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J Appl Physiol 99: 1245–1246, 2005;
doi:10.1152/japplphysiol.00609.2005.
Invited Editorial
Yet another oxygen paradox
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consumption of ⬃40% are seen, with a concomitant loss of
mitochondrial volume density and oxidative enzyme activity,
(reviewed in Refs. 5, 7). Muscles remodel, in general, toward
smaller, more glycolytic phenotypes at these altitudes. Importantly, muscle biopsies show evidence of oxidative stress in
regions of mitochondria, as evidenced by accumulation of
lipofuscin (5, 7), a finding also recently observed in chronic
obstructive pulmonary disease patients (1). Further circumstantial evidence for oxidative stress in extreme hypoxia is seen
throughout the animal kingdom, from insect larvae to hibernating mammals, in which the most common genomic response to prolonged hypoxia is an elevation in antioxidant
enzyme activities (6). Therefore, elevations in oxidant production may be a ubiquitous but poorly recognized response to
severe hypoxic environments.
Many important questions remain. First, to what extent does
the oxidative stress in severe hypoxia reflect nutritional or
absorptive abnormalities in the whole animal? Human subjects
at severe altitude can experience anorexia (3) with simultaneous elevations in resting energy consumption, resulting in
severe strains on metabolism. Malnutrition, particularly protein
malnutrition, can result in oxidative stress and loss of antioxidant defense. Second, to what extent does severe hypoxia
initiate inflammatory responses that could result in inflammatory cell-derived ROS? At a moderately high altitude of 15,500
ft., there is some evidence for activation of inflammatory
cascades, with increases in C-reactive protein, IL-6, and
TNF-␣ (2, 3), but we know little about cytokine signaling at
extreme altitude. Third, could the presence of oxidative stress
in hypoxia reflect the process of skeletal fiber remodeling? An
important characteristic of severe hypoxia exposure is a kind of
muscle atrophy in which fiber size decreases while mitochondria and other organelles are being eliminated. Since disuse
atrophy is associated with increased oxidant production (10),
could the hypoxia-induced atrophy involve a regulated form of
oxidation that targets proteins for ubiquitination and subsequent digestion? After long-term adaptation, when remodeling
would presumably reach a new equilibrium state, would we
expect to see the same kinds of oxidative stress? It is interesting that Himalayan natives, born to high altitude, show basal
elevations in some antioxidant enzymes and little accumulation
of lipofuscin during altitude exposure (5).
In conclusion, life exists within the crazy world where the
free electron flows; where too much and too little oxygen
stimulate oxygen radicals; where oxidants can precondition
hearts to save them and cause unrecoverable damage during
reperfusion; where they can induce apoptosis, inhibit apoptosis, or can play a critical role in cell mitosis, depending on the
situation; and where the “Janus” face of nitric oxide likes to
frequently stare back at perplexed physiologists and laugh. Our
growing understanding as scientists of the manifestations of
dioxygen, with its unique capacity to carry four electrons in
various reactive states, resembles what primitive man must
have felt with the discovery of fire: “The funny stuff keeps the
soup warm, but darn if it can’t set the village to flames.”
REFERENCES
1. Allaire J, Maltais F, LeBlanc P, Simard PM, Whittom F, Doyon JF,
Simard C, and Jobin J. Lipofuscin accumulation in the vastus lateralis
8750-7587/05 $8.00 Copyright © 2005 the American Physiological Society
1245
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ONE OF THE EMERGING COMPLEXITIES in free-radical biology is that
reactive oxygen species (ROS) are elevated in response to both
“high” and “low” oxygen in some biological systems. The
concept that hyperoxia elevates ROS formation is generally
well known because it is entrenched in our physiological group
consciousness as we teach medical students about the dangers
of oxygen toxicity to the lung or retina. It is further reinforced
by the classic literature by Chance et al. (4), who showed that
the rate of endogenous H2O2 production in liver is directly
related to the level of PO2. PO2-driven ROS appears to be an
important player in many physiological settings, such as the
efferent limb of an oxygen-sensing system in the pulmonary
vasculature (9).
In contrast, scientists have been hesitant to embrace the idea
that conditions of hypoxia induce ROS in the absence of
reoxygenation. The publication in this issue by Magalhães et
al. (8) provides some of the strongest arguments to date that, in
limb skeletal muscles, exposure to relatively extreme hypoxia
induces an apparent oxidative stress. Muscles from rats exposed to 48 h of severe hypoxia were characterized by protein
oxidation, glutathione and vitamin E depletion, metabolic enzyme inactivation, and mitochondrial dysfunction. Interestingly, much of the apparent oxidative damage could be attenuated by vitamin E supplementation. It is important to emphasize that the hypoxia the rats experienced was extreme, being
equivalent to living at 27,500 ft., without the benefit of extensive acclimatization. By contrast, the summit of Mt. Everest is
⬃29,000 ft. Nevertheless, the report is extremely interesting
and timely and may have many implications in other areas of
biology and medicine, particularly in chronic heart and lung
disease.
The idea that hypoxia can induce elevations in ROS has a
history, but almost nothing substantial is known about the
mechanism for the phenomenon. The term “reductive stress”
has been applied, which reflects the idea that, under conditions
of hypoxia, reducing equivalents in the form of NADH build
up in both the cytosol and mitochondria, thus increasing the
electrical potential for single electron reduction of oxygen to
superoxide. Because there is only a slow reaction of NADH
with oxygen, some form of NADH oxidase or a reduced
electron carrier such as ubiquinone in the mitochondria must be
involved. A number of other investigators have provided evidence for acute hypoxia-induced ROS formation, particularly
in muscle phenotypes (e.g., Refs. 11, 12). It is possible that the
phenomenon may be specific to some cell types, since reports
in nonmuscle cells are rare.
Perhaps muscle cells use ROS during hypoxia, as in other
stress exposures, to initiate cell-signaling events that ensure
tolerance to subsequent stress, i.e., a form of preconditioning.
However, in the extreme case of prolonged exposure to hypoxia, such as in the experimental setting of Magalhães et al.
(8), the system may be activated for such a prolonged time that
normal antioxidant networks become exhausted, moving the
tissue away from normal redox equilibrium.
In a related application of the work, our understanding of
how skeletal muscles respond to high altitude has been drastically altered in recent years. In humans at altitudes above
⬃18,000 ft. for 8 –10 wk, reductions in maximal oxygen
Invited Editorial
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99 • OCTOBER 2005 •
Thomas Clanton
Department of Internal Medicine
Dorothy Davis Heart & Lung Research Institute
Pulmonary, Critical Care, and Sleep Division
Ohio State University
Columbus, Ohio 43210
e-mail: [email protected]
www.jap.org
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