Departments of Medicine and Surgery, North Shore University Hospital, Manhasset 10030; and Cornell University Medical College, New York, New York 10021
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ABSTRACT |
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The
low-T3 syndrome is a metabolic
response resulting in a decreased serum triiodothyronine
(T3) concentration that has
uncertain effects on thyroid hormone-responsive gene expression and
function. We measured cardiac myocyte gene expression and cardiac
contractility in young adult female rats using chronic calorie
deprivation as a model of the
low-T3 syndrome. Sarcoplasmic
reticulum calcium adenosinetriphosphatase (SERCA2) and myosin heavy
chain (MHC) isoform mRNA content were measured after 28 days on a 50%
calorie-restricted diet (low T3)
with or without T3 treatment (6 µg · kg body
wt1 · day
1).
The low-T3 animals had decreased
maximal rates of contraction (
13%;
P < 0.05) and relaxation
(
18%; P < 0.05) compared
with the control and the
T3-treated groups. There was a
21% (P < 0.05) increase in left
ventricular (LV) relaxation time in the
low-T3 animals vs. both control
and T3-treated groups. The LV
content of the SERCA2 mRNA was decreased significantly (37%) in the
low-T3 rats and was increased
(P < 0.05) with
T3 treatment vs. controls. The
-MHC mRNA isoform decreased in the
low-T3 animals but was unchanged
in the T3-treated animals.
T3 supplementation normalized both
cardiac function and phenotype of calorie-restricted animals, suggesting a role for the low-T3
syndrome in the pathophysiological response to calorie restriction.
triiodothyronine; energy expenditure; sarcoplasmic reticulum calcium-binding protein; myosin heavy chain; euthyroid sick syndrome; left ventricular function
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INTRODUCTION |
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THE EUTHYROID SICK or low-T3 syndrome is a series of alterations in the pituitary-thyroidal axis resulting in a decreased serum and nonthyroidal tissue concentration of the active thyroid hormone triiodothyronine (T3) (31). The severity of this syndrome increases with the severity of the underlying illness and is associated with an increase in mortality in hospitalized patients (25). Although the low-T3 syndrome has been thought to enhance survival during illness by decreasing whole body energy expenditure and rates of protein catabolism and by reducing the loss of lean body mass, this adaptation may also be associated with impaired cardiac and skeletal muscle function (28, 31). Thyroxine therapy has no significant effect on biochemical or physiological parameters in this disorder. An important unanswered question is whether the low-T3 syndrome directly or indirectly impairs the effects of thyroid hormones on thyroid hormone-responsive gene expression and compromises organ-specific function.
Weight loss due to chronic caloric restriction and acute or chronic illness is associated with a low serum T3 concentration due, in part, to an inhibition of the type I 5'-iodothyronine deiodinase, which converts the prohormone L-thyroxine (T4) to its active metabolite, T3 (29). Impaired transport of T4 from the blood into hepatocytes may also be a significant factor, decreasing availability of substrate to be converted to T3 (30). Despite low serum levels of T3, serum thyrotropin [thyroid-stimulating hormone (TSH)] levels are within the normal range. These characteristics define the low-T3 syndrome, and potential contributing factors to this syndrome during acute stress include elevations in serum cortisol, tumor necrosis factor, and specific cytokines (9, 21, 31).
Chronic food restriction in experimental animals has been associated
with altered cardiac function, including decreased maximum rate of
contraction, decreased cardiac index, and a prolonged isovolumic
relaxation time (1, 15). These functional changes may, in part, be the
result of changes in mitochondrial oxidative enzyme activity and myosin
adenosinetriphosphatase (ATPase) activity, which is determined by the
relative expression of - and
-myosin heavy chain (MHC)
genes (12, 14). Diastolic relaxation time is partially determined
by the rate of calcium uptake into the sarcoplasmic reticulum (SR) by
an SR membrane calcium ATPase (2). The alterations in MHC isoform
expression in heart during undernutrition are similar to those observed
in experimental hypothyroidism (13). Thyroid hormone response elements
(TREs) have been identified within the promoter regions of several
cardiac genes, including
- and
-MHC,
-skeletal actin, and SR
calcium ATPase (SERCA2) (13, 18). Thyroid hormone deficiency in the
adult rodent heart is characterized by a shift in expression of the
-MHC to
-MHC isoform and a decrease in SERCA2 enzyme activity
(13).
