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A fundamental question in evolutionary biology concerns the relative contributions of phenotypic plasticity vs. local adaptation (genotypic specialization) in enabling wide-ranging species to inhabit diverse environmental conditions. Here we conduct a long-term hypoxia acclimation experiment to assess the relative roles of local adaptation and plasticity in enabling highland and lowland deer mice (Peromyscus maniculatus) to sustain aerobic thermogenesis at progressively increasing elevations. We assessed the relative physiological performance capacities of highland and lowland natives as they were exposed to progressive, stepwise increases in hypoxia, simulating the gradual ascent from sea level to an elevation of 6000 m. The final elevation of 6000 m far exceeds the highest attainable elevations within the species' range, and therefore tests the animals' ability to tolerate levels of hypoxia that surpass the prevailing conditions within their current distributional limits. Our results demonstrate that highland natives exhibit superior thermogenic capacities at the most severe levels of hypoxia, suggesting that the species' broad fundamental niche and its ability to inhabit such a broad range of elevational zones is attributable to a combination of genetically based local adaptation and plasticity. Transcriptomic and physiological measurements identify evolved changes in the acclimation response to hypoxia that contribute to the enhanced thermogenic capacity of highland natives.
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Diving animals must sustain high muscle activity with finite oxygen (O2) to forage underwater. Studies have shown that some diving mammals exhibit changes in the metabolic phenotype of locomotory muscles compared with non-divers, but the pervasiveness of such changes across diving animals is unclear, particularly among diving birds. Here, we examined whether changes in muscle phenotype and mitochondrial abundance are associated with dive capacity across 17 species of ducks from three distinct evolutionary clades (tribes) in the subfamily Anatinae: the longest diving sea ducks, the mid-tier diving pochards and the non-diving dabblers. In the gastrocnemius (the primary swimming and diving muscle), mitochondrial volume density in both oxidative and glycolytic fiber types was 70% and 30% higher in sea ducks compared with dabblers, respectively. These differences were associated with preferential proliferation of the subsarcolemmal subfraction, the mitochondria adjacent to the cell membrane and nearest to capillaries, relative to the intermyofibrillar subfraction. Capillary density and capillary-to-fiber ratio were positively correlated with mitochondrial volume density, with no variation in the density of oxidative fiber types across tribes. In the pectoralis, sea ducks had greater abundance of oxidative fiber types than dabblers, whereas pochards were intermediate between the two. These data suggest that skeletal muscles of sea ducks have a heightened capacity for aerobic metabolism and an enhanced ability to utilize O2 stores in the blood and muscle while diving.
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Buceo , Patos , Músculo Esquelético , Fenotipo , Animales , Patos/fisiología , Buceo/fisiología , Músculo Esquelético/fisiología , Músculo Esquelético/metabolismo , Mitocondrias Musculares/metabolismoRESUMEN
Aerobic metabolism underlies vital traits such as locomotion and thermogenesis, and aerobic capacity influences fitness in many animals. The heart is a key determinant of aerobic capacity, but the relative influence of cardiac output versus other steps in the O2 transport pathway remains contentious. In this Commentary, we consider this issue by examining the mechanistic basis for adaptive increases in aerobic capacity (thermogenic VÌO2,max; also called summit metabolism) in deer mice (Peromyscus maniculatus) native to high altitude. Thermogenic VÌO2,max is increased by acclimation to cold hypoxia (simulating high-altitude conditions), and high-altitude populations generally have greater VÌO2,max than their low-altitude counterparts. This plastic and evolved variation in VÌO2,max is associated with corresponding variation in maximal cardiac output, along with variation in other traits across the O2 pathway (e.g. arterial O2 saturation, blood haemoglobin content and O2 affinity, tissue O2 extraction, tissue oxidative capacity). By applying fundamental principles of gas exchange, we show that the relative influence of cardiac output on VÌO2,max depends on the O2 diffusing capacity of thermogenic tissues (skeletal muscles and brown adipose tissues). Functional interactions between cardiac output and blood haemoglobin content determine circulatory O2 delivery and thus affect VÌO2,max, particularly in high-altitude environments where erythropoiesis can increase haematocrit and blood viscosity. There may also be functional linkages between cardiac output and tissue O2 diffusion due to the role of blood flow in determining capillary haematocrit and red blood cell flux. Therefore, the functional interactions between cardiac output and other traits in the O2 pathway underlie the adaptive evolution of aerobic capacities.
