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The cold and hypoxic conditions at high altitude necessitate high metabolic O2 demands to support thermogenesis while hypoxia reduces O2 availability. Skeletal muscles play key roles in thermogenesis, but our appreciation of muscle plasticity and adaptation at high altitude has been hindered by past emphasis on only a small number of muscles. We examined this issue in deer mice (Peromyscus maniculatus). Mice derived from both high-altitude and low-altitude populations were born and raised in captivity and then acclimated as adults to normoxia or hypobaric hypoxia (12 kPa O2 for 6–8 wk). Maximal activities of citrate synthase (CS), cytochrome c oxidase (COX), β-hydroxyacyl-CoA dehydrogenase (HOAD), hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) were measured in 20 muscles involved in shivering, locomotion, body posture, ventilation, and mastication. Principal components analysis revealed an overall difference in muscle phenotype between populations but no effect of hypoxia acclimation. High-altitude mice had greater activities of mitochondrial enzymes and/or lower activities of PK or LDH across many (but not all) respiratory, limb, core and mastication muscles compared with low-altitude mice. In contrast, chronic hypoxia had very few effects across muscles. Further examination of CS in the gastrocnemius showed that population differences in enzyme activity stemmed from differences in protein abundance and mRNA expression but not from population differences in CS amino acid sequence. Overall, our results suggest that evolved increases in oxidative capacity across many skeletal muscles, at least partially driven by differences in transcriptional regulation, may contribute to high-altitude adaptation in deer mice. NEW & NOTEWORTHY: Most previous studies of muscle plasticity and adaptation in high-altitude environments have focused on a very limited number of skeletal muscles. Comparing high-altitude versus low-altitude populations of deer mice, we show that a large number of muscles involved in shivering, locomotion, body posture, ventilation, and mastication exhibit greater mitochondrial enzyme activities in the high-altitude population. Therefore, evolved increases in mitochondrial oxidative capacity across skeletal muscles contribute to high-altitude adaptation. [ABSTRACT FROM AUTHOR]

Bar-headed geese fly at altitudes of up to 9,000 m on their biannual migration over the Himalayas. To determine whether the flight muscle of this species has evolved to facilitate exercise at high altitude, we compared the respiratory properties of permeabilized muscle fibers from bar-headed geese and several low-altitude waterfowl species. Respiratory capacities were assessed for maximal ADP stimulation (with single or multiple inputs to the electron transport system) and cytochrome oxidase excess capacity (with an exogenous electron donor) and were generally 20-40% higher in bar-headed geese when creatine was present. When respiration rates were extrapolated to the entire pectoral muscle mass, bar-headed geese had a higher mass-specific aerobic capacity. This may represent a surplus capacity that counteracts the depressive effects of hypoxia on mitochondrial respiration. However, there were no differences in activity for mitochondrial or glycolytic enzymes measured in homogenized muscle. The [ADP] leading to half-maximal stimulation ([K.sub.m]) was approximately twofold higher in bar-headed geese (10 vs. 4-6 [micro]M), and, while creatine reduced [K.sub.m] by 30% in this species, it had no effect on Km in low-altitude birds. Mitochondrial creatine kinase may therefore contribute to the regulation of oxidative phosphorylation in flight muscle of bar-headed geese, which could promote efficient coupling of ATP supply and demand. However, this was not based on differences in creatine kinase activity in isolated mitochondria or homogenized muscle. The unique differences in bar-headed geese existed without prior exercise or hypoxia exposure and were not a result of phylogenetic history, and may, therefore, be important evolutionary specializations for high-altitude flight. high-altitude adaptation; hypoxia tolerance; mitochondrial metabolism; phylogenetically independent contrasts; physiological evolution doi: 10.1152/ajpregu.00241.2009