Recent data suggest that the observed changes in cardiac function in undernutrition may be the result of the accompanying low serum T3 levels. Dillmann and co-workers (8) were able to prevent acute starvation-induced alterations in cardiac myosin ATPase activity by T3 supplementation. We undertook the present study to measure cardiac contractile function during nutrition-induced weight loss, using the isolated perfused heart protocol, and to correlate function with changes in the expression of the SERCA and the MHC genes. Furthermore, we studied whether supplementation with T3 could prevent the functional and phenotypic changes associated with the nutritionally induced low-T3 syndrome.
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METHODS |
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Animal protocols.
Sprague-Dawley female rats (200-225 g) obtained from Harlan
Sprague Dawley Labs (Indianapolis, IN) were individually housed in
polycarbonate cages and separated into five groups of six animals. The
control group was fed ad libitum with standard rat chow (Purina Rat
Chow; Ralston Purina, St. Louis, MO) and given free access to water.
Two energy-restricted (ER) groups were fed diets at 75 and 50%
(25% ER and
50% ER) of the calorie intake of the control group. Two additional groups of calorie-restricted rats were
supplemented with T3 (
25%
ER + T3 and
50% ER + T3) by infusion of
3,5,3'-triiodo-L-thyronine
(Sigma, St. Louis, MO) at a rate of 600 ng · day
1 · 100 g body wt
1, using a
subcutaneously placed osmotic minipump (model 2002, Alza, Altec,
CA). All four groups were treated for 28 days. On completion of the study, body weights were recorded, animals were anesthetized, and the hearts were rapidly removed and the great vessels
and atria resected. The ventricles were frozen in liquid nitrogen and
weighed before extraction of RNA. Blood was collected from the open
chest cavity for thyroid hormone analysis. A separate cohort of female
Sprague-Dawley rats (200-225 g) was used for analysis of left
ventricular (LV) function by the isolated heart perfusion procedure.
This cohort consisted of four groups of eight rats: control (fed ad
libitum),
50% ER,
50% ER + T3, and thyroidectomized (hypothyroid). The hypothyroid rats were surgically thyroidectomized 2 wk before the start of the study protocol, and the adequacy of the
procedure was determined by measuring serum thyroid hormone levels at 1 wk postsurgery.
Analysis of serum T3 and T4. Serum concentrations of T3 and T4 were measured by sensitive and specific radioimmunoassays, using thyroid hormone-depleted rat sera for standards.
Measurements of LV function. After the 28-day study protocol, rats received an injection of heparin sodium (500 U) intraperitoneally, 30 min before anesthesia with pentobarbital sodium (60 mg/kg ip). Hearts were removed and immediately placed in ice-cold heparinized saline. The hearts were then perfused in an orthograde fashion through the coronary arteries, as previously described (22), according to method of Langendorff, at a constant pressure of 95 cmH2O. A latex balloon (Hugo-Sacks Elecktronik, Hamburg, Germany) connected to a pressure transducer was inserted through the mitral valve into the left ventricle. The volume of the balloon was 0.06 ml for hearts <450 mg and was 0.10 ml for hearts >450 mg.
The perfusate was a modified Krebs-Henseleit buffer consisting of (in mM) 118 NaCl, 6.1 KCl, 2.5 CaCl2, 1.2 MgSO4, 25 NaHCO3, 1.0 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, and 11.1 glucose. Complete buffer was prepared on the day of the experiment by mixing the proper amounts of concentrated stock solutions, to which the appropriate quantities of glucose and calcium chloride were added. All concentrated solutions, with the exception of the magnesium sulfate, were treated with chelating resin beads (Chelex 100, iminodiacetic acid; Sigma) to minimize trace heavy metal contamination. To develop a relationship between left ventricular end-diastolic pressure (LVEDP) and the maximal rates of contraction (+dP/dtmax) and relaxation (Total RNA isolation and Northern blot
analysis.
Total cellular RNA was extracted from the left ventricle, using the
acidic-phenol method with modifications as previously published (5).