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Evolución Biológica , Gasto Cardíaco , Corazón , Peromyscus , Animales , Peromyscus/fisiología , Corazón/fisiología , Gasto Cardíaco/fisiología , Altitud , Aclimatación/fisiología , Consumo de Oxígeno/fisiología , Termogénesis/fisiología , Oxígeno/metabolismo , AerobiosisRESUMEN
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), ß-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.
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Altitud , Peromyscus , Animales , Peromyscus/fisiología , Hipoxia/metabolismo , Músculo Esquelético/metabolismo , Aclimatación , FenotipoRESUMEN
Morphometric studies of 3D micro CT-scanned images can provide insights into the evolution of the brain and sensory structures but such data are still scarce for the most diverse mammalian order of rodents. From reviewed and new data, we tested for convergence to extreme aridity and high elevation in the sensory and brain morphology of rodents, from morphometric data from micro-CT X-ray scans of 174 crania of 16 species of three distantly related African murid (soft-furred mice, Praomyini, laminate-toothed rats, Otomyini, and gerbils, Gerbillinae) clades and one North American cricetid (deer mice and white-footed mice, Peromyscus) clade. Recent studies demonstrated convergent evolution acting on the oval window area of the cochlea (enlarged in extremely arid-adapted species of Otomyini and Gerbillinae) and on endocranial volume (reduced in high elevation taxa of Otomyini and Peromyscus). However, contrary to our predictions, we did not find evidence of convergence in brain structure to aridity, or in the olfactory/respiratory system (turbinate bones) to high elevation. Brain structure differed, particularly in the petrosal lobules of the cerebellum and the olfactory bulbs, between Otomyini and Gerbillinae, with extreme arid-adapted species in each clade being highly divergent (not convergent) from other species in the same clade. We observed greater "packing" of the maxillary turbinate bones, which have important respiratory functions, in Peromyscus mice from high and low elevations compared to the high-elevation African Praomyini, but more complex patterns within Peromyscus, probably related to trade-offs in respiratory physiology and heat exchange in the nasal epithelium associated with high-elevation adaptation.
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Muridae , Peromyscus , Ratas , Animales , Gerbillinae , Encéfalo , América del NorteRESUMEN
A key question in biology concerns the extent to which distributional range limits of species are determined by intrinsic limits of physiological tolerance. Here, we use common-garden data for wild rodents to assess whether species with higher elevational range limits typically have higher thermogenic capacities in comparison to closely related lowland species. Among South American leaf-eared mice (genus Phyllotis), mean thermogenic performance is higher in species with higher elevational range limits, but there is little among-species variation in the magnitude of plasticity in this trait. In the North American rodent genus Peromyscus, highland deer mice (Peromyscus maniculatus) have greater thermogenic maximal oxygen uptake ( V Ì O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ) than lowland white-footed mice (Peromyscus leucopus) at a level of hypoxia that matches the upper elevational range limit of the former species. In highland deer mice, the enhanced thermogenic V Ì O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ in hypoxia is attributable to a combination of evolved and plastic changes in physiological pathways that govern the transport and utilization of O2 and metabolic substrates. Experiments with Peromyscus mice also demonstrate that exposure to hypoxia during different stages of development elicits plastic changes in cardiorespiratory traits that improve thermogenic V Ì O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ via distinct physiological mechanisms. Evolved differences in thermogenic capacity provide clues about why some species are able to persist in higher-elevation habitats that lie slightly beyond the tolerable limits of other species. Such differences in environmental tolerance also suggest why some species might be more vulnerable to climate change than others.
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Diving animals must sustain high activity with limited O2 stores to successfully capture prey. Studies suggest that increasing body O2 stores supports breath-hold diving, but less is known about metabolic specializations that underlie underwater locomotion. We measured maximal activities of 10 key enzymes in locomotory muscles (gastrocnemius and pectoralis) to identify biochemical changes associated with diving in pathways of oxidative and substrate-level phosphorylation and compared them across three groups of ducks-the longest diving sea ducks (eight spp.), the mid-tier diving pochards (three spp.) and the non-diving dabblers (five spp.). Relative to dabblers, both diving groups had increased activities of succinate dehydrogenase and cytochrome c oxidase, and sea ducks further showed increases in citrate synthase (CS) and hydroxyacyl-CoA dehydrogenase (HOAD). Both diving groups had relative decreases in capacity for anaerobic metabolism (lower ratio of lactate dehydrogenase to CS), with sea ducks also showing a greater capacity for oxidative phosphorylation and lipid oxidation (lower ratio of pyruvate kinase to CS, higher ratio of HOAD to hexokinase). These data suggest that the locomotory muscles of diving ducks are specialized for sustaining high rates of aerobic metabolism, emphasizing the importance of body O2 stores for dive performance in these species.
