Biology subjects

Kenzior, A.

Publications and source records attributed to Kenzior, A..

7 recordsLinked to original sources

bioRxiv2024

Cave Adaptation Favors Aging Resilience in the Mexican Tetra

All animals age, but the rate at which some species age varies widely. What environmental pressures and what molecular factors underlie the remarkable diversity in aging and lifespan across species remains largely enigmatic. The Mexican tetra, Astyanax mexicanus, serves as an intriguing new model to study how adaptations to different environments can change aging. This species exists as two morphotypes: the river-dwelling surface fish, which inhabits environments rich in food and light, and the blind cave-adapted cavefish, that thrive in dark, nutrient-limited but predator free environments. Nutrient limitation and lack of predation are known to impact lifespan, however, how adaption to such environments changes the aging trajectory in this species remains unknown. Here, we compared aging markers between surface and cavefish populations, focusing on morphological and behavioral changes, as well as molecular signatures, and found that aging markers are pronounced and evident in surface fish, whereas these signatures are less distinct in aged cavefish. Using zebrafish, we explored the contribution of the cavefish insulin receptor mutation to longevity. Although the insulin receptor mutation is sufficient to increase lifespan in fish, our findings suggest its impact is limited. Instead, our data indicate that metabolic shifts, particularly those related to mitochondrial function, may be key contributors to the extended longevity observed in cavefish.

evolutionary biology↗

bioRxiv2024

A repeatedly evolved mutation in Cryptochrome-1 of subterranean animals alters behavioral and molecular circadian rhythms

The repeated evolution of similar phenotypes in independent lineages often occurs in response to similar environmental pressures, through similar or different molecular pathways. Recently, a repeatedly occurring mutation R263Q in a conserved domain of the protein Cryptochrome-1 (CRY1) was reported in multiple species inhabiting subterranean environments. Cryptochromes regulate circadian rhythms, and glucose and lipid metabolism. Subterranean species show changes to their circadian rhythm and metabolic pathways, making it likely that this mutation in CRY1 contributes to adaptive phenotypic changes. To identify the functional consequences of the CRY1 R263Q mutation, we generated a mouse model homozygous for this mutation. Indirect calorimetry experiments revealed delayed energy expenditure, locomotor activity and feeding patterns of mutant mice in the dark phase, but no further metabolic phenotypes - unlike a full loss of function of CRY1. Gene expression analyses showed altered expression of several canonical circadian genes in the livers of the mutant mice, fortifying the notion that CRY1 R263Q impacts metabolism. Our data provide the first characterization of a novel mutation that has repeatedly evolved in subterranean environments, supporting the idea that shared environmental constraints can drive the evolution of similar phenotypes through similar genetic changes.

evolutionary biology↗

bioRxiv2022

Metabolic reprogramming underlies cavefish muscular endurance despite loss of muscle mass and contractility

Physical inactivity - specifically the lack of moderate-to-vigorous activity - is a scourge to human health, promoting metabolic disease and muscle wasting. Interestingly, multiple ecological niches have relaxed investment into physical activity, providing unique evolutionary insight into adaptive physical inactivity. The Mexican cavefish Astyanax mexicanus lost moderate-to-vigorous activity following cave colonization, reaching basal swim speeds ~3-fold slower than their river-dwelling counterpart. We found that this was accompanied by a marked shift in body composition, decreasing muscle mass by 30% and increasing fat mass by 40%. This shift persisted at the single muscle fiber level via increased lipid and sugar accumulation at the expense of myofibrillar volume. Transcriptomic analysis of laboratory-reared and wild-caught cavefish indicated this shift in investment is driven by increased expression of ppar{gamma} - the master regulator of adipogenesis - with a simultaneous decrease in fast myosin heavy chain expression. Ex vivo and in vivo analysis confirmed these investment strategies come with a functional trade-off, decreasing cavefish muscle fiber shortening velocity, time to maximal force, and ultimately maximal swimming velocity. Despite this, cavefish displayed a striking degree of muscular endurance, reaching maximal swim speeds ~3.5-fold faster than their basal swim speeds. Multi-omics analysis indicated metabolic reprogramming, specifically increased phosphoglucomutase-1 abundance, phosphorylation, and activity, as contributing mechanisms enhancing cavefish glycogen utilization under metabolically strenuous conditions. Collectively, we reveal broad skeletal muscle reprogramming following cave colonization, displaying an adaptive skeletal muscle phenotype reminiscent to mammalian disuse and high-fat models while simultaneously maintaining a unique capacity for sustained muscle contraction under fatiguing conditions. SignificanceThe evolutionary consequence of decreased physical activity upon skeletal muscle physiology remains unexplored. Using the Mexican cavefish, we find loss of moderate-to-vigorous swimming following cave colonization has resulted in broad shifts in skeletal muscle investment - away from muscle mass and instead toward fat and sugar accumulation - ultimately decreasing muscle fiber twitch kinetics. Surprisingly though, cavefish possessed marked muscular endurance, reaching maximal swimming speeds rivaling their river-dwelling counterpart. Multi-omics analysis revealed carbohydrate metabolic reprogramming as a contributing component, most notably elevated abundance and phosphorylation of the glycogenolytic enzyme Phosphoglucomutase-1 - a likely adaptation to cave-specific hypoxia. These findings emphasize the impact multiple selective pressures have on skeletal muscle physiology, providing the first evolutionary insight into skeletal muscle adaptation following decreased activity.

evolutionary biology↗

bioRxiv2021

Enhanced lipogenesis through Pparγ helps cavefish adapt to food scarcity.

