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Department of Cell and Molecular Biology (A.M., B.V.) and Department of Clinical Neuroscience (F.U., L.L.), Karolinska Institute, S-171 77 Stockholm, Sweden, Noll Physiological Research Center and Department of Cellular and Molecular Physiology (F.U., L.L.), Pennsylvania State University, University Park, Pennsylvania 16802; and Department of Human Genetics (D.F.), Mount Sinai School of Medicine, New York, New York 10029
Address all correspondence and requests for reprints to: Dr. Bjorn Vennstrom, Department of Cell and Molecular Biology, Karolinska Institute, Room D427, Doktorsringen 2D, Soina, Sweden S-171 77. E-mail: bjorn.vennstrom{at}cmb.ki.se
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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1 and TRß mediate the regulatory effects of T3
and have profound effects on the cardiovascular system. We have
analyzed the expression of the cardiac myosin heavy chain (MyHC) genes
and ß in mouse strains deficient for one or several TR genes to
identify specific regulatory functions of TR1 and TRß. The results
show that TR1 deficiency, which slows the heart rate, causes chronic
overexpression of MyHCß. However, MyHCß was still suppressible by
T3 in both TR1- and TRß-deficient mice, indicating
that either receptor can mediate repression of MyHCß.
T3-dependent induction of the positively regulated MyHC
gene was similar in both TR1- and TRß-deficient mice. The data
identify a specific role for TR1 in the negative regulation of
MyHCß, whereas TR1 and TRß appear interchangeable for
hormone-dependent induction of MyHC. This suggests that TR isoforms
exhibit distinct specificities in the genes that they regulate within a
given tissue type. Thus, dysregulation of MyHCß is likely to
contribute to the critical role of TR1 in cardiac function. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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1,
TR2, TRß1, and TRß2, of which all but TR2 bind
T3 in their C-terminal domains. Deletion studies
in mice have shown that loss of TR1 slows heart rate and prolongs
ventricular repolarization (6), whereas the loss of TRß
slightly elevates heart rate, probably through the higher levels of
T3 in these mice acting through TR1 (7, 8). Deletion of both TR1 and TRß results in a similar
phenotype as deletion of TR1 alone, thus indicating that TR1 has
the primary role in regulating heart rate (Refs.
9, 10, 11).
The cardiac muscle myosin heavy chain (MyHC) and ß genes
mediate contractility and are critical for normal heart function
(12, 13, 14). The MyHC genes are known to be regulated by
T3, suggesting that their regulation underlies
some of the major actions of T3 in heart. The
MyHC and ß proteins form homo- or heterodimers: MyHC
homodimers form the high- ATPase, V1 isoform; MyHCß homodimers
form the low-ATPase, V3 isoform; and MyHC/ß heterodimers form
the V2 isoform (for review see Ref. 15). Each of these
native myosin isoforms contains the same complement of myosin light
chain. The compositions of myosin reflect the mechanical performance of
the heart. In adult rat with fast contracting ventricles, MyHC (V1)
dominates (80–90%), whereas, during embryonic and fetal development,
MyHCß is the predominant isoform. The shift in expression of MyHC at
birth is coincident with a perinatal increase in circulating TH levels,
indicating that TH is an important mediator of this transition. Thyroid
response elements (TREs) have been located in both MyHC and MyHCß
genes, with MyHC being positively regulated and MyHCß negatively
regulated (4, 16, 17).
TRs interact with specific TREs in target genes and thereby activate or repress transcription (18, 19). On a positive TRE, TR can activate gene expression in the presence of T3 and repress basal gene transcription in the absence of T3, thus indicating that TRs can also regulate transcription in a ligand-independent way. However, expression of certain target genes is down-regulated by the ligand-bound receptor via a negative TRE (19, 20).
Here we investigated the specific roles of the individual TR isoforms
in regulation of the cardiac MyHC and ß genes, using TR1- and
TRß-deficient strains. Our results show that the MyHC genes are
regulated by TRs in an isoform- and target gene-specific manner and
identify molecular defects that underlie the cardiac phenotype in
TR1-deficient mice.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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positively and MyHCß negatively, we determined the ratio of MyHC
to MyHCß expression in different TR-deficient mouse strains. We
prepared polyA+ RNA from the hearts of 4- to 6-month-old mice
from three different TR-deficient strains and their corresponding
wild-type (wt) animals. TR1-/- mice produce all TR isoforms except
TR1, TRß-/- mice express none of the TRß isoforms, whereas
TR1-/-ß-/- animals express only TR2 (Refs. 6 11A, 21, 22).
