Development of homeothermic endothermy is delayed in high-altitude native deer mice (
            Peromyscus maniculatus)

Altricial mammals begin to independently thermoregulate during the first few weeks of postnatal development. In wild rodent populations, this is also a time of high mortality (50–95%), making the physiological systems that mature during this period potential targets for selection. High altitude (HA) is a particularly challenging environment for small endotherms owing to unremitting low O 2 and ambient temperatures. While superior thermogenic capacities have been demonstrated in adults of some HA species, it is unclear if selection has occurred to survive these unique challenges early in development. We used deer mice ( Peromyscus maniculatus ) native to high and low altitude (LA), and a strictly LA species ( Peromyscus leucopus ), raised under common garden conditions, to determine if postnatal onset of endothermy and maturation of brown adipose tissue (BAT) is affected by altitude ancestry. We found that the onset of endothermy corresponds with the maturation and activation of BAT at an equivalent age in LA natives, with 10-day-old pups able to thermoregulate in response to acute cold in both species. However, the onset of endothermy in HA pups was substantially delayed (by approx. 2 days), possibly driven by delayed sympathetic regulation of BAT. We suggest that this delay may be part of an evolved cost-saving measure to allow pups to maintain growth rates under the O 2 -limited conditions at HA.

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Plasticity of non-shivering thermogenesis and brown adipose tissue in high-altitude deer mice

Journal of Experimental Biology ◽

10.1242/jeb.242279 ◽

2021 ◽

Author(s):

Soren Z. Coulson ◽

Cayleih E. Robertson ◽

Sajeni Mahalingam ◽

Grant B. McClelland

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Altitude ◽

Heat Production ◽

Mitochondrial Function ◽

Mitochondrial Respiration ◽

Deer Mice ◽

Brown Adipose ◽

Hypoxia Acclimation ◽

Shivering Thermogenesis

High altitude environments challenge small mammals with persistent low ambient temperatures that require high rates of aerobic heat production in face of low O2 availability. An important component of thermogenic capacity in rodents is non-shivering thermogenesis (NST) mediated by uncoupled mitochondrial respiration in brown adipose tissue (BAT). NST is plastic, and capacity for heat production increases with cold acclimation. However, in lowland native rodents, hypoxia inhibits NST in BAT. We hypothesize that highland deer mice (Peromyscus maniculatus) overcome the hypoxic inhibition of NST through changes in BAT mitochondrial function. We tested this hypothesis using lab born and raised highland and lowland deer mice, and a lowland congeneric (P. leucopus), acclimated to either warm normoxia (25°C, 760 mmHg) or cold hypoxia (5°C, 430 mmHg). We determined the effects of acclimation and ancestry on whole-animal rates of NST, the mass of interscapular BAT (iBAT), and uncoupling protein (UCP)-1 protein expression. To identify changes in mitochondrial function, we conducted high-resolution respirometry on isolated iBAT mitochondria using substrates and inhibitors targeted to UCP-1. We found that rates of NST increased with cold hypoxia acclimation but only in highland deer mice. There was no effect of cold hypoxia acclimation on iBAT mass in any group, but highland deer mice showed increases in UCP-1 expression and UCP-1 stimulated mitochondrial respiration in response to these stressors. Our results suggest that highland deer mice have evolved to increase the capacity for NST in response to chronic cold hypoxia, driven in part by changes in iBAT mitochondrial function.

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Adaptive shifts in gene regulation underlie a developmental delay in thermogenesis in high-altitude deer mice

10.1101/2019.12.17.880112 ◽

2019 ◽

Author(s):

Jonathan P. Velotta ◽

Cayleih E. Robertson ◽

Rena M. Schweizer ◽

Grant B. McClelland ◽

Zachary A. Cheviron

Keyword(s):

