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or both
1 and
Departments of 1 Physiology and Pharmacology and 2 Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden; and 3 Department of Human Genetics, Mount Sinai University, New York, New York 10029
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have used a
telemetry system to record heart rate, body temperature,
electrocardiogram (ECG), and locomotor activity in awake, freely moving
mice lacking thyroid hormone receptor (TR)-
or
TR-
1 and -
(TR-1/). The
TR-1/-deficient mice had a
reduced heart rate compared with wild-type controls. The
TR--deficient mice showed an elevated heart rate, which, however,
was unresponsive to thyroid hormone treatment regardless of hormonal
serum levels. ECG revealed that the TR--deficient mice had a
shortened Q-Tend time in contrast
to the TR-1/-deficient mice,
which exhibited prolonged P-Q and
Q-Tend times. Mental or
pharmacological stimulation of the sympathetic nervous system resulted
in a parallel increase in heart rate in all animals. A single injection
of a nonselective -adrenergic-receptor blocker resulted in a
parallel decrease in all mice. The
TR-1/-deficient mice also
had a 0.4°C lower body temperature than controls, whereas no
difference was observed in locomotor activity between the different
strains of mice. Our present and previous results support the
hypothesis that TR-1 has a
major role in determining heart rate under baseline conditions and body
temperature and that TR- mediates a hormone-induced increase in
heart rate.
knockout mice; heart rate; electrocardiogram
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THYROID DISORDERS resulting in hypo- or
hyperthyroidism cause a great variety of clinical symptoms, including
disturbances in cardiac function, thermoregulation, metabolism, and
mental capacity. Thyroid hormone levels are under normal conditions
strictly regulated by a feedback mechanism affecting the thyroid,
pituitary, and hypothalamic glands. It was not until 1986 that it was
found that the effects of the hormone were mediated through different subtypes of thyroid hormone receptors (TR) that belong to the superfamily of nuclear hormone receptors (18). Four different mammalian
TR, encoded by two different genes, have been characterized to date:
TR-1,
TR-2,
TR-1, and
TR-2 (8, 19, 22). All of them
except TR-2 bind
triiodothyronine (T3) and
thyroxine (T4) and repress or
activate target genes as a consequence of ligand binding. The function
of TR-2 is unclear, although it has been reported to be able to repress genes that are subject to
regulation by thyroid hormones in tissue culture (13, 14). The fact
that the TR- and TR- proteins are expressed at distinct levels in
different tissues has suggested that they have distinct functions (4,
5, 7); indeed, deletion of the TR- gene function from the mouse
genome results in congenital deafness and elevated levels of serum
T3,
T4, and thyroid-stimulating
hormone (4, 5).
We showed previously (12, 23) that
TR-1-deficient mice, which
still express the non-hormone binding protein
TR-2, are normal with respect
to gross anatomy and reproduction. Young male mice but not females or
older animals have low serum levels of T4 but normal
T3 levels, thus exhibiting a mild
hypothyroidism. In addition, the
TR-1-deficient mice have a 20%
lower heart rate and exhibit prolonged P-Q, QRS, and
Q-Tend times in the
electrocardiogram (ECG), indicating that at least two parameters of
cardiac function have been affected by the gene deletion. Finally, the
mice have a 0.5°C lower body temperature compared with wild-type controls.
In this study we have examined further the roles of TR in physiology by
using TR-- or
TR-1/-deficient mice. The
TR--deficient mice lack both
TR-1 and
TR-2, whereas the
TR-1/ mice encode no known
T3 receptor while still expressing
the TR-2 protein. Our results
provide further evidence for a major role of
TR-1 in the regulation of heart
rate and control of body temperature and offer novel platforms for
unraveling different types of thyroid hormone diseases.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Twenty-four male TR--deficient mice and twenty age-matched wild-type
control animals, all between 9 and 15 wk of age and weighing 22-37
g, were used. Both strains of mice are of a mixed 129/Sv and C57Bl/6J
genetic background and were generated from TR- 
/
heterozygote backcrosses. Experiments were also performed in eight male
TR-1/-deficient mice and
eight wild-type control animals weighing 23-32 g and aged
15-24 wk. These mice were generated by crossing
TR-1 / (129 Ola
Hsd × BALB/C) mice with the TR- / mice described
above. The resulting TR-1/
(/, /) and wild-type strains thus had a
genetic background from 129/Sv, 129 Ola Hsd, BALB/C, and C57Bl/6J.