The Northern blot analyses (Fig. 1
)
showed that the expression of MyHCß was elevated 10- to 20-fold in
TR1-/- and 50-fold in TR1-/-ß-/- mice, when comparing the
different TR-deficient strains with their corresponding wt mice. This
50-fold induction of MyHCß in TR1-/-ß-/- mice was observed
in repeated experiments (Fig. 1 and data not shown). A slight elevation
of MyHCß was also seen in TRß-/- mice. In contrast, no major
difference in MyHC expression was detectable in the different mouse
strains. The results suggest that the different TR isoforms have
distinct functions in regulation of the MyHCß gene and indicate that
TR1 has the primary role in regulation of basal expression of the
MyHCß gene. The exacerbated elevation of MyHCß in
TR1-/-ß-/- mice, however, reveals the same phenotype in the
absence of all known TRs and indicates a minor contributory role for
TRß isoforms.
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1-/-
and TRß-/- Mice1 and TRß to
regulate MyHC expression in vivo, the response of
hypothyroid TR1-/- and TRß-/- mice to increasing doses of
injected T3 was first determined. Animals (six
mice per group) were first made hypothyroid by dietary treatment
[iodine-deficient diet plus methimazole (LID + MMI)], after which the
mice were injected for 5 d with either a low dose of
T3 (0.05 µg T3/d; LID +
MMI + lT3) or a higher dose (0.2 µg
T3/d; LID + MMI + hT3). Table 1 shows the resultant serum levels of
free T3 (FT3) and
T4 (FT4). The higher dose
of injected T3, raised the level of
FT3 to 19–24 pM in the
TRß-/- and corresponding wt strains. It is suggested that these
mice yielded higher levels of FT3 as compared
with the TR1 strain due to their different genetic backgrounds,
which also results in distinct levels of 5'-deiodinase in peripheral
organs (23).
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, A and B, shows that although untreated
TR1-/- mice expressed 13-fold higher levels of MyHCß RNA than
the control animals, hypothyroidism resulted in similar, elevated
levels in both animal groups. Injection of the low dose of
T3 resulted in a 20-fold reduction in the wt
animals, whereas only a 6-fold reduction was seen in TR1-/- mice.
The high dose of T3 reduced the levels in both
animal groups to below that seen in untreated wt mice. This shows that
the TRß isoforms, at normal or low hormone levels, are insufficient
for normal suppression of the MyHCß gene, whereas higher hormone
levels enable TRß to suppress fully.
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).
However, the increase was only 16-fold in the TRß-deficient mice as
compared with 170-fold in wt controls. This reflects the higher TH
levels observed in TRß -/- animals achieved after the LID + MMI
treatment and indicates that the treatment was not sufficient to
achieve severe hypothyroidism in these mice. After
T3 injections the MyHCß gene was suppressed
equally in both TRß-/- and wt mice (Table 1
). We conclude from
these experiments that TR1 is needed to repress basal expression of
MyHCß in the euthyroid state, and that both TR1 and TRß isoforms
can repress the MyHCß gene after T3
injections.
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expression
levels, when comparing the TR1-/- and TRß-/- mice with their
respective wt controls (Figs. 2C and 3B). Upon TH deprivation, all
groups of mice significantly reduced the MyHC expression levels.
Subsequent T3 injections resulted in elevated
MyHC levels in all groups, as compared with their hypothyroid
expression levels. Next, we subjected mice devoid of all known
T3 binding TRs [TR1-/-ß-/- mice,
Göthe et al. (21)] to hypo- and
hyperthyroidism essentially as was done for the individual TR knockout
strains. This allowed us to test whether hormonal regulation of MyHC
is mediated by nuclear TRs or through nongenomic pathways. Figure 4 shows that MyHC expression
levels was unchanged in TR1-/-ß-/- mice during hypo- and
hyperthyroidism. In this experiment a 2.5-fold higher
T3 dose was used, which could explain the higher
induction of MyHC seen in wt mice. We conclude that regulation of
MyHC requires nuclear TRs, but it is isoform independent (Figs. 2C, 3B, and 4, and Mansén, A., unpublished data).
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1-/- mice and the 50-fold
increase in TR1-/-ß-/- mice caused a 16 ± 3% and
25 ± 4% increase (P < 0.001)
in the relative content of the MyHCß
protein isoform, respectively (Figs. 5, A and B, and
6). No MyHCß protein was detectable in
untreated wt or TRß-/- mice.
