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Summary Although Astyanax mexicanus surface fish regenerate their hearts after injury, their Pachón cave-dwelling counterparts cannot and, instead, form a permanent fibrotic scar, similar to the human heart. Myocardial proliferation peaks at similar levels in both surface fish and Pachón 1 week after injury. However, in Pachón, this peak coincides with a strong scarring and immune response, and ultimately, cavefish cardiomyocytes fail to replace the scar. We identified lrrc10 to be upregulated in surface fish compared with Pachón after injury. Similar to cavefish, knockout of lrrc10 in zebrafish impairs heart regeneration without affecting wound cardiomyocyte proliferation. Furthermore, using quantitative trait locus (QTL) analysis, we have linked the degree of heart regeneration to three loci in the genome, identifying candidate genes fundamental to the difference between scarring and regeneration. Our study provides evidence that successful heart regeneration entails a delicate interplay between cardiomyocyte proliferation and scarring., Graphical Abstract, Highlights • Astyanax mexicanus surface fish regenerate their hearts, but Pachón cavefish cannot • Successful regeneration is a delicate interplay between proliferation and scarring • lrrc10 is required for heart regeneration • Using QTL analysis, we have identified three genomic loci linked to heart regeneration, Stockdale et al. identify the Mexican cavefish as a model for heart regeneration research. This model provides an opportunity for direct comparison of natural regeneration versus scarring within a single species. Furthermore, they have identified key genomic regions regulating heart regeneration using an unbiased quantitative trait loci analysis approach.

Lay Summary: Different species of vertebrates have conditions similar to human obesity, insulin resistance and type 2 diabetes. Increasing number of studies are now revealing that the causes and interrelationships between these states are substantially different in different species. Comparative physiology may turn out to be an eye opener for evolutionary theories of diabetes. Obesity induced insulin resistance is believed to be central to type 2 diabetes. Recent work on Mexican cavefish, Astyanax mexicanus, has revealed a hyperglycemic phenotype similar to human type 2 diabetes but here insulin resistance is the cause of obesity rather than an effect. Instead of developing diabetic complications, the hyperglycemic fish lead a healthy and long life. In addition to fish, insulin resistance in hibernating bears, dolphins, horses, bonnet macaques and chimpanzees demonstrate that the relationship between diet, obesity, insulin sensitivity and diabetes is widely different in different species. Evolutionary hypotheses about type 2 diabetes should explain these differences.