Telemetry system. As described earlier (11) the telemetry system (Data Sciences, St. Paul, MN) consists of implantable transmitters (TA10ETA-F20), telemetry receivers (RA1010), a consolidation matrix (BCM100), and four universal adapters (UA 10 PC). The data acquisition system consists of a Data Translation (DT 2801) analog-digital converter in a Pentium computer. The computer program PC-LAB version 5.0 (1) sampled calibrated values of body temperature and ECG and noncalibrated locomotor activity counts repeatedly during the course of the experiments. The calculation of data was described earlier (11).
Operation procedure.
The surgical procedure was as described earlier (11). In brief, the
animals were anesthetized with intraperitoneal injection of 0.07 ml/10
g of a mixture of 0.315 mg/kg fentanyl and 10 mg/ml fluanisone
(Hypnorm), 5 mg/ml midazolam (Dormicum), and sterilized water in a
1-to-1-to-2 ratio. The transmitter was implanted in the peritoneal
cavity of each mouse at least 10 days before start of the experiments.
The electrodes were seated subcutaneously, the () lead was
positioned and sutured subcutaneously at the right shoulder, and the
(+) lead was sutured towards the lower left chest.
Experimental protocol.
Experiments were performed on either TR--deficient or
TR-1/-deficient mice and
respective wild-type controls. Baseline registration, starting at 1 PM,
for either 72 (TR--deficient mice) or 48 (TR-1/-deficient mice) h was
performed. Thereafter, the mice were given a single dose of a
cholinergic blocker (scopolamine methyl bromide, 0.1 mg/kg sc;
Sigma). After another 20 min a single dose of a
nonselective -adrenergic receptor blocker (timolol, 1 mg/kg sc;
Sigma) was injected.
-deficient mice and controls were
made hypothyroid by administration of an iodine-deficient diet
(Analyzen, Odal, Sweden) for 2 wk, followed by supplementation of the
drinking water with 0.04% methimazole (Sigma) and 1%
NaClO4 (Kebo) for an additional 3 wk. The animals were then injected daily with
T3 (0.1 mg/kg sc; Sigma) for 4 days to induce a hyperthyroidal state. In another group of mice with a
similar background, free T4 levels
(and T3) were measured
(Amerlex-MAB FT3 kit, Amersham) with the same protocol to ascertain
that the desired serum levels of hormone had been reached. It was shown
previously that thyroid hormone levels are increased in
TR--deficient mice compared with controls (5). After 5 wk of
treatment with the iodine-deficient diet and methimazole in the
drinking water for the last 2 wk, T4 levels were low in the
TR--deficient mice (0.3 ± 0.2 pmol/l, n = 11) and controls (0.03 ± 0.02 pmol/l, n = 9). After
T3 treatment, the
T3 levels were increased in both
TR--deficient mice (14 ± 2 pmol/l,
n = 6) and controls (15 ± 5 pmol/l, n = 6).
Air jet experiment. After 30 min of baseline registration a jet of air was blown through plastic tubing into the cage for 15 min, inducing acute mental stress, without physically harming the animals. We have previously described similar methods used in rats (15).
Statistics. All parameters were expressed as means ± SE. Student's t-test was used for the comparison of paired or individual means. For multiple treatments a two-way ANOVA followed by Tukey's multiple-comparison test was used. Statistical significance was defined by a P value <0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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To obtain baseline recordings for heart rate, body temperature, and
locomotor activity an appropriate telemetric system was used. Data
collection was done for 72 h with the TR--deficient and wild-type
control mice and for 48 h with the
TR-1/-deficient mice and
their respective controls. Figure 1 shows a
clear circadian rhythm of the measured parameters in all animal groups,
indicative of a complete recovery from the implantation of the
telemetry devices. The difference in the values observed for the two
groups of control mice is likely to be caused by their distinct genetic backgrounds.