Five micrograms of total RNA were denatured in the presence of 2.2 M
formaldehyde, 33% formamide,
3-(N-morpholino)propanesulfonic acid [19.5 mM
3-(N-morpholino)propanesulfonic
acid], pH 7.0, 5 mM sodium acetate, and 1 mM EDTA at 65°C for
5 min and separated by electrophoresis on formaldehyde-1% agarose
gels. The ribosomal RNA bands were visualized by ethidium bromide
staining, and the RNA was transferred to Duralon ultraviolet (UV)
membrane (Stratagene, San Diego, CA) by capillary blotting and then
cross-linked to the membrane by exposure to UV light. Membranes were
prehybridized at 42°C for 6-8 h in a solution containing
5× SSPE (0.75 M NaCl, 50 mM sodium phosphate, pH 7.4, 3,335 mM
EDTA), 5× Denhardt's solution (0.1% Ficoll, 0.1%
polyvinylpyrrolidone, 5% bovine serum albumin), 50% formamide, 1%
sodium dodecyl sulfate (SDS), and 100 µg/ml denatured salmon sperm
DNA. Hybridization with a radiolabeled SERCA2 cDNA probe (kindly
provided by W. H. Dillmann, University of California San
Diego, La Jolla, CA), added at
106
disintegrations · min1
(dpm) · ml hybridization
solution
1, was carried out
at 42°C for 18 h. Membranes were washed at high stringency in
0.2× SSPE, 1% SDS at 65°C for 30 min and were then exposed
to X-ray film with intensifying screens at
80°C. To
normalize for sample loading variability, Northern blots were washed
and reprobed with a glyceraldehyde-3-phosphate dehydrogenase
oligodeoxynucleotide probe (Oncogene Science, Uniondale, NY).
Hybridization conditions were similar to the cDNA probe except that the
stringent washes used 2× SSPE, 1% SDS at 65°C for 30 min.
The mRNA was quantified by laser scanning densitometry of the
autoradiograms at various exposure times to assure that the values were
not saturating.
S1 nuclease protection analysis.
The - and
-MHC mRNAs were quantified in the same sample of total
RNA by using a single oligonucleotide probe in an S1 nuclease mapping
assay as previously described (20). The end-labeled 61-base
oligodeoxynucleotide probe was complementary to a 38-base coding
sequence common to both
- and
-MHC mRNAs and to an additional 8 bases unique to
-MHC mRNA, thereby allowing the resolution of the
two protected mRNAs by polyacrylamide electrophoresis. The MHC mRNA
species were quantified by laser densitometric scanning of the
autoradiograms, and the amount of each MHC mRNA was expressed as a
fraction of the sum of the two isoforms.
Statistical analysis. The results are reported as means ± SE. Comparisons of body weight, serum thyroid hormone levels, and measures of contractility and gene expression in the calorie-restricted groups vs. control and T3-treatment groups were performed, using analysis of variance techniques and the Student-Newman-Keuls test (3). Standard linear regression techniques were used to analyze the relationship between thyroid hormones and body weight.
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RESULTS |
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Effects of calorie restriction on serum thyroid hormones. Calorie restriction for 28 days produced a low-T3 state as measured by serum levels of T3 and T4. The serum concentration of T3 in the 25% calorie-restricted group was significantly lower than controls (24.8 ± 3.3 and 61.7 ± 5 ng/dl, respectively), whereas serum T4 levels were not significantly different (3.9 ± 0.5 and 4.3 ± 0.8 µg/dl, respectively), as is characteristic of the low-T3 syndrome (Table 1). The 50% calorie-restricted group showed an 82% decrease in serum T3 levels compared with controls (P < 0.02), with a significant (P < 0.05) decrease in serum T4 concentration (2.9 ± 0.6 vs. 4.3 ± 0.8 µg/dl) (Table 1). The decrease in the serum T3 level in the two groups of calorie-restricted rats was directly proportional to the nutritionally induced decrease in body weight gain (r = 0.83; P < 0.001) (Fig. 1). T3 supplementation maintained serum T3 concentrations in both groups of calorie-restricted rats in the normal range of T3 serum values (45-85 ng/dl), with only the 25% ER group exhibiting a higher mean concentration of T3 (P < 0.01) (Table 1). Serum T4 levels were suppressed to undetectable levels in both T3 replacement groups.