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Patos , Locomoción , Animales , Metabolismo de los Lípidos , Anaerobiosis , Músculos PectoralesRESUMEN
Phenotypic plasticity can play an important role in the ability of animals to tolerate environmental stress, but the nature and magnitude of plastic responses are often specific to the developmental timing of exposure. Here, we examine changes in gene expression in the diaphragm of highland deer mice (Peromyscus maniculatus) in response to hypoxia exposure at different stages of development. In highland deer mice, developmental plasticity in diaphragm function may mediate changes in several respiratory traits that influence aerobic metabolism and performance under hypoxia. We generated RNAseq data from diaphragm tissue of adult deer mice exposed to (1) life-long hypoxia (before conception to adulthood), (2) post-natal hypoxia (birth to adulthood), (3) adult hypoxia (6-8 weeks only during adulthood) or (4) normoxia. We found five suites of co-regulated genes that are differentially expressed in response to hypoxia, but the patterns of differential expression depend on the developmental timing of exposure. We also identified four transcriptional modules that are associated with important respiratory traits. Many of the genes in these transcriptional modules bear signatures of altitude-related selection, providing an indirect line of evidence that observed changes in gene expression may be adaptive in hypoxic environments. Our results demonstrate the importance of developmental stage in determining the phenotypic response to environmental stressors.
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Hipoxia , Peromyscus , Animales , Peromyscus/genética , Hipoxia/metabolismo , Respiración , Adaptación Fisiológica/genética , AltitudRESUMEN
Climate change is leading to rapid change in aquatic environments, increasing the mean and variability of temperatures, and increasing the incidence of hypoxia. We investigated how acclimation to constant temperatures or to diel temperature fluctuations affects hypoxia tolerance in mummichog killifish (Fundulus heteroclitus). Killifish were acclimated to constant cool (15°C), constant warm (25°C) or a diel temperature cycle (15°C at night, 25°C during day) for 6â weeks. We then measured hypoxia tolerance (time to loss of equilibrium in severe hypoxia, tLOE; critical O2 tension, Pcrit), whole-animal metabolism, gill morphology, haematology and tissue metabolites at 15°C and 25°C in a full factorial design. Among constant temperature groups, tLOE was highest and Pcrit was lowest in fish tested at their acclimation temperature. Warm-acclimated fish had lower metabolic rate at 25°C and greater gill surface area (less coverage of lamellae by interlamellar cell mass, ILCM), but cool-acclimated fish had greater brain glycogen stores. Therefore, effects of constant temperature acclimation on hypoxia tolerance were temperature specific and not exhibited broadly across test temperatures, and they were associated with different underlying mechanisms. Hypoxia tolerance was less sensitive to test temperature in fish acclimated to fluctuating temperatures compared with fish acclimated to constant temperature. Acclimation to fluctuating temperatures also increased haemoglobin-O2 affinity of the blood (decreased P50) compared with constant temperature groups. Therefore, acclimation to fluctuating temperatures helps maintain hypoxia tolerance across a broader range of temperatures, and leads to some distinct physiological adjustments that are not exhibited by fish acclimated to constant temperatures.
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Fundulidae , Animales , Temperatura , Fundulidae/fisiología , Hipoxia , Aclimatación/fisiología , FríoRESUMEN
To better understand functional morphological adaptations to high elevation (> 3000 m above sea level) life in both North American and African mountain-associated rodents, we used microCT scanning to acquire 3D images and a 3D morphometric approach to calculate endocranial volumes and skull lengths. This was done on 113 crania of low-elevation and high-elevation populations in species of North American cricetid mice (two Peromyscus species, n = 53), and African murid rodents of two tribes, Otomyini (five species, n = 49) and Praomyini (four species, n = 11). We tested two distinct hypotheses for how endocranial volume might vary in high-elevation populations: the expensive tissue hypothesis, which predicts that brain and endocranial volumes will be reduced to lessen the costs of growing and maintaining a large brain; and the brain-swelling hypothesis, which predicts that endocranial volumes will be increased either as a direct phenotypic effect or as an adaptation to accommodate brain swelling and thus minimize pathological symptoms of altitude sickness. After correcting for general allometric variation in cranial size, we found that in both North American Peromyscus mice and African laminate-toothed (Otomys) rats, highland rodents had smaller endocranial volumes than lower-elevation rodents, consistent with the expensive tissue hypothesis. In the former group, Peromyscus mice, crania were obtained not just from wild-caught mice from high and low elevations but also from those bred in common-garden laboratory conditions from parents caught from either high or low elevations. Our results in these mice showed that brain size responses to elevation might have a strong genetic basis, which counters an opposite but weaker environmental effect on brain volume. These results potentially suggest that selection may act to reduce brain volume across small mammals at high elevations but further experiments are needed to assess the generality of this conclusion and the nature of underlying mechanisms.
