Thyroid hormone receptor α1 at the crossroad of autonomic and cardiac functions in mice

Thyroid hormone and its receptor TR alpha1 are well known to control heart rate in humans and mice. According to textbook knowledge, these actions are primarily mediated by the transcriptional regulation of the cardiac pacemaker channels Hcn2 and Hcn4. Our recent studies in mice and individuals with a mutation in TR alpha1, however, challenge these assumptions, as the induction of these two genes by thyroid hormone is intact, but it is insufficient to overcome the bradycardia. Consequently, the regulation of additional genes is required to mediate the thyroid hormone induced tachycardia. Furthermore, it remains to date unclear, in how far indirect actions of the hormone e.g. in the brain may contribute to adjusting the heart rate. In the proposed project we now aim to decipher the molecular mechanisms that underlie the regulation of heart rate by thyroid hormone, combining pharmacological experiments in isolated atria, in vivo radio telemetry and electrocardiogram recordings and targeted AAV mediated changes in gene expression in different animal models. In addition, we will use a recently discovered population of hypothalamic parvalbumin neurons that depend on thyroid hormone to control heart rate as starting point to understand the role of the brain in the adjustment of heart rate to environmental changes and altered thyroid status by employing in vivo fibre photometry or AAV mediated neuronal ablations in combination with radio telemetry recordings. Taken together, our project will improve our understanding of the interplay between the cardiac and central actions of thyroid hormone in regulating heart rate. The findings will be of relevance for patients with rare genetic disorders causing thyroid hormone resistance, as well as for the risk assessment of patients with (sub)clinical hyper- or hypothyroidism. Moreover, they could provide new treatment strategies for arrhythmias, a leading cause of sudden death.