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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0552
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 353-358
Copyright © 2007 by The Endocrine Society

BRIEF REPORT

Thyroid Hormone Increases mRNA and Protein Expression of Na+-K+-ATPase {alpha}2 and ß1 Subunits in Human Skeletal Muscles

Bunyong Phakdeekitcharoen, Suchart Phudhichareonrat, Chathchai Pookarnjanamorakot, Chusak Kijkunasathian, Nattha Tubtong, Wassana Kittikanokrat and Piyanuch Radinahamed

Division of Nephrology, Department of Medicine (B.P., P.R.), and Departments of Orthopedics (C.P., C.K.) and Pathology (N.T.), Research Center (W.K.), Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; and Department of Pathology (S.P.), Prasat Neurological Institute, Bangkok 10400, Thailand

Address all correspondence and requests for reprints to: Bunyong Phakdeekitcharoen, Division of Nephrology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. E-mail: RABPD{at}mucc.mahidol.ac.th.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Thyroid hormone regulates specific Na+-K+-ATPase isoforms in rodent skeletal muscles. No study has examined this relationship in human tissues.

Objective: This study investigated the effect of hyperthyroid status on the expression of the {alpha}- and ß-subunits of the Na+-K+-ATPase.

Design: The vastus lateralis muscles from eight hyperthyroid patients were biopsied before and after treatment. Ten age-matched euthyroid subjects served as controls.

Results: In hyperthyroid patients, the average T3 level was three times higher in pretreatment compared with posttreatment (262 ± 75 vs. 86 ± 21 ng/dl, P = 0.001). The relative mRNA expression of the {alpha}2, but not {alpha}1 or {alpha}3, subunit was increased approximately 3-fold in pretreatment (2.98 ± 0.52 vs. 0.95 ± 0.40, P < 0.01), whereas that of ß1, not ß2 or ß3, subunit was increased approximately 2.8-fold in pretreatment (2.83 ± 0.38 vs. 1.10 ± 0.27, P < 0.01). The relative mRNA expression of the {alpha}2 and ß1 subunits was positively correlated with the serum T3 (r = 0.75, P = 0.001 and r = 0.66, P = 0.003, respectively). Immunohistochemistry studies revealed an increase in protein abundance of the {alpha}2 and ß1, but not {alpha}1 or ß2, subunits in the plasma membrane of muscle fibers of hyperthyroid patients, which decreased after treatment.

Conclusions: This provides the first evidence that, in human skeletal muscles, thyroid hormone up-regulates the Na+-K+-ATPase protein expression at least, in part, at mRNA level, and the {alpha}2 and ß1 subunits play the important role in this regulation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE NA+-K+-ATPase is an integral membrane protein responsible for maintaining transmembrane ionic and electrochemical gradients (1). The enzyme is comprised of two subunits that are present in an equimolar ratio (2) that is a heterodimeric molecule consisting of a catalytic {alpha}-subunit and a glycosylate ß-subunit (3, 4). Different species and different tissues have different isoforms of the {alpha}- and ß-subunits (5, 6). In mammals, the {alpha}-subunit exists in at least four isoforms, {alpha}1–{alpha}4 (7, 8). By immunological and biochemical studies, {alpha}2 is the major catalytic isoform expressed in rodent skeletal muscles (2, 9, 10). Hundal et al. (11) have also shown that the {alpha}2 subunit is a prominent subunit in human skeletal muscles. In contrast, the ß-subunit exists in at least three isoforms, ß1–ß3 (8, 12), and appears to be important for the preservation of the stability of the {alpha}-subunits and transport of mature enzyme complexes to the plasma membrane (6, 13, 14). The ß1 subunit is an important subunit in rodent (15, 16) and human skeletal muscles (11, 17).

Thyroid hormone regulates the activity (18) and the number (19) of the Na+-K+-ATPase pumps in rodent skeletal muscles. In human skeletal muscles, thyroid hormone correlates with the number of the pumps (20). Isoform {alpha}2- and ß2-mRNA and protein abundance are increased significantly in rat skeletal muscles when there is a transition from the hypothyroid to the euthyroid stage (21). No information is currently available concerning the correlation of thyroid hormone and Na+-K+-ATPase mRNA and protein abundance in human skeletal muscles. Therefore, this study aimed to examine the expression of the {alpha}- and ß-subunits of the Na+-K+-ATPase and thyroid hormone levels in the skeletal muscle of hyperthyroid patients.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Six females and two males with first diagnosis of Graves’ disease were enrolled for the studies. The diagnosis of Graves’ disease was based on symptoms and signs of clinical thyrotoxicosis, laboratory confirmation, and positive antithyroid antibodies. Seven patients had medical treatment with either propylthiouracil or methimazole. One patient was treated with subtotal thyroidectomy. For a control group, 10 age-matched subjects undergoing elective knee or hip surgery with euthyroid were included for the study.