The bar-headed goose flies over the Himalayan mountains on its migratory route between South and Central Asia, reaching altitudes of up to 9,000 m. We compared control of breathing in this species with that of low-altitude waterfowl by exposing birds to step decreases in inspired [O.sub.2] under both poikilocapnic and isocapnic conditions. Bar-headed geese breathed substantially more than both greylag geese and pekin ducks during severe environmental (poikilocapnic) hypoxia (5% inspired [O.sub.2]). This was entirely due to an enhanced tidal volume response to hypoxia, which would have further improved parabronchial (effective) ventilation. Consequently, [O.sub.2] loading into the blood and arterial [Po.sub.2] were substantially improved. Because air convection requirements were similar between species at 5% inspired [O.sub.2], it was the enhanced tidal volume response (not total ventilation per se) that improved [O.sub.2] loading in bar-headed geese. Other observations suggest that bar-headed geese depress metabolism less than low-altitude birds during hypoxia and also may be capable of generating higher inspiratory airflows. There were no differences between species in ventilatory sensitivities to isocapnic hypoxia, the hypoxia-induced changes in blood C[O.sub.2] tensions or pH, or hypercapnic ventilatory sensitivities. Overall, our results suggest that evolutionary changes in the respiratory control system of bar-headed geese enhance [O.sub.2] loading into the blood and may contribute to this species' exceptional ability to fly high. hypoxic ventilatory response; birds; respiration; metabolism; carbon dioxide doi: 10.1152/ajpregu.00161.2007

The Amazonian oscar is extremely resistant to hypoxia, and tolerance scales with size. Overall, ionoregulatory responses of small (~15 g) and large oscars (~200 g) to hypoxia were qualitatively similar, but the latter were more effective. Large oscars exhibited a rapid reduction in unidirectional [Na.sup.+] uptake rate at the gills during acute hypoxia (P[O.sub.2] ~ 10 mmHg), which intensified with time (7 or 8 h); [Na.sup.+] efflux rates were also reduced, so net balance was little affected. The inhibitions were virtually immediate (1st h) and preceded a later 60% reduction (at 3 h) in gill [Na.sup.+]-[K.sup.+]-ATPase activity, reflected in a 60% reduction in maximum [Na.sup.+] uptake capacity without change in affinity (Km) for [Na.sup.+]. Upon acute restoration of normoxia, recovery of [Na.sup.+] uptake was delayed for 1 h. These data suggest that dual mechanisms may be involved (e.g., immediate effects of [O.sub.2] availability on transporters, channels, or permeability, slower effects of [Na.sup.+]-[K.sup.+]-ATPase regulation). Ammonia excretion appeared to be linked indirectly to [Na.sup.+] uptake, exhibiting a Michaelis-Menten relationship with external [[Na.sup.+]], but the Km was less than for [Na.sup.+] uptake. During hypoxia, ammonia excretion fell in a similar manner to [Na.sup.+] fluxes, with a delayed recovery upon normoxia restoration, but the relationship with [[Na.sup.+]] was blocked. Reductions in ammonia excretion were greater than in urea excretion. Plasma ammonia rose moderately over 3 h hypoxia, suggesting that inhibition of excretion was greater than inhibition of ammonia production. Overall, the oscar maintains excellent homeostasis of ionoregulation and N-balance during severe hypoxia. teleost fish; ionoregulation; nitrogen metabolism; sodium-potassiumATPase; ion channels doi:10.1152/ajpregu.00640.2006