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Heart rate.
Our results (Table 1 and Fig.
1A) from TR--deficient mice
show that they had an increased heart rate compared with wild-type controls. Because these animals have an intact
TR-1 gene and elevated thyroid
hormone levels, we attribute the slight tachycardia to a stimulatory
effect of the hormone on the basal heart rate mediated via the
remaining TR-1. To determine
whether the heart rate of these mice was as responsive to thyroid
hormone as that of the controls, the animals were made hypothyroid and
then injected with T3. The results
(Fig. 2) show that induction of hypothyroidism did not
affect heart rate significantly. Surprisingly, heart rate also failed
to increase in the TR--deficient mice (607 ± 14 beats/min; n = 5) as a response to
T3 compared with the control mice
(690 ± 27 beats/min; n = 6).
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-deficient mice, the
TR-1/-deficient mice
exhibited a mean heart rate 65 beats/min lower than that seen in the
wild-type controls, under baseline conditions (Table 1 and Fig. 1).
This finding is similar to that observed in the TR-1-deficient mice (12, 23).
Analysis of ECG.
The TR--deficient mice showed a shortened
Q-Tend time in the ECG but no
other alterations (Table 2).
Previous experiments performed in
TR-1-deficient mice showed
prolonged P-Q, QRS, and Q-Tend
times. The shortening observed in the mice in the present study is
presumably caused by the more pronounced stimulation of
TR-1, secondary to elevated
plasma levels of thyroid hormone. Analysis of the ECG from the
TR-1/-deficient mice
revealed that they have prolonged P-Q and
Q-Tend times compared with the
wild-type controls (Table 2 and Fig.
3B).
These results are similar to what was seen in the
TR-1-deficient animals (12,
23).
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Air jet.
To investigate the role of the sympathetic nervous system in mediating
the difference in heart rate between the receptor-deficient mice and
their controls, the animals were stressed by an air jet. The air stress
resulted in a parallel increase in heart rate in the TR-- and
TR-1/-deficient mice and
wild-type controls. The heart rate in the
TR-1/-deficient animals was
lower than that seen in controls before, during, and after the stress
(Fig. 4B). No
difference was observed between the TR--deficient mice and their
controls (Fig. 4A). The comparably
low baseline values are presumably caused by the fact that the
experiments were performed in the daytime, when mice are normally less
active.
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Cholinergic- and -adrenergic-receptor blockade.
To determine whether the low heart rate is a tissue-autonomous effect,
a functional heart denervation was achieved by pharmacological blockage
of the sympathetic and parasympathetic nervous systems. After either 2 or 3 days of baseline registration a single dose of an anticholinergic
agent (scopolamine methyl bromide, 0.1 mg/kg; Sigma) was injected,
resulting in a parallel increase in heart rate in the TR-- and
TR-1/-deficient mice and
wild-type controls (Fig. 5). A single dose of a
nonselective -adrenergic-receptor blocker (timolol, 1 mg/kg; Sigma)
was then administered, which yielded a parallel decrease in heart rate
in all animals (Fig. 5). We conclude that both animal types have intact
responses to stimulation of the autonomic nervous system. The data also
corroborates our previous suggestion that the low heart rate of the
TR-1-deficient mice is a
tissue-autonomous defect.
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Body temperature and locomotor activity.
TR-1-deficient mice have a
reduced body temperature. Therefore, we wanted to determine the
contribution of the individual TR to the control of body temperature.