High Altitude ◽

Developmental Delay ◽

System Development ◽

Nervous System Development ◽

Developmental Trajectory ◽

Aerobic Performance ◽

Deer Mice ◽

Adult Mice ◽

Brown Adipose ◽

Adaptive Shifts

AbstractAerobic performance is tied to fitness as it influences an animal’s ability to find food, escape predators, or survive extreme conditions. At high altitude, where low O2 availability and persistent cold prevail, maximum metabolic heat production (thermogenesis) is an aerobic performance trait that is intimately linked to survival. Understanding how thermogenesis evolves to enhance survival at high altitude will yield insight into the links between physiology, performance, and fitness. Recent work in deer mice (Peromyscus maniculatus) has shown that adult mice native to high-altitude have higher thermogenic capacities under hypoxia compared to lowland conspecifics, but developing high-altitude pups delay the onset of thermogenesis. This suggests that natural selection on thermogenic capacity varies across life stages. To determine the mechanistic cause of this ontogenetic delay, we analyzed the transcriptomes of thermo-effector organs – brown adipose tissue and skeletal muscle – in developing deer mice native to low- and high-altitude. We demonstrate that the developmental delay in thermogenesis is associated with adaptive shifts in the expression of genes involved in nervous system development, fuel/O2 supply, and oxidative metabolism gene pathways. Our results demonstrate that selection has modified the developmental trajectory of the thermoregulatory system at high altitude and has done so by acting on the regulatory systems that control the maturation of thermo-effector tissues. We suggest that the cold and hypoxic conditions of high altitude may force a resource allocation trade-off, whereby limited energy is allocated to developmental processes such as growth, versus active thermogenesis during early development.

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Developmental delay in shivering limits thermogenic capacity in juvenile high-altitude deer mice (Peromyscus maniculatus)

Journal of Experimental Biology ◽

10.1242/jeb.210963 ◽

2019 ◽

Vol 222 (21) ◽

pp. jeb210963 ◽

Cited By ~ 4

Author(s):

Cayleih E. Robertson ◽

Grant B. McClelland

Keyword(s):

High Altitude ◽

Developmental Delay ◽

Peromyscus Maniculatus ◽

Deer Mice ◽

Thermogenic Capacity

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Life-long exposure to hypoxia affects metabolism and respiratory physiology across life stages in high-altitude deer mice (Peromyscus maniculatus)

Journal of Experimental Biology ◽

10.1242/jeb.237024 ◽

2020 ◽

Vol 224 (1) ◽

pp. jeb237024 ◽

Cited By ~ 1

Author(s):

Catherine M. Ivy ◽

Graham R. Scott

Keyword(s):

High Altitude ◽

Peromyscus Maniculatus ◽

Adult Life ◽

Respiratory Physiology ◽

Deer Mice ◽

Continuous Exposure ◽

Life Stages ◽

Hypoxia Exposure ◽

In Captivity ◽

Haemoglobin Content

ABSTRACTHypoxia exposure can have distinct physiological effects between early developmental and adult life stages, but it is unclear how the effects of hypoxia may progress during continuous exposure throughout life. We examined this issue in deer mice (Peromyscus maniculatus) from a population native to high altitude. Mice were bred in captivity in one of three treatment groups: normoxia (controls), life-long hypoxia (∼12 kPa O2 from conception to adulthood) and parental hypoxia (normoxia from conception to adulthood, but parents previously exposed to hypoxia). Metabolic, thermoregulatory and ventilatory responses to progressive stepwise hypoxia and haematology were then measured at post-natal day (P) 14 and 30 and/or in adulthood. Life-long hypoxia had consistent effects across ages on metabolism, attenuating the declines in O2 consumption rate (V̇O2) and body temperature during progressive hypoxia compared with control mice. However, life-long hypoxia had age-specific effects on breathing, blunting the hypoxia-induced increases in air convection requirement (quotient of total ventilation and V̇O2) at P14 and P30 only, but then shifting breathing pattern towards deeper and/or less frequent breaths at P30 and adulthood. Hypoxia exposure also increased blood–O2 affinity at P14 and P30, in association with an increase in arterial O2 saturation in hypoxia at P30. In contrast, parental hypoxia had no effects on metabolism or breathing, but it increased blood–O2 affinity and decreased red cell haemoglobin content at P14 (but not P30). Therefore, hypoxia exposure has some consistent effects across early life and adulthood, and some other effects that are unique to specific life stages.

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Acclimatization of low altitude-bred deer mice (Peromyscus maniculatus) to high altitude

Journal of Applied Physiology ◽

10.1152/japplphysiol.01036.2017 ◽

2018 ◽

Vol 125 (5) ◽

pp. 1411-1423 ◽

Cited By ~ 1

Author(s):

D. Merrill Dane ◽

Khoa Cao ◽

Hua Lu ◽

Cuneyt Yilmaz ◽

Jamie Dolan ◽

...

