Physiological changes in mice deficient in different subtypes of thyroid hormone receptors : a focus on studies of heart and muscle

Sammanfattning: The aim of these studies was to determing the specific roles of the different subtypes of thyroid hormone receptors (TR), with focus on heart and muscle function, by using mice deficient in TR[alpha]1, TR[beta] (both TR[beta]1 and TR[beta]2 subtypes) and TR[alpha]1/[beta]. For this purpose, new techniques were set up to study various physiological parameters in these mice. These new techniques will presumably be of great importance in studies of cardiovascular variables in genetically manipulated mice. A telemetry system was set up which enabled measurements of heart rate (HR), ECG, body temperature and locomotor activity in awake, freely moving mice. In order to investigate the role of the autonomic nervous system, the animals were stressed or treated with an anticholinergic drug, or a [beta]-adrenergic receptor blocker. Binding studies were done to measure the [beta]-adrenergic receptor density. In vitro studies of constriction in soleus muscles were also performed. The results showed that the TR[alpha]1 deficient mice have a slower basal HR than wild types. Further investigation showed that these mice have a normal autonomic response and a normal [beta]-adrenergic receptor density. The PQ-, CARS- and QTend-times in ECG and the duration of the monophasic action potential were prolonged. This indicates that TR([alpha]1 deficient mice have specific defect in intrinsic (i.e. the rate that prevails after autonomic blockade) HR regulation, and that the conductance of the electrical activity in the heart is slowed compared to controls. All these parameters were responsive to T3 treatment, which indicates that TR[beta] activation or some unknown mechanism also contributes. TR[beta] deficient mice were hyperthyroid and showed an increased HR, normal [beta]-adrenergic receptor density and a shortened QTend-time in ECG under baseline conditions. However, with experimentally induced hypothyroidism, the TR[beta] deficient mice have a blunted increase in HR after T3 administration. We interpret the increased HR under baseline conditions to be due to the presence of TR[alpha]1, but that TR[beta] can mediate a T3 induced increase in HR. The TR[alpha]1/[beta] deficient mice are viable and have extremely high thyroid hormone (TH) levels. Our results from the telemetric recordings showed that these mice have a slower basal HR than wild types. They also have a lower [beta]-adrenergic receptor density in the heart and a normal autonomic response. The PQ- and QTend-time in ECG were prolonged. Apart from the [beta]-adrenergic receptor density, these findings were similar to those from the TR[alpha]1 deficient mice, thus supporting the idea that TR[alpha]1 is the most important TR for mediating TH effects on heart. The TR[alpha]1 and the TR[alpha]1/[beta], but not the TR[beta] deficient mice have a lower body than controls. This indicates that TR[alpha]1 has a specific physiological role in regulating body temperature. Lack of TR[alpha]1 makes soleus muscles slower both concerning speed of contraction and relaxation, and also makes them more resistant to fatigue; almost the opposite occurred in TR[beta] deficient mice. Others have shown that myosin isoforms are shifted towards more of the slow type, and Western blot analyses showed a decreased amount of the fast-type sarcoplasmatic reticulum ATPase (SERCa1). The data suggest that TR[alpha]1 has specific physiological roles in regulating body temperature and basal HR, whereas either one of the TRs is needed for regulation of [beta]adrenergic receptor density in the heart. Furthermore, TR[alpha]1 is the main mediator of TH effects on skeletal muscle. These results increase the understanding of the mechanisms of TH action and may lead to more specific treatment of patients with thyroid diseases.