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and MyHCß protein isoforms were not
affected by changes in TH levels in the TR1-deficient mice,
i.e. the relative amount of the MyHCß protein was 16
± 3%, 19 ± 5%, and 27 ± 3% in the untreated, LID +
MMI-treated, and LID + MMI + T3-treated animals
(Fig. 5, A and B). The wt mice, in contrast, showed an increase in the
MyHCß protein isoform (35 ± 11%) expression as a response to
LID + MMI treatment and a decrease in the MyHCß content (17 ±
4%) after the T3 injections.
The 2- to 3-fold elevation of MyHCß RNA seen in the TRß-/- mice
did not result in detectable MyHC protein (Fig. 5). However, the
MyHCß protein content increased in both TRß-/- and wt mice in
response to the LID + MMI diet. The 16-fold increase in MyHCß mRNA
content in TRß-/- and the 170-fold increase in the wt mice were
paralleled by a significant change at the protein level,
i.e. the MyHCß protein content was 15 ± 4% in
TRß-/- and 28 ± 8% in wt animals after LID + MMI treatment
as compared with 0% in the untreated TRß-/- and wt mice (Fig. 5, A
and C). T3 injections did not induce any further
change in MyHC isoform expression in either TRß-/- or wt mice.
The MyHCß contents were similar in untreated (25 ± 4%)
and LID + MMI-treated (19%, n = 1) TR1-/-ß-/- mice, and
the MyHCß protein contents observed in the LID + MMI-treated (34
± 18%) wt mice did not differ from that in TR1/ß-deficient
mice (Fig. 6).
The relatively high MyHCß protein content, in spite of the low mRNA level in the animals after T3 injections, is most probably related to the slow turnover rate of cardiac myosin protein [5–6 d half-life (24)] as compared with myosin mRNA [within hours (25)].
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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1 and ß regulate distinct functions,
e.g. TR1 plays an important role in determining basal
heart rate, whereas TRß is required for proper auditory functions and
eye development, as well as for regulation of several liver enzymes
(6, 21, 23, 26, 27, 28, 29). Here, we have studied the specific
regulation by TR isoforms of the MyHC and ß genes because they
are differentially regulated by TH and are expressed in the same cells
of the heart. The results show that the negatively regulated MyHCß
gene can be regulated by both TR1 and TRß. However, the receptors
have distinct roles. MyHCß expression was elevated both at the mRNA
and protein levels in untreated TR1-/- and TR1-/-ß-/-,
but not in TRß-/- mice, suggesting that TR1 is required for
suppression of basal levels of MyHCß expression. This is further
supported by Gloss et al. (10), who recently
noted that TRß-/- mice that had been rendered euthyroid
experimentally expressed levels of MyHCß similar to those of wt
controls.
The TR1-/-ß-/- mice, lacking all known
T3-binding receptors, had a 50-fold increase in
MyHCß mRNA (Fig. 1 and data not shown). This increase is similar to
that seen in the hypothyroid TR1-/- and wt animals. These
conclusions are reminiscent of previous observations with the
negatively regulated TSHß gene: mice lacking both TR1 and TRß
(TR1-/-ß-/-) have serum TSH and TSHß mRNA levels (Ref.
21 , and Mansén, A., unpublished data)
that are similar to those found in severely hypothyroid mice.
Thus, a mechanism of MyHCß gene activation by an aporeceptor may not
be required.
TR1 and TRß also exhibit differences in their ability to suppress
MyHCß expression after injection of T3. A low
dose of T3 allowed wt mice to down-regulate
MyHCß RNA 20-fold, whereas only a 6-fold reduction was seen in the
TR1-/- mice. This suggests that TRß is less efficient than
TR1 or, alternatively, that the two receptors act in concert in
suppressing MyHCß at low serum levels of T3.
However, our data also show that TRß can, at higher serum
T3 levels, efficiently suppress MyHCß. Taken
together, our results indicate that TR1 is more efficient than TRß
in suppressing MyHCß. TR2 appears to have, at most, a minor effect
on MyHCß expression.