Maintenance of ion balance requires that ionoregulatory epithelia modulate ion flux in response to internal or environmental osmotic challenges. We have explored the basis of this functional plasticity in the gills of the euryhaline killifish Fundulus heteroclitus. The expression patterns of several genes encoding ion transport proteins were quantified after transfer from near-isosmotic brackish water [10 parts/thousand (ppt)] to either freshwater (FW) or seawater (SW). Many changes in response to SW transfer were transient. Increased mRNA expression occurred 1 day after transfer for [Na.sup.+]-[K.sup.+]-ATPase-[[alpha].sub.1a], (3-fold), [Na.sup.+][K.sup.+]-2[Cl.sup.-]-cotransporter 1 (NKCC1) (3-fold), and glucocorticoid receptor (1.3-fold) and was paralleled by elevated [Na.sup.+]-[K.sup.+]-ATPase activity (2-fold). The transient increase in NKCC1 mRNA expression was followed by a later 2-fold rise in NKCC protein abundance. In contrast to the other genes studied in the present work, mRNA expression of the cystic fibrosis transmembrane conductance regulator (CFTR) [Cl.sup.-] channel generally remained elevated (2-fold) in SW. No change in protein abundance was detected, however, suggesting posttranscriptional regulation. The responses to FW transfer were quite different from those to SW transfer. In particular, FW transfer increased [Na.sup.+]-[K.sup.+]-ATPase-[[alpha].sub.1a]mRNA expression and [Na.sup.+]-[K.sup.+]-ATPase activity to a greater extent than did SW transfer but had no effect on V-type [H.sup.+]-ATPase expression, supporting the current suggestion that killifish gills transport [Na.sup.+] via [Na.sup.+]/[H.sup.+] exchange. These findings demonstrate unique patterns of ion transporter expression in killifish gills after salinity transfer and illustrate important mechanisms of functional plasticity in ion-transporting epithelia. [Na.sup.+]-[K.sup.+]-ATPase; [Na.sup.+]-[K.sup.+]-2[Cl.sup.-] cotransporter; cystic fibrosis transmembrane conductance regulator; glucocorticoid receptor; [H.sup.+]-ATPase

We examined the control of breathing by O2 and CO2 in deer mice native to high altitude to help uncover the physiological specializations used to cope with hypoxia in high-altitude environments. Highland deer mice (Peromyscus maniculatus) and lowland white-footed mice (P. leucopus) were bred in captivity at sea level. The first and second generation progeny of each population was raised to adulthood and then acclimated to normoxia or hypobaric hypoxia (12 kPa O2, simulating hypoxia at ~4,300 m) for 6 – 8 wk. Ventilatory responses to poikilocapnic hypoxia (stepwise reductions in inspired O2) and hypercapnia (stepwise increases in inspired CO2) were then compared between groups. Both generations of lowlanders appeared to exhibit ventilatory acclimatization to hypoxia (VAH), in which hypoxia acclimation enhanced the hypoxic ventilatory response and/or made the breathing pattern more effective (higher tidal volumes and lower breathing frequencies at a given total ventilation). In contrast, hypoxia acclimation had no effect on breathing in either generation of highlanders, and breathing was generally similar to hypoxia-acclimated lowlanders. Therefore, attenuation of VAH may be an evolved feature of highlanders that persists for multiple generations in captivity. Hypoxia acclimation increased CO2 sensitivity of breathing, but in this case, the effect of hypoxia acclimation was similar in highlanders and lowlanders. Our results suggest that highland deer mice have evolved high rates of alveolar ventilation that are unaltered by exposure to chronic hypoxia, but they have preserved ventilatory sensitivity to CO2. [ABSTRACT FROM AUTHOR]

The authors debate whether high altitude is for the birds or not. Based on evidences, a group of authors opined that high altitude is for the birds as birds have a greater tolerance of the hypoxia at high altitudes and have a greater capacity for exercise at high altitudes. Another group countered that high altitude is not for the birds as the embryos and hatchlings of these birds have not shown successful evolutionary adaptive strategies compared with the llama.