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Effects of calorie restriction on heart and body
weight changes.
The heart weights of the 25% and
50% underfed groups
were decreased 5.6% (P < 0.05) and
18.7% (P < 0.01) vs. control
hearts, whereas total body weight decreased 8.9%
(P < 0.05) and 21.4% (P < 0.01) compared with controls,
as reported in Table 1. This resulted in maintenance of the heart
weight-to-body weight ratios in both the 25 and 50% food-restricted
groups compared with the control animals. Animals that were
T3 treated and calorie restricted exhibited greater declines in body weight for the
25% (235 ± 12 vs. 256 ± 3 g; P < 0.05) and
50% calorie-restricted animals (201 ± 4 vs. 221 ± 6 g; P < 0.05). The heart
weights for the T3-treated plus
calorie-restricted groups were similar to those of food-matched groups,
resulting in an increase in the heart weight-to-body weight ratios by
9.0% (P < 0.01) and 3.3%
(P = not significant) in
the 25% ER + T3 and 50% ER + T3 groups vs. their food-matched
controls, respectively.
LV function in hypothyroid and calorie-restricted
rats.
Measurements of LV contractility and relaxation were obtained from
analysis of the LV pressure waveform of isolated perfused hearts, as
depicted in Fig. 2. The LV
+dP/dt at 5 mmHg of end-diastolic pressure was decreased 13.0% (P < 0.05) in the hearts of the 50% calorie-restricted group and was
normalized with T3 supplementation (50% ER + T3) as
reported in Table 2. Results were similar
for +dP/dt measured at 10 and 20 mmHg
of end-diastolic pressure (data not shown). The ventricular
dP/dt was decreased 19.3%
(P < 0.05) compared with results
from hearts of control rodents at 5 mmHg of end-diastolic pressure,
with similar findings at 10 and 20 mmHg. Supplementation with
T3 during 50% food restriction
maintained normal ventricular
dP/dt. The mean LV relaxation
time (
1/2) was increased in
the 50% food-restricted group by 21.6%
(P < 0.05) and was normal in the
T3-treated group (Table 2). The
relaxation time was not altered by increasing the end-diastolic
pressure to 10 or 20 mmHg (data not shown).
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Effects of calorie restriction on cardiac-specific
gene expression.
To understand a mechanism by which calorie restriction and
T3 modulate cardiac contractility,
we measured the mRNA content of the cardiac - and
-MHC and SERCA2
genes. Chronic underfeeding decreased SERCA2 mRNA content in a graded
fashion in both the 25% and 50% food-restricted groups compared with
controls (79.8 ± 5.6 and 66.1 ± 5.9 vs. 100 ± 8.5%;
P < 0.05). The
T3-supplemented groups had
increased levels of SERCA2 mRNA content vs. underfeeding alone (155 ± 23 and 175 ± 14% for
25 and
50% groups,
respectively; P < 0.01). The
relative mRNA content of the SERCA2 gene in the heart for the
50% ER and T3-treated
groups is depicted in Fig. 3.
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DISCUSSION |
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The cardiac-specific SERCA2 gene regulates cardiac myocyte relaxation
during diastole via control of the rate of SR calcium uptake (2).
Transcription of the gene encoding the SERCA2 protein is regulated in
vivo by thyroid hormone, and TREs have been identified as
the 5'-flanking region of this gene (23, 32). Both experimental hyperthyroidism and hypothyroidism in rodents have been shown to
produce alterations in both SERCA2 mRNA content and protein content
(24). This study is the first to describe a significant decrease in the
level of expression of the cardiac SERCA2 gene in response to the
low-T3 syndrome and to show that
parameters of cardiac relaxation
(dP/dt and
1/2) were
significantly altered compared with controls and were similar to values
obtained in hypothyroid animals. We also observed that maintenance of
physiological levels of T3
prevented the fall in SERCA2 mRNA content and maintained normal
measures of cardiac muscle relaxation, despite a relative weight loss.
Further evidence for an effect of the
low-T3 syndrome on both cardiac
gene expression and function is the observed alterations in MHC isoform
content and
+dP/dtmax.