The MyHC gene is, in contrast to MyHCß, induced by
T3. No significant differences in MyHC
expression were observed in three independent experiments between
untreated wt and the respective TR-deficient mice. Furthermore, the
regimen used for inducing a hypothyroid state in the mice achieved a
similar repression of MyHC RNA levels in the TR1-/-,
TRß-/-, and control strains. Thus, we cannot ascribe a specific TR
isoform a role in regulating the MyHC gene. It is also noteworthy
that the 5-d T3 injection regimen did not
significantly increase the MyHC levels above those seen in untreated
mice, irrespective of the mouse strain studied. We have therefore
examined the induction levels of MyHC 2 h after injection of
T3. This treatment did not result in an induction
of MyHC above that seen in untreated mice (data not shown).
Therefore, the data indicate that in vivo, the major role of
TRs in regulation of the MyHC gene is to suppress expression during
hypothyroidism and to relieve repression when ligand becomes
available.
Gloss et al. (10) reported that TR1 is
expressed 3-fold higher than TRß on the RNA level in the mouse heart.
It is therefore possible that the efficient suppression of MyHCß by
TR1 is due to its higher expression level. A further increase in
TR1 expression, as seen in the TR2 mice (11A ),
results in increased efficiency in hormone-dependent
down-regulation of MyHCß (Mansén, A., unpublished
data), thus supporting the hypothesis that receptor levels are
important for gene regulation in vivo. However, we cannot
exclude that possible differences between the receptors in binding to
promoter-specific TREs or to corepressors also contribute to the
relative efficacy of T3-dependent
TR1-mediated gene suppression. Nevertheless, MyHC and MyHCß are
expressed in the same cell type, indicating that TR1 and TRß have
distinct intrinsic gene-regulatory properties in vivo.
Adult mice have a high heart rate and accordingly express little or no
MyHCß (15). Recently, Tardiff et al.
(30) developed transgenic mice that significantly
overexpress MyHCß (+12%) in the heart. These mice exhibit a
decreased cardiac contractility, indicating that a shift in cardiac
myosin composition, such as those we have described, markedly affects
cardiac function. This is further supported by studies on transgenic
mice expressing a dominant negative TRß (31, 32). Both
mouse strains expressed highly elevated levels of MyHCß RNA, possibly
as a consequence of an inability of the mutant TRß to down-regulate
the MyHCß gene. Furthermore, a TR-deficient mouse strain different
from the one used by us showed a decreased MyHC expression, which
may be correlated to a shift in total myosin composition
(10). The mouse strains referred to above have diminished
contractile function, which was attributed to decreased MyHC and
sarcoplasmic reticulum Ca2+ ATPase levels
(10, 31, 32). Since the mice analyzed by us carried
genetically altered TRs similar to those studied by Gloss et
al. (10), it is highly likely that the
TR1-deficient mice we have studied have similar deficiencies in
contractile function.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Northern Blot Analyses
Polyadenylated RNA was prepared from frozen heart (ventricle and
atrium) (33). Each preparation corresponds to one or two
hearts as indicated in the figure legends and 2–5 µg mRNA were
loaded per lane. Northern blots were hybridized with oligonucleotide
probes specific for MyHC or MyHCß (34). Hybridization
with glyceraldehyde-3-phosphate dehydrogenase (G3PDH) probe
(CLONTECH Laboratories, Inc., Palo Alto, CA) served as a
control for equivalent loading of mRNA. Levels of MyHC and MyHCß
mRNA expression were normalized to that of G3PDH mRNA using a
PhosphorImager (Molecular Dynamics, Inc., Sunnyvale, CA) and
BAS-2500 film (Fuji Photo Film Co., Ltd., Stamford, CT)
for quantification. Data are presented as means ±
SEM.
Animals and Experimental Setup
The Institutional Animal Care and Use Committee approved the
studies. Genotyping was done by PCR or Southern blot analysis (6, 22). The genetic backgrounds of the mice differ among the
different mouse strains (6, 21, 22). However, all wt
control and TR-deficient mice used in this study were obtained from
crosses between heterozygotes for the respective knockout strain. The
control strains were bred in parallel form with the receptor-deficient
strains for three to four generations, at which point new heterozygotes
produced inbreeding, followed by renewed heterozygote breeding for
homozygote wt and knockout strains. The control strains therefore had
the same, mixed genetic background as their respective
receptor-deficient strain. In summary, TRß mice hybrid of 129/Sv
x C57Bl/6J, TR1 mice hybrid of 129/OlaHsd x BALB/c, and the
TR1/ß mice were obtained from crosses of the above lines. The
allele nomenclature suggested by the Mouse Nomenclature Guidelines &
Locus Symbol Registry at The Jackson Laboratory (Bar
Harbor, ME) is simplified in the text for readability. Thus
Thratm1Ven/tm1Ven is denoted
TR1-/-, Thrbtm1Df/tm1Df is denoted
TRß-/-, and finally
Thratm1Ven/tm1VenThrbtm1Df/tm1Df
is denoted TR1-/-ß-/-.