The Amazonian oscar is extremely resistant to hypoxia, and tolerance scales with size. Overall, ionoregulatory responses of small (~15 g) and large oscars (~200 g) to hypoxia were qualitatively similar, but the latter were more effective. Large oscars exhibited a rapid reduction in unidirectional Na+ uptake rate at the gills during acute hypoxia (Po2 ~10 mmHg), which intensified with time (7 or 8 h); Na+ efflux rates were also reduced, so net balance was little affected. The inhibitions were virtually immediate (1st h) and preceded a later 60% reduction (at 3 h) in gill Na+-K+-ATPase activity, reflected in a 60% reduction in maximum Na+ uptake capacity without change in affinity (Km) for Nat Upon acute restoration of normoxia, recovery of Na+ uptake was delayed for 1 h. These data suggest that dual mechanisms may be involved (e.g., immediate effects of O2 availability on transporters, channels, or permeability, slower effects of Na+-K+-ATPase regulation). Ammonia excretion appeared to be linked indirectly to Na+ uptake, exhibiting a Michaelis-Menten relationship with external [Na+], but the Km was less than for Na+ uptake. During hypoxia, ammonia excretion fell in a similar manner to Na+ fluxes, with a delayed recovery upon normoxia restoration, but the relationship with [Na+] was blocked. Reductions in ammonia excretion were greater than in urea excretion. Plasma ammonia rose moderately over 3 h hypoxia, suggesting that inhibition of excretion was greater than inhibition of ammonia production. Overall, the oscar maintains excellent homeostasis of ionoregulation and N-balance during severe hypoxia. [ABSTRACT FROM AUTHOR]

Hypoxia can have significant impacts on cardiovascular physiology, but the effects of chronic exposure to moderate hypoxia and how they differ between sexes remain poorly understood. We used physiological telemetry to examine this issue in CD-1 mice. Adult mice were chronically exposed to normoxia or hypobaric hypoxia (12 kPa O 2 ) for 6 wk and then subjected to telemetry measurements of routine physiology across the diel cycle. Heart rate ( f H ), mean arterial blood pressure ( P mean ), body temperature ( T b ), and activity were greater during the nighttime active phase than the daytime inactive phase. Chronic hypoxia had no effect on these traits at night but had sex-specific effects during the day, when chronic hypoxia reduced f H , T b , and activity in males but not females. These differences existed without any effect of chronic hypoxia on α-adrenergic or nitric oxide tone on the vasculature (assessed as P mean response to pharmacological blockade). Responses to acute hypoxia were then measured during stepwise reductions in inspired O 2 from 21 to 8 kPa O 2 . O 2 consumption rate, f H , P mean , and T b declined in severe hypoxia, but the O 2 tension at which this began was lower in mice held in chronic hypoxia. However, the hypoxic ventilatory response was augmented by exposure to chronic hypoxia in females but not in males. Females also exhibited larger increases in lung mass and less right ventricle hypertrophy than males in chronic hypoxia. Our results support the growing evidence that there can be considerable sex differences in the cardiorespiratory responses to hypoxia.

Hypoxia at high altitude can constrain metabolism and performance and can elicit physiological adjustments that are deleterious to health and fitness. Hypoxic pulmonary hypertension is a particularly serious and maladaptive response to chronic hypoxia, which results from vasoconstriction and pathological remodeling of pulmonary arteries, and can lead to pulmonary edema and right ventricle hypertrophy. We investigated whether deer mice ( Peromyscus maniculatus ) native to high altitude have attenuated this maladaptive response to chronic hypoxia and whether evolved changes or hypoxia-induced plasticity in pulmonary vasculature might impact ventilation-perfusion (V-Q) matching in chronic hypoxia. Deer mouse populations from both high and low altitudes were born and raised to adulthood in captivity at sea level, and various aspects of lung function were measured before and after exposure to chronic hypoxia (12 kPa O 2 , simulating the O 2 pressure at 4,300 m) for 6-8 wk. In lowlanders, chronic hypoxia increased right ventricle systolic pressure (RVSP) from 14 to 19 mmHg ( P = 0.001), in association with thickening of smooth muscle in pulmonary arteries and right ventricle hypertrophy. Chronic hypoxia also impaired V-Q matching in lowlanders (measured at rest using SPECT-CT imaging), as reflected by increased log SD of the perfusion distribution (log SD Q ) from 0.55 to 0.86 ( P = 0.031). In highlanders, chronic hypoxia had attenuated effects on RVSP and no effects on smooth muscle thickness, right ventricle mass, or V-Q matching. Therefore, evolved changes in lung function help attenuate maladaptive plasticity and contribute to hypoxia tolerance in high-altitude deer mice.

