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1. Coordinated changes across the O 2 transport pathway underlie adaptive increases in thermogenic capacity in high-altitude deer mice

   https://doi.org/10.1098/rspb.2019.2750  

   Tate, Kevin B. ; Wearing, Oliver H. ; Ivy, Catherine M. ; Cheviron, Zachary A. ; Storz, Jay F. ; McClelland, Grant B. ; Scott, Graham R. ( May 2020 , Proceedings of the Royal Society B: Biological Sciences)

   null (Ed.)

   Animals native to the hypoxic and cold environment at high altitude provide an excellent opportunity to elucidate the integrative mechanisms underlying the adaptive evolution and plasticity of complex traits. The capacity for aerobic thermogenesis can be a critical determinant of survival for small mammals at high altitude, but the physiological mechanisms underlying the evolution of this performance trait remain unresolved. We examined this issue by comparing high-altitude deer mice ( Peromyscus maniculatus ) with low-altitude deer mice and white-footed mice ( P. leucopus ). Mice were bred in captivity and adults were acclimated to each of four treatments: warm (25°C) normoxia, warm hypoxia (12 kPa O 2 ), cold (5°C) normoxia or cold hypoxia. Acclimation to hypoxia and/or cold increased thermogenic capacity in deer mice, but hypoxia acclimation led to much greater increases in thermogenic capacity in highlanders than in lowlanders. The high thermogenic capacity of highlanders was associated with increases in pulmonary O 2 extraction, arterial O 2 saturation, cardiac output and arterial–venous O 2 difference. Mechanisms underlying the evolution of enhanced thermogenic capacity in highlanders were partially distinct from those underlying the ancestral acclimation responses of lowlanders. Environmental adaptation has thus enhanced phenotypic plasticity and expanded the physiological toolkit for coping with the challenges at high altitude. 

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2. Chronic cold exposure induces mitochondrial plasticity in deer mice native to high altitudes

   https://doi.org/10.1113/JP280298  

   Mahalingam, Sajeni ; Cheviron, Zachary A. ; Storz, Jay F. ; McClelland, Grant B. ; Scott, Graham R. ( September 2020 , The Journal of Physiology)

   Small mammals native to high altitude must sustain high rates of thermogenesis to cope with cold. Skeletal muscle is a key site of shivering and non‐shivering thermogenesis, but the importance of mitochondrial plasticity in cold hypoxic environments remains unresolved.

   We examined high‐altitude deer mice, which have evolved a high capacity for aerobic thermogenesis, to determine the mechanisms of mitochondrial plasticity during chronic exposure to cold and hypoxia, alone and in combination.

   Cold exposure in normoxia or hypoxia increased mitochondrial leak respiration and decreased phosphorylation efficiency and OXPHOS coupling efficiency, which may serve to augment non‐shivering thermogenesis. Cold also increased muscle oxidative capacity, but reduced the capacity for mitochondrial respiration via complex II relative to complexes I and II combined.

   High‐altitude mice had a more oxidative muscle phenotype than low‐altitude mice.

   Therefore, both plasticity and evolved changes in muscle mitochondria contribute to thermogenesis at high altitude.

   Small mammals native to high altitude must sustain high rates of thermogenesis to cope with cold and hypoxic environments. Skeletal muscle is a key site of shivering and non‐shivering thermogenesis, but the importance of mitochondrial plasticity in small mammals at high altitude remains unresolved. High‐altitude deer mice (Peromyscus maniculatus) and low‐altitude white‐footed mice (P. leucopus) were born and raised in captivity, and chronically exposed as adults to warm (25°C) normoxia, warm hypoxia (12 kPa O₂), cold (5°C) normoxia, or cold hypoxia. We then measured oxidative enzyme activities, oxidative fibre density and capillarity in the gastrocnemius, and used a comprehensive substrate titration protocol to examine the function of muscle mitochondria by high‐resolution respirometry. Exposure to cold in both normoxia or hypoxia increased the activities of citrate synthase and cytochrome oxidase. In lowlanders, this was associated with increases in capillary density and the proportional abundance of oxidative muscle fibres, but in highlanders, these traits were unchanged at high levels across environments. Environment had some distinct effects on mitochondrial OXPHOS capacity between species, but the capacity of complex II relative to the combined capacity of complexes I and II was consistently reduced in both cold environments. Both cold environments also increased leak respiration and decreased phosphorylation efficiency and OXPHOS coupling efficiency in both species, which may serve to augment non‐shivering thermogenesis. These cold‐induced changes in mitochondrial function were overlaid upon the generally more oxidative phenotype of highlanders. Therefore, both plasticity and evolved changes in muscle mitochondria contribute to thermogenesis at high altitudes.

