Does Metabolism Regulate Cardiac Repair in the Regeneration Competent Axolotl Salamander?

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Adult human hearts form permanent scar tissue after a myocardial infarction, leaving millions of survivors in western societies with ongoing heart complications and increased risk of heart failure. Unlike, humans and other mammals, axolotl salamanders have an extraordinary ability to repair similar cardiac injuries. After forming an initial collagenous scar in response to a cryo-infarction, axolotls completely repair their heart, with existing cardiomyocytes dedifferentiating and proliferating, with the transient scar tissue eventually completely replaced by new functioning myocardium. The mechanisms leading to this immense discrepancy in capacity for repair within vertebrates is not fully understood, although the proliferative capacity of cardiomyocytes are a perquisite for regeneration. In recent years, research across species has demonstrated that metabolism may be instrumental in regulating cardiomyocyte proliferation and regeneration. In both adult and neonatal mice as well as zebrafish, studies have shown that a pro-glycolytic metabolic profile is favorable to regeneration, although the mechanisms involved are unclear. We hypothesize that metabolic adaptations are an instrumental part of the regenerative response in the axolotl and that thereby altering metabolism can both promote and inhibit cardiac regeneration in this animal model. In this currently ongoing study, we are employing a range of methods to uncover the interplay between metabolism and regeneration in the axolotl, combining whole-animal and high resolution cardiac respirometry as well as autoradiography to assess glucose and acetate consumption, metabolite analysis, immunochemistry and enzyme histochemistry. We are currently exploring if specific metabolic adaptations occur after injury both in the animal as a whole and locally in the different regions of the heart, which could help facilitate cardiac regeneration. In addition, we are looking at how altering axolotl metabolism can support or inhibit regeneration. For this purpose, axolotls are given the same type of cryoinjury and housed at different rearing temperatures (10 ◦C, 20 ◦C or 30 ◦C), or kept in isosmotic water, or fasted for the duration of regeneration which takes 60 - 90 days. By augmenting metabolism in this way in a regenerative animal model, we hope to uncover key insights about how metabolism affects cardiac regenerative ability.

Original languageEnglish
JournalThe FASEB Journal
Publication statusPublished - May 2022

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