Keyword(s):

Blood Flow ◽

High Altitude ◽

Lung Volume ◽

Pulmonary Blood Flow ◽

Peromyscus Maniculatus ◽

Deer Mice ◽

Alveolar Type ◽

Type I ◽

Lower Altitude ◽

Lung Expansion

A colony of deer mice subspecies ( Peromyscus maniculatus sonoriensis) native to high altitude (HA) has been maintained at sea level for 18–20 generations and remains genetically unchanged. To determine if these animals retain responsiveness to hypoxia, one group (9–11 wk old) was acclimated to HA (3,800 m) for 8 wk. Age-matched control animals were acclimated to a lower altitude (LA; 252 m). Maximal O2 uptake (V̇o2max) was measured at the respective altitudes. On a separate day, lung volume, diffusing capacity for carbon monoxide (DLCO), and pulmonary blood flow were measured under anesthesia using a rebreathing technique at two inspired O2 tensions. The HA-acclimated deer mice maintained a normal V̇o2max relative to LA baseline. Compared with LA control mice, antemortem lung volume was larger in HA mice in a manner dependent on alveolar O2 tension. Systemic hematocrit, pulmonary blood flow, and standardized DLCO did not differ significantly between groups. HA mice showed a higher postmortem alveolar-capillary hematocrit, larger alveolar ducts, and smaller distal conducting structures. In HA mice, absolute volumes of alveolar type I epithelia and endothelia were higher whereas that of interstitia was lower than in LA mice. These structural changes occurred without a net increase in whole-lung septal tissue-capillary volumes or surface areas. Thus, deer mice bred and raised to adulthood at LA retain phenotypic plasticity and adapt to HA without a decrement in V̇o2max via structural (enlarged airspaces, alveolar septal remodeling) and nonstructural (lung expansion under hypoxia) mechanisms and without an increase in systemic hematocrit or compensatory lung growth. NEW & NOTEWORTHY Deer mice ( Peromyscus maniculatus) are robust and very active mammals that are found across the North American continent. They are also highly adaptable to extreme environments. When introduced to high altitude they retain remarkable adaptive ability to the low-oxygen environment via lung expansion and remodeling of existing lung structure, thereby maintaining normal aerobic capacity without generating more red blood cells or additional lung tissue.

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Control of Breathing and Adaptation to High‐altitude Hypoxia in Deer Mice ( Peromyscus maniculatus )

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.686.4 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Catherine Ivy ◽

Graham Scott

Keyword(s):

High Altitude ◽

Peromyscus Maniculatus ◽

Control Of Breathing ◽

Deer Mice ◽

Altitude Hypoxia ◽

High Altitude Hypoxia

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Adaptive Shifts in Gene Regulation Underlie a Developmental Delay in Thermogenesis in High-Altitude Deer Mice

Molecular Biology and Evolution ◽

10.1093/molbev/msaa086 ◽

2020 ◽

Vol 37 (8) ◽

pp. 2309-2321 ◽

Cited By ~ 3

Author(s):

Jonathan P Velotta ◽

Cayleih E Robertson ◽

Rena M Schweizer ◽

Grant B McClelland ◽

Zachary A Cheviron

Keyword(s):

High Altitude ◽

Developmental Delay ◽

System Development ◽

Nervous System Development ◽

Developmental Trajectory ◽

Aerobic Performance ◽

Deer Mice ◽

Adult Mice ◽

Brown Adipose ◽

Adaptive Shifts

Abstract Aerobic performance is tied to fitness as it influences an animal’s ability to find food, escape predators, or survive extreme conditions. At high altitude, where low O2 availability and persistent cold prevail, maximum metabolic heat production (thermogenesis) is an aerobic performance trait that is closely linked to survival. Understanding how thermogenesis evolves to enhance survival at high altitude will yield insight into the links between physiology, performance, and fitness. Recent work in deer mice (Peromyscus maniculatus) has shown that adult mice native to high altitude have higher thermogenic capacities under hypoxia compared with lowland conspecifics, but that developing high-altitude pups delay the onset of thermogenesis. This finding suggests that natural selection on thermogenic capacity varies across life stages. To determine the mechanistic cause of this ontogenetic delay, we analyzed the transcriptomes of thermoeffector organs—brown adipose tissue and skeletal muscle—in developing deer mice native to low and high altitude. We demonstrate that the developmental delay in thermogenesis is associated with adaptive shifts in the expression of genes involved in nervous system development, fuel/O2 supply, and oxidative metabolism pathways. Our results demonstrate that selection has modified the developmental trajectory of the thermoregulatory system at high altitude and has done so by acting on the regulatory systems that control the maturation of thermoeffector tissues. We suggest that the cold and hypoxic conditions of high altitude force a resource allocation tradeoff, whereby limited energy is allocated to developmental processes such as growth, versus active thermogenesis, during early development.

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