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

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

doi:10.1101/2023.11.21.567193

bioRxiv · 10.1101/2023.11.21.567193

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

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

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Abstract

BackgroundThyroid hormones regulate cardiac functions mainly via direct actions in the heart and binding to the thyroid hormone receptor (TR) isoforms 1 and {beta}. While the role of the most abundantly expressed isoform, TR1, is widely studied and well characterized, the role of TR{beta} in regulating heart functions is still poorly understood, primarily due to the accompanying elevation of circulating thyroid hormone in mice lacking TR{beta} (TR{beta}-KO). However, their hyperthyroidism is ameliorated at thermoneutrality, which allows studying the role of TR{beta} without this confounding factor. MethodsHere we non-invasively monitored heart rate in TR{beta}-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. ResultsTR{beta}-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 TR{beta}-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 TR{beta}-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. ConclusionsThe phenotyping of TR{beta}-KO mice conducted at thermoneutrality allows novel insights on the role of TR{beta} in cardiac functions in absence of the usual confounding hyperthyroidism. Even though TR{beta} is expressed at lower levels than TR1 in the heart, our findings demonstrate an important role for this isoform in the cardiac response to thyroid hormones.

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Dore, R., Sentis, S. C., Johann, K., Lopez-Alcantara, N., Resch, J., Moeller, L. C., Fuehrer, D., Obermayer-Wasserscheid, B., Opitz, R., Mittag, J.. 2023-11-21. Partial resistance to thyroid hormone-induced tachycardia and cardiac hypertrophy in mice lacking thyroid hormone receptor beta. https://doi.org/10.1101/2023.11.21.567193

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