Untargeted Metabolomics of the Cavefish Astyanax mexicanus Reveals the Basis of Metabolic Strategies in Adaptation to Extreme Conditions

The Mexican tetra, Astyanax mexicanus, has undergone remarkable physiological and behavioral changes in order to colonize a number of subterranean caves in the Sierra de El Abra region of Mexico. A hallmark of cave-adapted populations is enhanced survival under low-nutrient conditions coupled with hyperglycemia, increased body fat, and insulin resistance, but cavefish appear to avoid the progression of the respective pathologies associated with these conditions and do not exhibit reduced longevity. The metabolic strategies underlying these adaptations are not fully 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 cavefish share many similarities with metabolic syndrome normally associated with the human state of obesity, important differences emerge, including cholesterol esters, urate, intermediates of protein glycation, metabolites associated with hypoxia and longevity, and unexpectedly elevated levels of ascorbate (vitamin C). This work highlights the fact that certain metabolic features associated with human pathologies are not intrinsically harmful in all organisms, and suggests promising avenues for future investigation into the role of certain metabolites in evolutionary adaptation and health. We provide a transparent pipeline for reproducing our analysis and a Shiny app for other researchers to explore and visualize our dataset.