A decrease in both
+dP/dtmax and
mRNA content of the -MHC in the calorie-restricted
low-T3 group of animals was
measured, with values equivalent to those of hypothyroid hearts (2,
17). Treatment with T3 normalized both the mRNA expression and physiological measure of pressure generation. The ATPase activity of the two isoforms of the MHC proteins
of the rat heart determines, in part, the rate of myofibrillar contraction, with the
-MHC isoform exhibiting a slower rate of ATP
hydrolysis compared with the
-MHC isoform (19, 27). These alterations in both SERCA2 and MHC gene expression and the
pathophysiological alterations in both cardiac contractility and
relaxation are consistent with the hypothesis that the
low-T3 syndrome is associated with alterations in thyroid hormone-responsive gene expression and physiological function similar to those observed in hypothyroidism. Supplementation with T3 to
maintain normal serum T3 levels
during chronic undernutrition was able to both normalize
parameters of cardiac contractility and maintain levels of expression
of both the SERCA2 and MHC genes.
In addition to their effects on MHC and SERCA gene expression, thyroid
hormones influence gene expression and function of other
muscle-specific proteins and intermediary metabolism of the myocyte.
These effects include a direct modulation of the responsiveness and
density of -adrenergic receptors, mitochondrial oxidative capacity,
and oxidative phosphorylation as well as total cellular protein
synthesis (5). Thyroid hormones also regulate the gene expression of
cytochrome c, malic enzyme, and
possibly other regulators of oxidative metabolism within the myocyte.
Maintenance of normal thyroid hormone action on the myocyte is thus
critical for both muscle mass and function.
The metabolic response to chronic energy restriction is an integrated series of hormonal responses that are time dependent. Initially, there is an acute rise in stress hormones, including cortisol and catecholamines, and then a reduction in both anabolic and catabolic hormones associated with a decrease in protein turnover and metabolic rate. It is uncertain whether treatment with T3 during energy restriction alters either serum levels or responsiveness to other hormones, including insulin or growth hormone. However, treatment with T3 during acute starvation did not alter the decrease in serum insulin or protein synthesis in a rodent model. Additionally, streptozocin-induced diabetes mellitus lowers both serum insulin and T3 as well as myosin ATPase activity (16). Treatment with T3 normalized myosin ATPase activity despite insulin deficiency, suggesting that at least a portion of the effects of T3 is independent of insulin. Dillmann et al. (7, 8) initially reported that acute starvation decreased myosin ATPase activity in the rat heart and that T3 supplementation normalized enzymatic activity. They also noted that supplementation with carbohydrate and inhibition of cardiac fatty acid metabolism during acute starvation prevented the decrease in myosin ATPase activity independent of thyroid hormones, suggesting that both metabolic fuel composition and thyroid hormones were independent regulators of cardiac myosin gene expression (6). The finding that these two distinct conditions produced both a low-T3 state and an alteration in a thyroid hormone-responsive gene function that is responsive to T3 treatment provides further evidence for a direct effect of the low-T3 state on thyroid hormonespecific gene expression in cardiac tissue.
In summary, decreases in the serum T3 concentration associated with chronic calorie restriction were associated with impaired cardiac contractility due, in part, to alterations in cardiac SERCA2 and MHC gene expression. Supplementation with T3 during nutritionally induced weight loss completely prevented the phenotypic and physiological changes in the heart, despite cardiac atrophy. These data support further research into the pathophysiological role of the low-T3 syndrome on thyroid hormone action in chronic disease states.
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ACKNOWLEDGEMENTS |
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We thank Catherine Demaso, Deborah Carman, Jeanmarie Finnerty, and Ellen Gurzenda for technical expertise.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-38337 (to H. L. Katzeff), National Heart, Lung, and Blood Institute Grant HL-45534, and American Heart Association Grant-in-Aids [to S. R. Powell (New York State) and to K. Ojamaa].
This work was presented in part at the 5th International Thyroid Congress, September 10-15, 1995, Toronto, Canada.
Address for reprint requests: H. L. Katzeff, Long Island Jewish Medical Center, New Hyde Park, NY 11040.
Received 13 December 1996; accepted in final form 7 July 1997.
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