    

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3. Botfly infections impair the aerobic performance and survival of montane populations of deer mice, Peromyscus maniculatus rufinus

   https://doi.org/10.1111/1365-2435.13276  

   Wilde, Luke R. ; Wolf, Cole J. ; Porter, Stephanie M. ; Stager, Maria ; Cheviron, Zachary A. ; Senner, Nathan R. ; White, ed., Craig ( January 2019 , Functional Ecology)

   Elevations >2,000 m represent consistently harsh environments for small endotherms because of abiotic stressors such as cold temperatures and hypoxia.

   These environmental stressors may limit the ability of populations living at these elevations to respond to biotic selection pressures—such as parasites or pathogens—that in other environmental contexts would impose only minimal energetic‐ and fitness‐related costs.

   We studied deer mice (Peromyscus maniculatus rufinus) living along two elevational transects (2,300–4,400 m) in the Colorado Rockies and found that infection prevalence by botfly larvae (Cuterebridae) declined at higher elevations. We found no evidence of infections at elevations >2,400 m, but that 33.6% of all deer mice, and 52.2% of adults, were infected at elevations <2,400 m.

   Botfly infections were associated with reductions in haematocrit levels of 23%, haemoglobin concentrations of 27% and cold‐induced VO_2maxmeasures of 19% compared to uninfected individuals. In turn, these reductions in aerobic performance appeared to influence fitness, as infected individuals exhibited 19‐34% lower daily survival rates.

   In contrast to studies at lower elevations, we found evidence indicating that botfly infections influence the aerobic capabilities and fitness of deer mice living at elevations between 2,000 and 2,400 m. Our results therefore suggest that the interaction between botflies and small rodents is likely highly context‐dependent and that, more generally, high‐elevation populations may be susceptible to additional biotic selection pressures.

   Aplain language summaryis available for this article.

    

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4. The adaptive benefit of evolved increases in hemoglobin-O2 affinity is contingent on tissue O2 diffusing capacity in high-altitude deer mice

   https://doi.org/10.1186/s12915-021-01059-4  

   Wearing, Oliver H. ; Ivy, Catherine M. ; Gutiérrez-Pinto, Natalia ; Velotta, Jonathan P. ; Campbell-Staton, Shane C. ; Natarajan, Chandrasekhar ; Cheviron, Zachary A. ; Storz, Jay F. ; Scott, Graham R. ( June 2021 , BMC Biology)

   Complex organismal traits are often the result of multiple interacting genes and sub-organismal phenotypes, but how these interactions shape the evolutionary trajectories of adaptive traits is poorly understood. We examined how functional interactions between cardiorespiratory traits contribute to adaptive increases in the capacity for aerobic thermogenesis (maximal O₂consumption,V̇O₂max, during acute cold exposure) in high-altitude deer mice (Peromyscus maniculatus). We crossed highland and lowland deer mice to produce F₂inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O₂affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O₂transport pathway to examine the links between cardiorespiratory traits andV̇O₂max.

   Physiological experiments revealed that increases in Hb-O₂affinity of red blood cells improved blood oxygenation in hypoxia but were not associated with an enhancement inV̇O₂max. Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O₂affinity onV̇O₂max in hypoxia was contingent on the capacity for O₂diffusion in active tissues.

   These results suggest that increases in Hb-O₂affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O₂diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O₂affinity is contingent on the capacity to extract O₂from the blood, which helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance.

    

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5. Gene regulatory changes underlie developmental plasticity in respiration and aerobic performance in highland deer mice

   https://doi.org/10.1111/mec.16953  

   Schweizer, Rena M. ; Ivy, Catherine M. ; Natarajan, Chandrasekhar ; Scott, Graham R. ; Storz, Jay F. ; Cheviron, Zachary A. ( April 2023 , Molecular Ecology)

   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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