Nutrient availability varies seasonally and spatially in the wild. The resulting nutrient limitation or restricted access to nutrients pose a major challenge for every organism. While many animals, such as hibernating animals, evolved strategies to overcome periods of nutrient scarcity, the cellular mechanisms of these strategies are poorly understood. Cave environments represent an extreme example of nutrient deprived environments since the lack of sunlight and therefore primary energy production drastically diminishes the nutrient availability. Here, we used Astyanax mexicanus, which includes river-dwelling surface fish and cave adapted cavefish populations to study the genetic adaptation to nutrient limitations. We show that cavefish populations store large amounts of fat in different body regions when fed ad libitum in the lab. We found higher expression of lipogenesis genes in cavefish livers when fed the same amount of food as surface fish, suggesting an improved ability of cavefish to use lipogenesis to convert available energy into triglycerides for storage into adipose tissue. Moreover, the lipid metabolism regulator, Peroxisome proliferator-activated receptor {gamma} (Ppar{gamma}), is upregulated at both transcript and protein levels in cavefish livers. Chromatin Immunoprecipitation sequencing (ChIP seq) showed that Ppar{gamma} binds cavefish promoter regions of genes to a higher extent than surface fish. Finally, we identified two possible regulatory mechanisms of Ppar{gamma} in cavefish: higher amounts of ligands of the nuclear receptor, and nonsense mutations in per2, a known repressor of Ppar{gamma}. Taken together, our study reveals that upregulated Ppar{gamma} promotes higher levels of lipogenesis in the liver and contributes to higher body fat accumulation in cavefish populations, an important adaptation to nutrient limited environments.

evolutionary biology↗

bioRxiv2020

Genome-wide analysis of cis-regulatory changes in the metabolic adaptation of cavefish

Changes in cis-regulatory elements play important roles in adaptation and phenotypic evolution. However, their contribution to metabolic adaptation of organisms is less understood. Here we have utilized a unique vertebrate model, Astyanax mexicanus, different morphotypes of which survive in nutrient-rich surface and nutrient-deprived cave water to uncover gene regulatory networks in metabolic adaptation. We performed genome-wide epigenetic profiling in the liver tissue of one surface and two independently derived cave populations. We find that many cis-regulatory elements differ in their epigenetic status/chromatin accessibility between surface fish and cavefish, while the two independently derived cave populations have evolved remarkably similar regulatory signatures. These differentially accessible regions are associated with genes of key pathways related to lipid metabolism, circadian rhythm and immune system that are known to be altered in cavefish. Using in vitro and in vivo functional testing of the candidate cis-regulatory elements, we find that genetic changes within them cause quantitative expression differences. We characterized one cis-regulatory element in the hpdb gene and found a genomic deletion in cavefish that abolishes binding of the transcriptional repressor IRF2 in vitro and derepresses enhancer activity in reporter assays. Genetic experiments further validated a cis-mediated role of the enhancer and suggest a role of this deletion in the upregulation of hpdb in wild cavefish populations. Selection of this mutation in multiple independent cave populations supports its importance in the adaptation to the cave environment, providing novel molecular insights into the evolutionary trade-off between loss of pigmentation and adaptation to a food-deprived cave environment.

genomics↗

bioRxiv2020

A chromosome level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution.

Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. In nature, adaptation to severe environmental change, such as encountered following colonization of caves, has dramatically altered genomes of species over varied time spans. Genomic sequencing approaches have identified mutations associated with troglomorphic trait evolution, but the functional impacts of these mutations remain poorly understood. The Mexican Tetra, Astyanax mexicanus, is abundant in the surface waters of northeastern Mexico, and also inhabits at least 30 different caves in the region. Cave-dwelling A. mexicanus morphs are well adapted to subterranean life and many populations appear to have evolved troglomorphic traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Here we present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, we performed quantitative trait locus (QTL) mapping analyses for pigmentation and eye size and found new candidate genes for eye loss such as dusp26. We used CRISPR gene editing in A. mexicanus to confirm the essential role of a gene within an eye size QTL, rx3, in eye formation. We also generated the first genome-wide evaluation of deletion variability that includes an analysis of the impact on protein-coding genes across cavefish populations to gain insight into this potential source of cave adaptation. The new surface fish genome reference now provides a more complete resource for comparative, functional, developmental and genetic studies of drastic trait differences within a species.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗

bioRxiv2019

Stable transgenesis in Astyanax mexicanus using the Tol2 transposase system.

Astyanax mexicanus is a well-established and widely used fish model system for evolutionary and developmental biology research. These fish exist as surface forms that inhabit rivers and 30 different populations of cavefish. The establishment of A. mexicanus as an emergent model organism for understanding the evolutionary basis of development and behavior has been accelerated by an increasing availability of genomic approaches to identify genotype-phenotype associations. Despite important progress in the deployment of new technologies, deep mechanistic insights into A. mexicanus evolution and development have been limited by a lack of transgenic lines commonly used in genetic model systems. Here, we expand the toolkit of transgenesis by characterizing two novel stable transgenic lines that were generated using the highly efficient Tol2 system, commonly used to generate transgenic zebrafish. A stable transgenic line consisting of the zebrafish ubiquitin promoter fused to eGFP expressed eGFP ubiquitously throughout development in a surface population of Astyanax. To define specific cell-types, we injected fish with a Cntnap2-mCherry construct that labels lateral line mechanosensory neurons in zebrafish. Strikingly, both constructs appear to label the predicted cell types, suggesting many genetic tools and defined promoter regions in zebrafish are directly transferrable to cavefish. The lines provide proof-of-principle for the application of Tol2 transgenic technology in A. mexicanus. Expansion on these initial transgenic lines will provide a platform to address broadly important problems in the quest to bridge the genotype to phenotype gap.

developmental biology↗