High-altitude natives have evolved to overcome environmental hypoxia and provide a compelling system to understand physiological function during reductions in oxygen availability. The sympathoadrenal system plays a key role in responses to acute hypoxia, but prolonged activation of this system in chronic hypoxia may be maladaptive. Here, we examined how chronic hypoxia exposure alters adrenal catecholamine secretion and how adrenal function is altered further in high-altitude natives. Populations of deer mice ( Peromyscus maniculatus ) native to low and high altitudes were each born and raised in captivity at sea level, and adults from each population were exposed to normoxia or hypobaric hypoxia for 5 mo. Using carbon fiber amperometry on adrenal slices, catecholamine secretion evoked by low doses of nicotine (10 µM) or acute hypoxia (Po 2 ∼15-20 mmHg) was reduced in lowlanders exposed to hypobaric hypoxia, which was attributable mainly to a decrease in quantal charge rather than event frequency. However, secretion evoked by high doses of nicotine (50 µM) was unaffected. Hypobaric hypoxia also reduced plasma epinephrine and protein expression of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase in the adrenal medulla of lowlanders. In contrast, highlanders were unresponsive to hypobaric hypoxia, exhibiting typically low adrenal catecholamine secretion, plasma epinephrine, and DOPA decarboxylase. Highlanders also had consistently lower catecholamine secretion evoked by high nicotine, smaller adrenal medullae with fewer chromaffin cells, and a larger adrenal cortex compared with lowlanders across both acclimation environments. Our results suggest that plastic responses to chronic hypoxia along with evolved changes in adrenal function attenuate catecholamine release in deer mice at high altitude.

We examined the control of breathing by O 2 and CO 2 in deer mice native to high altitude to help uncover the physiological specializations used to cope with hypoxia in high-altitude environments. Highland deer mice ( Peromyscus maniculatus) and lowland white-footed mice ( P. leucopus) were bred in captivity at sea level. The first and second generation progeny of each population was raised to adulthood and then acclimated to normoxia or hypobaric hypoxia (12 kPa O 2 , simulating hypoxia at ~4,300 m) for 6-8 wk. Ventilatory responses to poikilocapnic hypoxia (stepwise reductions in inspired O 2 ) and hypercapnia (stepwise increases in inspired CO 2 ) were then compared between groups. Both generations of lowlanders appeared to exhibit ventilatory acclimatization to hypoxia (VAH), in which hypoxia acclimation enhanced the hypoxic ventilatory response and/or made the breathing pattern more effective (higher tidal volumes and lower breathing frequencies at a given total ventilation). In contrast, hypoxia acclimation had no effect on breathing in either generation of highlanders, and breathing was generally similar to hypoxia-acclimated lowlanders. Therefore, attenuation of VAH may be an evolved feature of highlanders that persists for multiple generations in captivity. Hypoxia acclimation increased CO 2 sensitivity of breathing, but in this case, the effect of hypoxia acclimation was similar in highlanders and lowlanders. Our results suggest that highland deer mice have evolved high rates of alveolar ventilation that are unaltered by exposure to chronic hypoxia, but they have preserved ventilatory sensitivity to CO 2 .

The low O 2 experienced at high altitude is a significant challenge to effective aerobic locomotion, as it requires sustained tissue O 2 delivery in addition to the appropriate allocation of metabolic substrates. Here, we tested whether high- and low-altitude deer mice ( Peromyscus maniculatus ) have evolved different acclimation responses to hypoxia with respect to muscle metabolism and fuel use during submaximal exercise. Using F 1 generation high- and low-altitude deer mice that were born and raised in common conditions, we assessed 1 ) fuel use during exercise, 2 ) metabolic enzyme activities, and 3 ) gene expression for key transporters and enzymes in the gastrocnemius. After hypoxia acclimation, highland mice showed a significant increase in carbohydrate oxidation and higher relative reliance on this fuel during exercise at 75% maximal O 2 consumption. Compared with lowland mice, highland mice had consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius. In contrast, only after hypoxia acclimation did activities of hexokinase increase significantly in the muscle of highland mice to levels greater than lowland mice. Highland mice also responded to acclimation with increases in muscle gene expression for hexokinase 1 and 2 genes, whereas both populations increased mRNA expression for glucose transporters. Changes in skeletal muscle with acclimation suggest that highland mice had an increased capacity for the uptake and oxidation of circulatory glucose. Our results demonstrate that highland mice have evolved a distinct mode of hypoxia acclimation that involves an increase in carbohydrate use during exercise., (Copyright © 2017 the American Physiological Society.)

