exhibit high ROS production already at 17,000 ft. altitude, and that at the summit of Mt. Everest (approx. 29,000 ft.), almost 100% of muscle regions will have switched to high ROS production.


Oxygen pathway modeling estimates high reactive oxygen species production above the highest permanent human habitation.

Cano I, Selivanov V, Gomez-Cabrero D, Tegnér J, Roca J, Wagner PD, Cascante M - PLoS ONE (2014)

Mitochondrial Po2 () as a function of regional ratios of metabolic capacity () to blood flow () at four altitudes.The lower  (supply) is in relation to  (demand), the lower is  at any altitude; also,  at any  ratio falls with increasing altitude. Vertical dashed lines mark the normal range of . Both panels show the same data, but the lower panel expands the y-axis in its lower range to show when ROS generation is high (i.e., when ). Below 17,000ft, ROS generation remains low, but above this altitude, regions of normal muscle with high  ratio generate high ROS levels, until at the Everest summit, almost the entire muscle generates high ROS levels.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4222897&req=5

pone-0111068-g004: Mitochondrial Po2 () as a function of regional ratios of metabolic capacity () to blood flow () at four altitudes.The lower (supply) is in relation to (demand), the lower is at any altitude; also, at any ratio falls with increasing altitude. Vertical dashed lines mark the normal range of . Both panels show the same data, but the lower panel expands the y-axis in its lower range to show when ROS generation is high (i.e., when ). Below 17,000ft, ROS generation remains low, but above this altitude, regions of normal muscle with high ratio generate high ROS levels, until at the Everest summit, almost the entire muscle generates high ROS levels.
Mentions: When is high (metabolic capacity high in relation to O2 availability), mitochondrial Po2 will be low, and vice versa as shown in Figure 4 (simulated for several altitudes from sea level to 30,000 ft.). When expressed as the second moment of the distribution, on a log scale, the value is about 0.1. This can be compared to the identically computed and well-established index of ventilation/perfusion () inequality in the normal lung of 0.3–0.6 [31], which is generally regarded as small. Figure 4 also shows the range of ratios for a muscle with normal heterogeneity (i.e., dispersion of 0.1) as from about 0.15 to about 0.36, pointing out the large range of mitochondrial Po2 that this seemingly small amount of heterogeneity creates. Thus, muscle regions with a high ratio become susceptible to high ROS generation before those with lower ratio. With the critical switch from low to high ROS production occurring at a of about 0.1 mm Hg, Figure 4 shows that with normal heterogeneity, the muscle regions with highest exhibit high ROS production already at 17,000 ft. altitude, and that at the summit of Mt. Everest (approx. 29,000 ft.), almost 100% of muscle regions will have switched to high ROS production.

Bottom Line: However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery.This altitude roughly coincides with the highest location of permanent human habitation.Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the "death zone" in mountaineering.

View Article: PubMed Central - PubMed

Affiliation: Center for respiratory diagnoses, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES) and Universitat de Barcelona, Barcelona, Catalonia, Spain.

ABSTRACT
The production of reactive oxygen species (ROS) from the inner mitochondrial membrane is one of many fundamental processes governing the balance between health and disease. It is well known that ROS are necessary signaling molecules in gene expression, yet when expressed at high levels, ROS may cause oxidative stress and cell damage. Both hypoxia and hyperoxia may alter ROS production by changing mitochondrial Po2 (PmO2). Because PmO2 depends on the balance between O2 transport and utilization, we formulated an integrative mathematical model of O2 transport and utilization in skeletal muscle to predict conditions to cause abnormally high ROS generation. Simulations using data from healthy subjects during maximal exercise at sea level reveal little mitochondrial ROS production. However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. This altitude roughly coincides with the highest location of permanent human habitation. Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the "death zone" in mountaineering.

Show MeSH
Related in: MedlinePlus