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Muridae , Peromyscus , Animales , Ratas , Tamaño de los Órganos , Cráneo/diagnóstico por imagen , Cráneo/anatomía & histología , Cabeza/anatomía & histologíaRESUMEN
To gain insight into the mitochondrial mechanisms of hypoxia tolerance in high-altitude natives, we examined left ventricle mitochondrial function of highland deer mice compared with lowland native deer mice and white-footed mice. Highland and lowland native deer mice (Peromyscus maniculatus) and lowland white-footed mice (P. leucopus) were first-generation born and raised in common lab conditions. Adult mice were acclimated to either normoxia or hypoxia (60 kPa) equivalent to ~ 4300 m for at least 6 weeks. Left ventricle mitochondrial physiology was assessed by determining respiration in permeabilized muscle fibers with carbohydrates, lipids, and lactate as substrates. We also measured the activities of several left ventricle metabolic enzymes. Permeabilized left ventricle muscle fibers of highland deer mice showed greater rates of respiration with lactate than either lowland deer mice or white-footed mice. This was associated with higher activities of lactate dehydrogenase in tissue and isolated mitochondria in highlanders. Normoxia-acclimated highlanders also showed higher respiratory rates with palmitoyl-carnitine than lowland mice. Maximal respiratory capacity through complexes I and II was also greater in highland deer mice but only compared with lowland deer mice. Acclimation to hypoxia had little effect on respiration rates with these substrates. In contrast, left ventricle activities of hexokinase increased in both lowland and highland deer mice after hypoxia acclimation. These data suggest that highland deer mice support an elevated cardiac function in hypoxia, in part, with high ventricle cardiomyocyte respiratory capacities supported by carbohydrates, fatty acids, and lactate.
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Consumo de Oxígeno , Peromyscus , Animales , Peromyscus/fisiología , Consumo de Oxígeno/fisiología , Ventrículos Cardíacos , Hipoxia , Mitocondrias , Carbohidratos , Lactatos , AltitudRESUMEN
Climate warming could challenge the ability of endotherms to thermoregulate and maintain normal body temperature (Tb), but the effects of warming summer temperatures on activity and thermoregulatory physiology in many small mammals remain poorly understood. We examined this issue in deer mice (Peromyscus maniculatus), an active nocturnal species. Mice were exposed in the lab to simulated seasonal warming, in which an environmentally realistic diel cycle of ambient temperature (Ta) was gradually warmed from spring conditions to summer conditions (controls were maintained in spring conditions). Activity (voluntary wheel running) and Tb (implanted bio-loggers) were measured throughout, and indices of thermoregulatory physiology (thermoneutral zone, thermogenic capacity) were assessed after exposure. In control mice, activity was almost entirely restricted to the night-time, and Tb fluctuated â¼1.7°C between daytime lows and night-time highs. Activity, body mass and food consumption were reduced and water consumption was increased in later stages of summer warming. This was accompanied by strong Tb dysregulation that culminated in a complete reversal of the diel pattern of Tb variation, with Tb reaching extreme highs (â¼40°C) during daytime heat but extreme lows (â¼34°C) at cooler night-time temperatures. Summer warming was also associated with reduced ability to generate body heat, as reflected by decreased thermogenic capacity and decreased mass and uncoupling protein (UCP1) content of brown adipose tissue. Our findings suggest that thermoregulatory trade-offs associated with daytime heat exposure can affect Tb and activity at cooler night-time temperatures, impacting the ability of nocturnal mammals to perform behaviours important for fitness in the wild.