Hypothyroidism was induced by an initial treatment of 2- to 5-month-old
male mice with LID (R584, AnalyCen, Nordic AB, Lidköping, Sweden)
for 14 d, followed by addition of 0.05% MMI and 1% potassium
perchlorate to the drinking water) for an additional 21 d (LID +
MMI). Thereafter, the mice were injected daily with either a low dose
T3 (0.05 µg T3/d; LID +
MMI + lT3) or a higher dose
T3 (0.2 µg T3/d; LID +
MMI+ hT3) for an additional 5 d to induce
hyperthyroidism (Table 1) (27). The low dose of
T3 was designed to raise the serum levels in
hypothyroid mice to below normal. The treatment with LID + MMI
significantly lowered the
FT3/FT4 levels as compared
with untreated mice. Since all animals given T3
injections were first made hypothyroid, we achieved maximal response to
the T3 injections. The experimental setup for the
TR1-/-ß-/- and their wt controls was essentially as above;
however, the LID treatment was extended to 21 d, followed by a
period of 5 weeks on LID + MMI treatment, and finally 5 d of
T3 injections (0.5 µg
T3/d). Serum and organs were collected 1 d
after the last T3 injection. A total of 24 mice
of each TR1-/- and TRß-/- plus an additional 24 of the
respective wt animals was used in the experiments. The number of
TR1-/-ß-/- and wt mice used was 18 of each genotype. Six
animals from each group were killed for analysis at each change of
diet, although serum samples for hormone determinations were obtained
from all mice. Animals that responded well to the dietary treatments,
as judged by their FT3 and
FT4 levels (Table 1), were selected for further
Northern analyses.
The experiments in Fig. 1 have been repeated three times; those in
Figs. 2 and 3 were repeated four times, respectively, and that in Fig. 4 was repeated once. The samples shown in Fig. 1 represent a pool of
RNA from two animals (females, 4 to 6 months old) of each genotype (12
mice total).
Electrophoretic Separation of Cardiac MyHC Isoform
Composition
Frozen hearts (left and right ventricles) from a total of 88
mice of different TR strains were sectioned 10 µm thick with a
cryotome (2800 Frigocut-E, Reichert-Jung GmbH, Heidelberg, Germany) at
-20 C. Appropriate amounts of sample buffer (333 µl sample buffer/1
mg of wet tissue) were added according to the areas of each
cross-section (3 x 105
µm2/1 µl sample buffer). The loading volumes
of each sample were kept at 4 µl.
The MyHC composition was determined by SDS-PAGE (35). The total bis-acrylamide concentrations were 4% (wt/vol) in the stacking gel and 7% in the running gel (0.75 mm thick), with acrylamide: N,N'-methylene-bis-acrylamide in the ratio of 50:1. The gel matrix (both stacking and separating gels) included 5% glycerol as described previously (36). The gels were placed in the electrophoresis apparatus (SE 600 vertical slab gel unit, Hoefer Scientific, San Francisco, CA) connected to a power supply and a cooling unit. Electrophoresis was performed at 215 V for 22 h with a Tris-glycine electrode buffer (pH 8.3) at 10 C. Separating gels were silver stained and subsequently scanned in a soft laser densitometer (Molecular Dynamics, Inc.) with a high spatial resolution (50-µm pixel spacing) and 4,096 OD levels to determine the relative contents of the MyHC isoforms. The volume integration function was used to quantify the relative amount of protein (37), and background activity was subtracted from all pixel values (ImageQuant Software version 3.3, Molecular Dynamics, Inc.).
Means and SEM values were calculated from individual values by standard procedures. A two-way ANOVA was applied to test for the effect of TR deficiency and TH levels within each mouse strain. Differences were considered significant at P < 0.05.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: FT3, Free T3; G3PDH, glyceraldehyde-3-phosphate dehydrogenase; hT3, high T3; LID, synthetic iodine-deficient diet; lT3, low T3; MMI, methimazole; MyHC, cardiac muscle myosin heavy chain; TH, thyroid hormone; TRE, thyroid response element; wt, wild type.
Received for publication May 18, 2001. Accepted for publication August 8, 2001.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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