Postoperative recordings ~3 h after surgery showed that the
TR-1/-deficient mice had a
lower body temperature (32°C) than the wild-type animals
(35.5°C). In addition, postoperative recovery of body weight was
delayed (data not shown). Carefully controlled recordings of body
temperature for at least 48 h showed that their 24-h mean temperature
was 0.4°C lower than that of wild-type controls (Table 1). In
contrast, the body temperature of the TR--deficient mice was not
significantly different compared with that of the wild-type control
strain. There was no difference in gross locomotor activity between the receptor-deficient mice and their respective controls (Table 1).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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That thyroid hormone affects heart rate and other parameters of cardiac
activity is well known (3). To address the question of how the hormone
exerts its cardiac effects we previously studied mice deficient for
TR-1 (12, 23); these mice have
bradycardia and prolonged P-Q, QRS, and
Q-Tend durations in the ECG, which is also seen in hypothyroidism in some cases (9). That the bradycardia
is a tissue-autonomous effect caused by the deletion of the
TR-1 gene became clear from
subsequent experiments, which showed that air stress and
pharmacological blockage of the sympathetic and parasympathetic nervous
systems still resulted in a lower heart rate compared with controls
(12).
In this paper, we have further analyzed the roles of TR in cardiac
function. We first analyzed mice that lack all known
T3 binding receptors but that
still express the TR-2 protein.
Our results show that these mice had specific cardiac abnormalities, bradycardia and prolonged P-Q and
Q-Tend times in the ECG. The changes are similar to those seen in rodents made hypothyroid with
drugs (9) and in mice lacking
TR-1 (12, 23). Several reports
have indicated that thyroid hormone may act also via nonnuclear pathways, and administration of T3
in in vitro systems has been reported (20) to affect action potential
duration within a few minutes, a time too short to allow TR to activate
nuclear target genes. Our data with the
TR-1/-deficient mice do not
support the suggestion that T3
acts via other signaling pathways, because the
TR-1/-deficient mice have
T3 and
T4 levels at least 40-fold higher
than those of normal mice (B. Vennström, unpublished
observation). Despite this, they show no signs of
overactivity (Table 1).
TR--deficient mice also have elevated thyroid hormone levels, three-
to fourfold higher than normal (5). Our data show that these mice have
an elevated heart rate and a shortened
Q-Tend time in the ECG. We
interpret this as an effect of the increased serum levels of
T3 acting on
TR-1 in the heart.
Surprisingly, the heart rate of these mice failed to respond to
T3 administration. We showed
previously (12, 23) that the mean heart rate of TR-1-deficient mice is reduced
by 20% but that it responds to T3
stimulation. Taken together, our data presented here and in previous
communications (12, 23) suggest that the basal heart rate is mainly
determined by TR-1, because the
mean heart rate is reduced by 20% in
TR-1-deficient mice and is
increased by 7% in the hyperthyroid TR--deficient mice. TR-, on
the other hand, appears to have a major function in mediating a
T3-induced increase in heart rate.
The TR-1-deficient mice respond
to T3, whereas the
TR--deficient mice fail to do so. The exact physiological mechanisms
for this are still unclear.
We also show here that the Q-Tend
time, indicative of the repolarization phase in the ECG, is prolonged
in the TR-1/-deficient mice,
whereas the TR--deficient animals have a shortened duration. These
results are in concordance with our previous results with TR-1-deficient mice, which
exhibited an ECG similar to that of the
TR-1/-deficient animals. We
therefore conclude that the repolarization process can be modulated by
TR-1.
How does TR-1 affect heart
function? The most likely mechanisms include a change in ion transport,
i.e., up- or downregulation of
Na+-,
Ca2+-, and/or
K+-channel genes or other genes,
which in turn control the activity of these ion transporters.
TR-1 deficiency leads to
alterations in at least two parameters of cardiac function, heart rate
and ventricular repolarization. The heart rate, or the pacemaker
function, has been described to be mediated by currents such as
the hyperpolarization-activated "pacemaker" current,
L-type voltage-activated calcium-channel currents (10), or
possibly also T-type voltage-activated calcium-channel currents. The
repolarization phase of the cardiac action potential is known to be
caused by different types of K+
channels. Our results, however, do not yet allow an identification of
the precise targets of TR-1
action in the heart. The notion that ion channels and/or pumps are
affected is supported by the observation that the TR--deficient
mice, in contrast to the TR-1 / mice, have severely deficient hearing (5), although no histological aberrancies are detectable in the inner ear or in its
innervation. Recently, Rüsch et al. (18a) showed that these mice
have a defect in the ion current mediating repolarization. We have
therefore investigated the expression of these genes. We have
investigated the expression of the genes for Na-K-ATPase, the
Ca2+/Na+
exchanger, and the Kv1.5 voltage-gated channel that all have been
reported to be direct targets for TR in the heart (2, 16, 17). No
alterations compared with wild-type control animals were seen with the
TR-1 or TR- /
mice, irrespective of whether the mice had been made hypo- or
hyperthyroid (B. Vennström, unpublished observation).