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Actividad Motora , Peromyscus , Animales , Temperatura , Estaciones del Año , Peromyscus/fisiología , Regulación de la Temperatura Corporal/fisiologíaRESUMEN
The impacts of warming temperatures associated with climate change on performance are poorly understood in most mammals. Thermal performance curves are a valuable means of examining the effects of temperature on performance traits, but they have rarely been used in endotherms. Here, we examined the thermal performance curve of endurance running capacity at high temperatures in the deer mouse (Peromyscus maniculatus). Endurance capacity was measured using an incremental speed test on a treadmill, and subcutaneous temperature in the abdominal region was measured as a proxy for body temperature (Tb). Endurance time at 20°C was repeatable but varied appreciably across individuals, and was unaffected by sex or body mass. Endurance capacity was maintained across a broad range of ambient temperatures (Ta) but was reduced above 35°C. Tb during running varied with Ta, and reductions in endurance were associated with Tb greater than 40°C when Ta was above 35°C. At the high Ta that limited endurance running capacity (but not at lower Ta), Tb tended to rise throughout running trials with increases in running speed. Metabolic and thermoregulatory measurements at rest showed that Tb, evaporative water loss and breathing frequency increased at Ta of 36°C and above. Therefore, the upper threshold temperatures at which endurance capacity is impaired are similar to those inducing heat responses at rest in this species. These findings help discern the mechanisms by which deer mice are impacted by warming temperatures, and provide a general approach for examining thermal breadth of performance in small mammals.
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Calor , Carrera , Animales , Temperatura , Peromyscus , Regulación de la Temperatura Corporal/fisiología , Carrera/fisiologíaRESUMEN
The evolution of endothermy was instrumental to the diversification of birds and mammals, but the energetic demands of maintaining high body temperature could offset the advantages of endothermy in some environments. We hypothesized that reductions in body temperature help high-altitude natives overcome the metabolic challenges of cold and hypoxia in their native environment. Deer mice (Peromyscus maniculatus) from high-altitude and low-altitude populations were bred in captivity to the second generation and were acclimated as adults to warm normoxia or cold hypoxia. Subcutaneous temperature (Tsub, used as a proxy for body temperature) and cardiovascular function were then measured throughout the diel cycle using biotelemetry. Cold hypoxia increased metabolic demands, as reflected by increased food consumption and heart rate (associated with reduced vagal tone). These increased metabolic demands were offset by plastic reductions in Tsub (approx. 2°C) in response to cold hypoxia, and highlanders had lower Tsub (approx. 1°C) than lowlanders in both environmental treatments. Empirical and theoretical evidence suggested that these reductions could together reduce metabolic demands by approximately 10-30%. Therefore, plastic and evolved reductions in body temperature can help mammals overcome the metabolic challenges at high altitude and may be a valuable energy-saving strategy in some non-hibernating endotherms in extreme environments.
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Altitud , Peromyscus , Aclimatación , Animales , Temperatura Corporal , Regulación de la Temperatura Corporal , Hipoxia , Peromyscus/fisiología , PlásticosRESUMEN
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 O2) for 6 wk and then subjected to telemetry measurements of routine physiology across the diel cycle. Heart rate (fH), mean arterial blood pressure (Pmean), body temperature (Tb), 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 fH, Tb, 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 Pmean response to pharmacological blockade). Responses to acute hypoxia were then measured during stepwise reductions in inspired O2 from 21 to 8 kPa O2. O2 consumption rate, fH, Pmean, and Tb declined in severe hypoxia, but the O2 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.
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Óxido Nítrico , Respiración , Aclimatación/fisiología , Adrenérgicos , Animales , Femenino , Frecuencia Cardíaca/fisiología , Hipoxia , Masculino , Ratones , Consumo de Oxígeno/fisiologíaRESUMEN
The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.
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The gene encoding HIF-2α, Epas1, has experienced a history of natural selection in many high-altitude taxa, but the functional role of mutations in this gene is still poorly understood. We investigated the influence of the high-altitude variant of Epas1 in North American deer mice (Peromyscus maniculatus) on the control of breathing and carotid body growth during chronic hypoxia. We created hybrids between high- and low-altitude populations of deer mice to disrupt linkages between genetic loci so that the physiological effects of Epas1 alleles (Epas1H and Epas1L , respectively) could be examined on an admixed genomic background. In general, chronic hypoxia (4 weeks at 12 kPa O2 ) enhanced ventilatory chemosensitivity (assessed as the acute ventilatory response to hypoxia), increased total ventilation and arterial O2 saturation during progressive poikilocapnic hypoxia, and increased haematocrit and blood haemoglobin content across genotypes. However, the effects of chronic hypoxia on ventilatory chemosensitivity were attenuated in mice that were homozygous for the high-altitude Epas1 allele (Epas1H/H ). Carotid body growth and glomus cell hyperplasia, which was strongly induced in Epas1L/L mice in chronic hypoxia, was not observed in Epas1H/H mice. Epas1 genotype also modulated the effects of chronic hypoxia on metabolism and body temperature depression in hypoxia, but had no effects on haematological traits. These findings confirm the important role of HIF-2α in modulating ventilatory sensitivity and carotid body growth in chronic hypoxia, and show that genetic variation in Epas1 is responsible for evolved changes in the control of breathing and metabolism in high-altitude deer mice. KEY POINTS: High-altitude natives of many species have experienced natural selection on the gene encoding HIF-2α, Epas1, including high-altitude populations of deer mice. HIF-2α regulates ventilation and carotid body growth in hypoxia, and so the genetic variants in Epas1 in high-altitude natives may underlie evolved changes in control of breathing. Deer mice from controlled crosses between high- and low-altitude populations were used to examine the effects of Epas1 genotype on an admixed genomic background. The high-altitude variant was associated with reduced ventilatory chemosensitivity and carotid body growth in chronic hypoxia, but had no effects on haematology. The results help us better understand the genetic basis for the unique physiological phenotype of high-altitude natives.