Buildups of ammonia can cause potentially fatal brain swelling in mammals, but such swelling is reversible in the anoxia- and ammonia-tolerant goldfish (Carassius auratus). We investigated brain swelling and its possible relationship to oxidative stress in the brain and liver of goldfish acutely exposed to high external ammonia (HEA; 5 mmol/l NH 4 Cl) at two different acclimation temperatures (14°C, 4°C). Exposure to HEA at 14°C for 72h resulted in increased internal ammonia and glutamine concentrations in the brain, and it caused cellular oxidative damage in the brain and liver. However, oxidative damage was most pronounced in brain, in which there was a twofold increase in thiobarbituric acid-reactive substances, a threefold increase in protein carbonylation, and a 20% increase in water volume (indicative of brain swelling). Increased activities of catalase, glutathione peroxidase, and glutathione reductase in the brain suggested that goldfish upregulate their antioxidant capacity to partially offset oxidative stress during hyperammonemia at 14°C. Notably, acclimation to colder (4°C) water completely attenuated the oxidative stress response to HEA in both tissues, and there was no change in brain water volume despite similar increases in internal ammonia. We suggest that ammonia-induced oxidative stress may be responsible for the swelling of goldfish brain during HEA, but further studies are needed to establish a mechanistic link between reactive oxygen species production and brain swelling. Nevertheless, a high capacity to withstand oxidative stress in response to variations in internal ammonia likely explains why goldfish are more resilient to this stressor than most other vertebrates., (Copyright © 2017 the American Physiological Society.)

The hypoxic and cold environment at high altitudes requires that small mammals sustain high rates of O2 transport for exercise and thermogenesis while facing a diminished O2 availability. We used laboratory-born and -raised deer mice (Peromyscus maniculatus) from highland and lowland populations to determine the interactive effects of ancestry and hypoxia acclimation on exercise performance. Maximal O₂consumption (V̇o(2max)) during exercise in hypoxia increased after hypoxia acclimation (equivalent to the hypoxia at ∼4,300 m elevation for 6-8 wk) and was consistently greater in highlanders than in lowlanders. V̇o(2max) during exercise in normoxia was not affected by ancestry or acclimation. Highlanders also had consistently greater capillarity, oxidative fiber density, and maximal activities of oxidative enzymes (cytochrome c oxidase and citrate synthase) in the gastrocnemius muscle, lower lactate dehydrogenase activity in the gastrocnemius, and greater cytochrome c oxidase activity in the diaphragm. Hypoxia acclimation did not affect any of these muscle traits. The unique gastrocnemius phenotype of highlanders was associated with higher mRNA and protein abundances of peroxisome proliferator-activated receptor γ (PPARγ). Vascular endothelial growth factor (VEGFA) transcript abundance was lower in highlanders, and hypoxia acclimation reduced the expression of numerous genes that regulate angiogenesis and energy metabolism, in contrast to the observed population differences in muscle phenotype. Lowlanders exhibited greater increases in blood hemoglobin content, hematocrit, and wet lung mass (but not dry lung mass) than highlanders after hypoxia acclimation. Genotypic adaptation to high altitude, therefore, improves exercise performance in hypoxia by mechanisms that are at least partially distinct from those underlying hypoxia acclimation., (Copyright © 2015 the American Physiological Society.)