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1. 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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2. 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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3. To what extent do physiological tolerances determine elevational range limits of mammals?

   https://doi.org/10.1113/JP284586  

   Storz, Jay F. ; Scott, Graham R. ( October 2023 , The Journal of Physiology)

   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 (genusPhyllotis), 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 genusPeromyscus, highland deer mice (Peromyscus maniculatus) have greater thermogenic maximal oxygen uptake () 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 in hypoxia is attributable to a combination of evolved and plastic changes in physiological pathways that govern the transport and utilization of O₂and metabolic substrates. Experiments withPeromyscusmice also demonstrate that exposure to hypoxia during different stages of development elicits plastic changes in cardiorespiratory traits that improve thermogenic 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.image

    

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4. Genetic variation in haemoglobin is associated with evolved changes in breathing in high-altitude deer mice

   https://doi.org/10.1242/jeb.243595  

   Ivy, Catherine M. ; Wearing, Oliver H. ; Natarajan, Chandrasekhar ; Schweizer, Rena M. ; Gutiérrez-Pinto, Natalia ; Velotta, Jonathan P. ; Campbell-Staton, Shane C. ; Petersen, Elin E. ; Fago, Angela ; Cheviron, Zachary A. ; et al ( January 2022 , Journal of Experimental Biology)

   ABSTRACT Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated whether genetic variants in haemoglobin (Hb) that contribute to high-altitude adaptation in deer mice (Peromyscus maniculatus) are associated with evolved changes in the control of breathing. We created F2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of α- and β-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb–O2 affinity that were associated with differences in arterial O2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O2 uptake in hypoxia. Mice with highland α-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2, and this difference was comparable to the evolved changes in breathing pattern in deer mouse populations native to high altitude. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland β-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb–O2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb–O2 affinity) had no effect on breathing in normoxia or hypoxia. Therefore, adaptive variation in Hb may have unexpected effects on physiology in addition to the canonical function of this protein in circulatory O2 transport. 

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5. Adrenergically induced translocation of red blood cell β-adrenergic sodium-proton exchangers has ecological relevance for hypoxic and hypercapnic white seabass

   https://doi.org/10.1152/ajpregu.00175.2021  

   Harter, Till S. ; Clifford, Alexander M. ; Tresguerres, Martin ( November 2021 , American Journal of Physiology-Regulatory, Integrative and Comparative Physiology)

   White seabass ( Atractoscion nobilis) increasingly experience periods of low oxygen (O 2 ; hypoxia) and high carbon dioxide (CO 2 , hypercapnia) due to climate change and eutrophication of the coastal waters of California. Hemoglobin (Hb) is the principal O 2 carrier in the blood and in many teleost fishes Hb-O 2 binding is compromised at low pH; however, the red blood cells (RBC) of some species regulate intracellular pH with adrenergically stimulated sodium-proton-exchangers (β-NHEs). We hypothesized that RBC β-NHEs in white seabass are an important mechanism that can protect the blood O 2 -carrying capacity during hypoxia and hypercapnia. We determined the O 2 -binding characteristics of white seabass blood, the cellular and subcellular response of RBCs to adrenergic stimulation, and quantified the protective effect of β-NHE activity on Hb-O 2 saturation. White seabass had typical teleost Hb characteristics, with a moderate O 2 affinity (Po 2 at half-saturation; P 50 2.9 kPa) that was highly pH-sensitive (Bohr coefficient −0.92; Root effect 52%). Novel findings from super-resolution microscopy revealed β-NHE protein in vesicle-like structures and its translocation into the membrane after adrenergic stimulation. Microscopy data were corroborated by molecular and phylogenetic results and a functional characterization of β-NHE activity. The activation of RBC β-NHEs increased Hb-O 2 saturation by ∼8% in normoxic hypercapnia and by up to ∼20% in hypoxic normocapnia. Our results provide novel insight into the cellular mechanism of adrenergic RBC stimulation within an ecologically relevant context. β-NHE activity in white seabass has great potential to protect arterial O 2 transport during hypoxia and hypercapnia but is less effective during combinations of these stressors. 

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