Partial resistance to thyroid hormone-induced tachycardia and cardiac hypertrophy in mice lacking thyroid hormone receptor β

Abstract

AbstractBackgroundThyroid hormones regulate cardiac functions mainly via direct actions in the heart and binding to the thyroid hormone receptor (TR) isoforms α1 and β. While the role of the most abundantly expressed isoform, TRα1, is widely studied and well characterized, the role of TRβ in regulating heart functions is still poorly understood, primarily due to the accompanying elevation of circulating thyroid hormone in mice lacking TRβ (TRβ-KO). However, their hyperthyroidism is ameliorated at thermoneutrality, which allows studying the role of TRβ without this confounding factor.MethodsHere we non-invasively monitored heart rate in TRβ-KO mice over several days using radiotelemetry at different housing temperatures (22°C and 30°C), and upon T3 administration in comparison to wildtype animals.ResultsTRβ-KO mice displayed normal average heart rate at both 22°C and 30°C with only minor changes in heart rate frequency distribution, which was confirmed by independent electrocardiogram recordings in freely-moving conscious mice. Parasympathetic nerve activity was, however, impaired in TRβ-KO mice at 22°C, and only partly rescued at 30°C. As expected, oral treatment with pharmacological doses of T3 at 30°C led to tachycardia in wildtypes, accompanied by broader heart rate frequency distribution and increased heart weight, while TRβ-KO mice showed blunted tachycardia, as well as resistance to changes in heart rate frequency distribution and heart weight. At the molecular level, these observations were paralleled by a blunted cardiac mRNA induction of several important genes, including the pacemaker channelsHcn2andHcn4, as well asKcna7.ConclusionsThe phenotyping of TRβ-KO mice conducted at thermoneutrality allows novel insights on the role of TRβ in cardiac functions in absence of the usual confounding hyperthyroidism. Even though TRβ is expressed at lower levels than TRα1 in the heart, our findings demonstrate an important role for this isoform in the cardiac response to thyroid hormones.