Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation

Thyroid hormone (TH) serves as a master regulator in our body, governing body metabolism and growth. Circulating TH level has been demonstrated to correlate with cardiac regenerative potential by modulating cell-cycle arrest and polyploidization in cardiomyocytes (CMs), while the molecular mechanism is still unknown. Here, we investigated the molecular mechanisms of TH signalling on heart regeneration through a time-course sequencing experiment. We disrupted the TH signalling in a zebrafish model by thyroid hormone receptor alpha a (thraa) knockout (KO). The thraa-KO zebrafish demonstrated an accelerated heart regenerative process, indicating that TH through thyroid hormone receptors (TRs) impaired heart regeneration. Our study discovered that diminished TH signalling in thraa-KO zebrafish alters the pro-inflammatory response and the regenerative process of cardiac tissue through myocardial metabolic switch. Moreover, TH signalling was shown to modulate the restoration of hypoxic response via hif3a. Altogether, our study highlighted that the role of TH signalling in modulating the progress of heart regeneration in zebrafish. We designed a time-course RNA-seq experiments to study the heart regeneration process in zebrafish. We utilized apex amputation as an approach to study heart regeneration. Apex or injured zone tissue of both WT and thraa+/- were collected in uninjured state, 8 hpi, 1 dpi , 3 dpi , 7 dpi, and 15 dpi for RNA-seq. Additionally, we sequenced the entire hearts of both WT and thraa-/- to investigate transcriptomic differences in heart development.