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Cuerpo Carotídeo , Aclimatación/fisiología , Altitud , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Cuerpo Carotídeo/metabolismo , Variación Genética , Hipoxia , Peromyscus/genéticaRESUMEN
Aerobic energy demands have led to the evolution of complex mitochondrial reticula in highly oxidative muscles, but the extent to which metabolic challenges can be met with adaptive changes in physiology of specific mitochondrial fractions remains unresolved. We examined mitochondrial mechanisms supporting adaptive increases in aerobic performance in deer mice (Peromyscus maniculatus) adapted to the hypoxic environment at high altitude. High-altitude and low-altitude mice were born and raised in captivity, and exposed as adults to normoxia or hypobaric hypoxia (12 kPa O2 for 6-8 weeks). Subsarcolemmal and intermyofibrillar mitochondria were isolated from the gastrocnemius, and a comprehensive substrate titration protocol was used to examine mitochondrial physiology and O2 kinetics by high-resolution respirometry and fluorometry. High-altitude mice had greater yield, respiratory capacity for oxidative phosphorylation, and O2 affinity (lower P50 ) of subsarcolemmal mitochondria compared to low-altitude mice across environments, but there were no species difference in these traits in intermyofibrillar mitochondria. High-altitude mice also had greater capacities of complex II relative to complexes I + II and higher succinate dehydrogenase activities in both mitochondrial fractions. Exposure to chronic hypoxia reduced reactive oxygen species (ROS) emission in high-altitude mice but not in low-altitude mice. Our findings suggest that functional changes in subsarcolemmal mitochondria contribute to improving aerobic performance in hypoxia in high-altitude deer mice. Therefore, physiological variation in specific mitochondrial fractions can help overcome the metabolic challenges of life at high altitude.
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Altitud , Peromyscus , Animales , Hipoxia , Mitocondrias , Mitocondrias Musculares , Músculo Esquelético , Peromyscus/fisiologíaRESUMEN
Studies of animals native to high altitude can provide valuable insight into physiological mechanisms and evolution of performance in challenging environments. We investigated how mechanisms controlling cardiovascular function may have evolved in deer mice (Peromyscus maniculatus) native to high altitude. High-altitude deer mice and low-altitude white-footed mice (P. leucopus) were bred in captivity at sea level, and first-generation lab progeny were raised to adulthood and acclimated to normoxia or hypoxia. We then used pharmacological agents to examine the capacity for adrenergic receptor stimulation to modulate heart rate (f H) and mean arterial pressure (P mean) in anaesthetized mice, and used cardiac pressure-volume catheters to evaluate the contractility of the left ventricle. We found that highlanders had a consistently greater capacity to increase f H via pharmacological stimulation of ß1-adrenergic receptors than lowlanders. Also, whereas hypoxia acclimation reduced the capacity for increasing P mean in response to α-adrenergic stimulation in lowlanders, highlanders exhibited no plasticity in this capacity. These differences in highlanders may help augment cardiac output during locomotion or cold stress, and may preserve their capacity for α-mediated vasoconstriction to more effectively redistribute blood flow to active tissues. Highlanders did not exhibit any differences in some measures of cardiac contractility (maximum pressure derivative, dP/dtmax, or end-systolic elastance, Ees), but ejection fraction was highest in highlanders after hypoxia acclimation. Overall, our results suggest that evolved changes in sensitivity to adrenergic stimulation of cardiovascular function may help deer mice cope with the cold and hypoxic conditions at high altitude.