Dore, R.; Sentis, S. C.; Johann, K.; Lopez-Alcantara, N.; Resch, J.; Moeller, L. C.; Fuehrer, D.; Obermayer-Wasserscheid, B.; Opitz, R.; Mittag, J.

Background: Thyroid hormones regulate cardiac functions mainly via direct actions in the heart and binding to the thyroid hormone receptor (TR) isoforms alpha1 and beta. While the role of the most abundantly expressed isoform, TRalpha1, is widely studied and well characterized, the role of TRbeta in regulating heart functions is still poorly understood, primarily due to the accompanying elevation of circulating thyroid hormone in mice lacking TRbeta (TRbeta-KO). However, their hyperthyroidism is ameliorated at thermoneutrality, which allows studying the role of TRbeta without this confounding factor. Methods: Here we non-invasively monitored heart rate in TRbeta-KO mice over several days using radiotelemetry at different housing temperatures (22 degrees C and 30 degrees C), and upon T3 administration in comparison to wildtype animals. Results: TRbeta-KO mice displayed normal average heart rate at both 22 degrees C and 30 degrees 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 TRbeta-KO mice at 22 degrees C, and only partly rescued at 30 degrees C. As expected, oral treatment with pharmacological doses of T3 at 30 degrees C led to tachycardia in wildtypes, accompanied by broader heart rate frequency distribution and increased heart weight, while TRbeta-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 channels Hcn2 and Hcn4, as well as Kcna7. Conclusions: The phenotyping of TRbeta-KO mice conducted at thermoneutrality allows novel insights on the role of TRbeta in cardiac functions in absence of the usual confounding hyperthyroidism. Even though TRbeta is expressed at lower levels than TRalpha1 in the heart, our findings demonstrate an important role for this isoform in the cardiac response to thyroid hormones.