Zebrafish ankrd1a as a common player in heart regeneration and skeletal muscle repair – a new prospect for unlocking regenerative potential of human heart – ZEBARR

ZEBARR refers to the limiting capacity of human heart to regenerate after injury

Heart diseases are still the leading cause of death worldwide and a major global health burden, with numbers reaching epidemic proportions. Our attention is focused on myocardial infarction, a condition which results in massive loss of cardiomyocytes. Subsequent pathological remodeling of the cardiac muscle leads to heart failure. Physical exercise is beneficial for recovery of injured heart and it is included in rehabilitation after myocardial infarction.

The problem is that the human heart has very limited regenerative capacity and is unable to fully replenish lost cardomyocytes. Promising strategy to overcome this problem is to stimulate heart regeneration. We propose the ZEBARR concept as a novel experimental approach to identify dormant regenerative mechanisms in the human heart, which we can target for reactivation. To do this we will employ zebrafish as a model.

Analogous regenerative machinery present in zebrafish also exists in the human heart, but is not activated to the extent sufficient for successful regeneration.  Accordingly, we will use zebrafish as a platform to reveal potential methods to stimulate human heart regeneration. 

ZEBARR hypothesis

Zebrafish efficiently regenerates injured heart, in contrast to humans. On the other hand, both zebrafish and humans are able to repair skeletal muscle injury. This implies that the key for unlocking the endogenous regenerative potential of the human heart may be hidden in skeletal muscle. Another element of the ZEBARR concept is muscle remodeling induced by exercise, which facilitates heart healing. Therefore, the ZEBARR concept integrates three beneficial processes: regeneration of the heart, repair of skeletal muscle and exercise induced muscle remodeling. Genes active in all these processes fulfill the requirements of the ZEBARR concept and hold the promise of unlocking mechanisms for regeneration of the human heart.

– the first ZEBARR candidate

The main goal of our project is to test the ZEBARR concept. The first candidate is ankrd1a, homologue to the human gene ANKRD1, implicated in heart development and muscle stress response. According to our preliminary results, this gene is upregulated upon injury and in response to exercise in both zebrafish heart and skeletal muscle. Moreover, ankrd1a is upregulated only in cardiomyocytes within the injury border zone, where they extensively proliferate to replace lost muscle cells.

Using mutant and reporter lines that we generated, we will determine the expression profile of ankrd1a after heart and skeletal muscle injury, dissect its function in regeneration of heart and repair of skeletal muscle and identify downstream targets and pathways regulated by this gene. We also expect to discover new candidates to test by the ZEBARR concept. Finally, we will investigate the mediator role of ankrd1a in the beneficial effect of exercise on muscle healing. Methodologically, our project relies on genetic engineering, advanced microscopy techniques and next-generation sequencing.