The metabolome of Mexican cavefish shows a convergent signature highlighting sugar, antioxidant, and Ageing-Related metabolites

Abstract

Insights from organisms, which have evolved natural strategies for promoting survivability under extreme environmental pressures, may help guide future research into novel approaches for enhancing human longevity. The cave-adapted Mexican tetra, Astyanax mexicanus, has attracted interest as a model system for metabolic resilience, a term we use to denote the property of maintaining health and longevity under conditions that would be highly deleterious in other organisms (Figure 1). Cave-dwelling populations of Mexican tetra exhibit elevated blood glucose, insulin resistance and hypertrophic visceral adipocytes compared to surface-dwelling counterparts. However, cavefish appear to avoid pathologies typically associated with these conditions, such as accumulation of advanced-glycation-end-products (AGEs) and chronic tissue inflammation. The metabolic strategies underlying the resilience properties of A. mexicanus cavefish, and how they relate to environmental challenges of the cave environment, are poorly understood. Here, we provide an untargeted metabolomics study of long- and short-term fasting in two A. mexicanus cave populations and one surface population. We find that, although the metabolome of cavefish bears many similarities with pathological conditions such as metabolic syndrome, cavefish also exhibit features not commonly associated with a pathological condition, and in some cases considered indicative of an overall robust metabolic condition. These include a reduction in cholesteryl esters and intermediates of protein glycation, and an increase in antioxidants and metabolites associated with hypoxia and longevity. This work suggests that certain metabolic features associated with human pathologies are either not intrinsically harmful, or can be counteracted by reciprocal adaptations. We provide a transparent pipeline for reproducing our analysis and a Shiny app for other researchers to explore and visualize our dataset.

3D spheroid culturing of Astyanax mexicanus liver‐derived cell lines recapitulates distinct transcriptomic and metabolic states of in vivo tissue environment

“…However, we did not detect any significant differences in levels of antioxidative capacity between SFL and CFL spheroids. This is in contrast to Medley et al (2022), which showed an increased antioxidant response in cavefish livers compared to surface fish livers. However, it is important to note that these experiments were performed in vivo in which the cavefish livers are exposed to large amounts of body and liver fat accumulation.…”

“…We noticed an enrichment for transporter activities such as “ inorganic cation transmembrane transporter activity ,” “ metal ion transmembrane transporter activity ,” and “ cation transmembrane transporter activity .” Also, we observed an enrichment of peptidase‐related terms such as “ peptidase activity ” and “ exopeptidase activity .” The analysis also highlighted several antioxidative pathways such as “ antioxidant activity ,” “ glutathione transferase activity ,” “ peroxidase activity ,” and “ oxidoreductase activity, acting on peroxide as acceptor .” Genes like prdx5 , gpx4a , gstr and gsta.1 which are known to be involved in antioxidative pathways (Sharma et al, 2004; Walbrecq et al, 2015; Yant et al, 2003) were upregulated in 3D spheroids (Figure 4a,b). As antioxidants regulating oxidative stress as well as peptidase activity represent essential aspects of liver metabolism (Cichoż‐Lach, 2014; Domínguez‐Vías et al, 2020; Medley et al, 2022; Mooli et al, 2022), these data suggest that culturing the liver‐derived cells in 3D increases their ability to perform liver metabolic functions. Since antioxidative capacity is particularly associated with responses to environmental stress, we aimed to investigate and compare the activity of this pathway in 3D spheroids and 2D culture.…”

“…Genes like prdx5, gpx4a, gstr and gsta.1 which are known to be involved in antioxidative pathways (Sharma et al, 2004;Walbrecq et al, 2015;Yant et al, 2003) were upregulated in 3D spheroids (Figure 4a,b). As antioxidants regulating oxidative stress as well as peptidase activity represent essential aspects of liver metabolism (Cichoż-Lach, 2014;Domínguez-Vías et al, 2020;Medley et al, 2022;Mooli et al, 2022), these data suggest that culturing the liver-derived cells in 3D increases their ability to perform liver metabolic functions. Since antioxidative capacity is particularly associated with responses to environmental stress, we aimed to investigate and compare the activity of this pathway in 3D spheroids and 2D culture.…”

Circadian rhythm disruption is associated with skeletal muscle dysfunction within the blind Mexican Cavefish

“…In fact, amino acid levels are under circadian control, with their rhythmicity coinciding with proteasomal gene expression (Eckel-Mahan et al 2013). Recent metabolomic analysis from our group underscores this relationship, finding reduced cavefish muscle free amino acid levels coupled with decreased muscle mass and contractility (Medley et al 2022; Olsen et al 2022). For example, the anabolic amino acid leucine is decreased ~2-fold within cavefish skeletal muscle, with its transporter ( slc7a8 ) lacking rhythmicity exclusively within cavefish (Fig.…”

Potential role of microRNAs in regulating transcriptional profile, and sculpting development and metabolism in cavefish

“…47, 48 Cavefish are adapted to be resilient to long periods of starvation and are also hyperglycemic, 3, 7, 49 thereby potentially necessitating enhanced antioxidant capacity in cavefish to protect against oxidative stress. 50…”