Further electrophysiological studies on the hearts are therefore in progress.
The TR-1/-deficient mice
also have a lower body temperature. Our present data do not allow a
detailed molecular explanation for this effect. Because mice deficient
for only TR-1 have a similar
reduction in body temperature whereas the TR--deficient animals have
a normal body temperature regardless of serum thyroid hormone levels,
we conclude that maintenance of a normal body temperature is dependent
on TR-1. Both the
TR-1- and the
TR-1/-deficient mice exhibit
normal locomotor activities (Table 1, Refs. 13, 25), and the latter
mice are known to possess adipose tissue (white and brown) and skeletal
muscle in normal proportions (B. Vennström, unpublished
observation). It is therefore likely that the reduced body temperature
is caused by physiological defects (as opposed to differences in
labor-induced heat or fat distribution). Thermogenesis is to a large
extent mediated by uncoupling proteins present in brown adipose tissue
and skeletal muscle (21). In-depth studies are underway to clarify
whether the expression or function of these is altered in TR-deficient mice.
It is interesting to note that rats made hypothyroid during fetal and postnatal development have grossly reduced body temperature (9), a reduction much more pronounced than that seen in the receptor-deficient mice. The reason for this discrepancy could be differences between the two species. However, an alternative mechanism is possible. An unoccupied TR (as in the case of the hypothyroid rats) can strongly repress the basal level expression of target genes, whereas an absence of receptor would allow the genes to be expressed at a basal level but not regulated by thyroid hormone (as in the case of the TR-deficient mice). The physiological consequences would therefore differ: the hypothyroid animals would be likely to exhibit more severe symptoms of the hormonal disorder compared with receptor-deficient mice. Further studies are required to discriminate between these alternatives.
Perspectives.
Thyroid hormone is involved in control of many physiological and
developmental processes and has a wide range of cardiovascular effects.
Thyroid hormone binds to three distinct intranuclear receptors
(TR-1,
TR-1, and
TR-2). The present study
contributes to our knowledge about the functional role of the different TR.
1 and
TR- have distinct effects in the heart.
TR-1 appears to be involved in
determining basal heart rate and ventricular repolarization. That a
lack of TR- but not TR-1
results in a blunted hormone-induced increase in heart rate indicates
that T3 can act via TR- to
increase heart rate. Moreover, the body temperature is apparently set
by TR1, whereas TR1, again, can mediate a
hormone-induced increase. Taken together, the results indicate that
novel receptor-specific agonists or antagonists, if developed, also
would have the potential to yield tissue-specific effects.
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ACKNOWLEDGEMENTS |
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Dr. Kristina Nordström, Dept. of Cellular and Molecular Biology, Karolinska Institute, is gratefully acknowledged for help with animal breeding.
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FOOTNOTES |
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This study was supported by grants from the Swedish Medical Research Council (no. 4764), Human Frontier Science program (RG0 318/1997), Swedish Heart and Lung Foundation (no. 71354), Cancerfonden, Medicinska forskningsrådet, and funds at the Karolinska Institute.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: Catarina Johansson, Dept. of Physiology and Pharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden (E-mail: Catarina.Johansson{at}fyfa.ki.se).
Received 24 September 1998; accepted in final form 29 January 1999.
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
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;
n = 10) and wild-type control (
;
n = 10) mice
(A) and
TR-
;
n = 8)
(B). Each symbol represents a mean
value (±SE) calculated from 6 h of recording. Active/dark period is
between 7 PM and 7 AM (black bars on
x-axis). A clear time correlation
among the 3 parameters studied can be seen.
significant
difference in 24-h mean values between conditions within same group
(P < 0.05).
