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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. Transcriptomic profiles of muscular dystrophy with myositis (mdm) in extensor digitorum longus, psoas, and soleus muscles from mice

   https://doi.org/10.1186/s12864-022-08873-2  

   Hettige, Pabodha ; Tahir, Uzma ; Nishikawa, Kiisa C. ; Gage, Matthew J. ( December 2022 , BMC Genomics)

   Abstract Background Titinopathies are inherited muscular diseases triggered by genetic mutations in the titin gene. Muscular dystrophy with myositis ( mdm ) is one such disease caused by a LINE repeat insertion, leading to exon skipping and an 83-amino acid residue deletion in the N2A-PEVK region of mouse titin. This region has been implicated in a number of titin—titin ligand interactions, hence are important for myocyte signaling and health. Mice with this mdm mutation develop a severe and progressive muscle degeneration. The range of phenotypic differences observed in mdm mice shows that the deletion of this region induces a cascade of transcriptional changes extending to numerous signaling pathways affected by the titin filament. Previous research has focused on correlating phenotypic differences with muscle function in mdm mice. These studies have provided understanding of the downstream physiological effects resulting from the mdm mutation but only provide insights on processes that can be physiologically observed and measured. We used differential gene expression (DGE) to compare the transcriptomes of extensor digitorum longus (EDL), psoas and soleus muscles from wild-type and mdm mice to develop a deeper understand of these tissue-specific responses. Results The overall expression pattern observed shows a well-differentiated transcriptional signature in mdm muscles compared to wild type. Muscle-specific clusters observed within the mdm transcriptome highlight the level of variability of each muscle to the deletion. Differential gene expression and weighted gene co-expression network analysis showed a strong directional response in oxidative respiration-associated mitochondrial genes, which aligns with the poor shivering and non-shivering thermogenesis previously observed. Sln, which is a marker associated with shivering and non-shivering thermogenesis, showed the strongest expression change in fast-fibered muscles. No drastic changes in MYH expression levels were reported, which indicated an absence of major fiber-type switching events. Overall expression shifts in MYH isoforms, MARPs, and extracellular matrix associated genes demonstrated the transcriptional complexity associated with mdm mutation. The expression alterations in mitochondrial respiration and metabolism related genes in the mdm muscle dominated over other transcriptomic changes, and likely account for the late stage cellular responses in the mdm muscles. Conclusions We were able to demonstrate that the complex nature of mdm mutation extends beyond a simple rearrangement in titin gene. EDL, psoas and soleus exemplify unique response modes observed in skeletal muscles with mdm mutation. Our data also raises the possibility that failure to maintain proper energy homeostasis in mdm muscles may contribute to the pathogenesis of the degenerative phenotype in mdm mice. Understanding the full disease-causing molecular cascade is difficult using bulk RNA sequencing techniques due to intricate nature of the disease. The development of the mdm phenotype is temporally and spatially regulated, hence future studies should focus on single fiber level investigations. 

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

   https://doi.org/10.1093/molbev/msaa086  

   Velotta, Jonathan P ; Robertson, Cayleih E ; Schweizer, Rena M ; McClelland, Grant B ; Cheviron, Zachary A ( April 2020 , Molecular Biology and Evolution)

   Ruvinsky, Ilya (Ed.)

   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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4. A comparative and ontogenetic examination of mitochondrial function in Antarctic notothenioid species

   https://doi.org/10.1007/s00360-022-01461-6  

   Mandic, Milica ; Frazier, Amanda J. ; Naslund, Andrew W. ; Todgham, Anne E. ( November 2022 , Journal of Comparative Physiology B)

   Notothenioidei fishes have evolved under stable cold temperatures; however, ocean conditions are changing globally, with polar regions poised to experience the greatest changes in environmental factors, such as warming. These stressors have the potential to dramatically affect energetic demands, and the persistence of the notothenioids will be dependent on metabolic capacity, or the ability to match energy supply with energy demand, to restore homeostasis in the face of changing climate conditions. In this study we examined aerobic metabolic capacity in three species,Trematomus bernacchii,T. pennelliiandT. newnesi, and between two life stages, juvenile and adult, by assessing mitochondrial function of permeabilized cardiac fibers. Respiratory capacity differed among the adult notothenioids in this study, with greater oxidative phosphorylation (OXPHOS) respiration in the pelagicT. newnesithan the benthicT. bernacchiiandT. pennellii. The variation in mitochondrial respiratory capacity was likely driven by differences in the mitochondrial content, as measured by citrate synthase activity, which was the highest inT. newnesi. In addition to high OXPHOS,T. newnesiexhibited lower LEAK respiration, resulting in greater mitochondrial efficiency than eitherT. bernacchiiorT. pennellii. Life stage largely had an effect on mitochondrial efficiency and excess complex IV capacity, but there were little differences in OXPHOS respiration and electron transfer capacity, pointing to a lack of significant differences in the metabolic capacity between juveniles and adults. Overall, these results demonstrate species-specific differences in cardiac metabolic capacity, which may influence the acclimation potential of notothenioid fishes to changing environmental conditions.

    

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5. 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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