Adaptations of the Autonomous Nervous System Controlling Heart Rate Are Impaired by a Mutant Thyroid Hormone Receptor-α1

Thyroid hormone has profound direct effects on cardiac function, but the hormonal interactions with the autonomic control of heart rate are unclear. Because thyroid hormone receptor (TR)-alpha 1 has been implicated in the autonomic control of brown adipose energy metabolism, it might also play an important role in the central autonomic control of heart rate. Thus, we aimed to analyze the role of TR alpha 1 signaling in the autonomic control of heart rate using an implantable radio telemetry system. We identified that mice expressing the mutant TR alpha 1R384C (TR alpha 1+m mice) displayed a mild bradycardia, which becomes more pronounced during night activity or on stress and is accompanied by a reduced expression of nucleotide-gated potassium channel 2 mRNA in the heart. Pharmacological blockage with scopolamine and the beta-adrenergic receptor antagonist timolol revealed that the autonomic control of cardiac activity was similar to that in wild-type mice at room temperature. However, at thermoneutrality, in which the regulation of heart rate switches from sympathetic to parasympathetic in wild-type mice, TR alpha 1+m mice maintained sympathetic stimulation and failed to activate parasympathetic signaling. Our findings demonstrate a novel role for TR alpha 1 in the adaptation of cardiac activity by the autonomic nervous system and suggest that human patients with a similar mutation in TR alpha 1 might exhibit a deficit in cardiac adaptation to stress or physical activity and an increased sensitivity to beta-blockers. (Endocrinology 151: 2388-2395, 2010)