Muscle biopsy

Muscle biopsies were taken before and after treatment of thyrotoxicosis. After local anesthesia, a small incision was made through the skin and fascia. A vastus lateralis muscle sample was then excised and divided into two parts for quantitative mRNA expression assay, and for immunoblotting and immunohistochemical studies. Muscle samples were immediately snap frozen in liquid nitrogen and stored at –80 C. For control subjects, only skeletal muscles that showed no sign of necrosis and that were judged to be well perfused and oxygenated were used. All participants gave their written informed consent after receiving oral and written information concerning the study according to the Declaration of Helsinki II. The study protocol was approved by the Ethical Committee for Research Involving Human Subjects of the Ramathibodi Hospital, Mahidol University.

Real-time RT-PCR study

Muscle samples were weighed and minced into small pieces. Total RNA was extracted from 10–50 mg muscle using a commercially available kit (TRIzol; Life Technologies Inc., Carlsbad, CA). The purity of the RNAs measured by the UV spectrophotometer 260/280 was approximately 1.8–2.0. For each sample, 1 µg of RNA was transcribed into cDNA using the Promega AMV RT kit (Promega, Madison, WI). The cDNA was stored at –20 C.

Specific primers and probes as previously published (22) were used to amplify mRNA sequences of the {alpha}1, {alpha}2, and ß1 subunits. The primer sequences for amplifying the {alpha}3, ß2, and ß3 subunits included 5'-AGACTGTGTGCAGGGTTTGAC-3' and 5'-TGGCGTGAGTGCGTTAGG-3', 5'-GGACTCCACCCACTATGGTTACA-3' and 5'-CATAGAAGTTGATGACCCGGTTCA-3', and 5'-GTCCAGTTTATGTTGCATGTCAGTT-3' and 5'-GGGTTTCCTTGAGAATAGCCAAAATC-3', respectively. Specific probes of {alpha}3, ß2, and ß3 were 5'-CAAAGCCCAGGAGATCC-3', 5'-CAGCCCTGTGTCTTCA-3', and 5'-CTGCATGCTTGAAGTAATGA-3', respectively. Probes were labeled with 6-carboxyfluorescein at the 5' end and 6-carboxy-N,N,N',N'-tetramethylrhodamine at the 3' end. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA content was determined by using commercially available primers and probes (P/N 4326317E; Applied Biosystems, Foster City, CA). Primers and probe optimization and validation of amplification efficiency were carried out. The ABI 7000 real-time PCR system was used for relative quantification. The PCR and condition were used as previously published (22). The comparative cycle threshold method (multiplex PCR, same tube) was used to calculate the relative gene expression (Applied Biosystems). The average cycle threshold of GAPDH mRNA in each group was 27.1 ± 2.2 for {alpha}1, 27.2 ± 2.2 for {alpha}2, 28.1 ± 1.4 for {alpha}3, 28.2 ± 1.6 for ß1, 26.8 ± 2.2 for ß2, and 27.5 ± 2.9 for ß3. There was no statistical difference among the groups (P = 0.13).

Immunohistochemistry study

Muscle samples were fixed with cryomatrix (Thermo Shandon, Pittsburgh, PA) at –20 C and were used to generate ultra-thin transverse cryostat sections (10 µm). Muscle sections were then either treated with no primary antibody or with specific antibodies overnight at 4 C. The specific antibodies included anti-{alpha}1 monoclonal antibody (lot no. 05369), anti-{alpha}2 polyclonal antibody (lot no. 06168), anti-ß1 polyclonal antibody (lot no. 06170), and anti-ß2 polyclonal antibody (lot no. 06171; Upstate Biotechnology, Lake Placid, NY). The dilution of anti-{alpha}1 antibody is 1:40, anti-{alpha}2 is 1:20, anti-ß1 is 1:40, and anti-ß2 is 1:100. After two washes, the sections were incubated with secondary antibodies for 1 h at room temperature and washed again. The secondary antibody for monoclonal and polyclonal antibodies were fluorescein isothiocyanate-conjugated antimouse IgG dilution 1:100 and tetramethylrhodamine isothiocyanate-conjugated antirabbit IgG dilution 1:50 (Dako, Glostrup, Denmark), respectively. All sections were viewed using an inverted Nikon phase/fluorescence microscope and photographed using Fujichrome (ISO 50/18 degree) slide color films.

Western blot analysis

Muscle samples of 30 mg were homogenized on ice in a buffer as previously published (23). Twenty (ß1 and ß2) or 40 µg ({alpha}1 and {alpha}2) of protein was loaded in 10% separating gel. After electrophoresis, the protein was transferred to a nitrocellulose membrane and blocked with blocking buffer [5% nonfat milk in Tris-buffered saline-Tween 20 (TBST)]. Membranes were incubated overnight at 4 C in primary antibodies diluted in blocking solution. The dilution of anti-{alpha}1 and anti-{alpha}2 antibodies was 1:2000, and the dilution of anti-ß1 and anti-ß2 was 1:5000. Membranes were washed and incubated for 1 h in horseradish peroxidase-conjugated secondary antibodies (goat antimouse or goat antirabbit immunoglobulins) diluted 1:10,000 in TBST solution. After three washes, membranes were incubated with chemiluminescent substrate (Pierce SuperSignal, West Pico, IL). The signal was detected and imaged (Pierce CL-X Posure). Resulting autoradiographs were densitometrically scanned and quantified.

Statistical analysis

Statistics were analyzed with SPSS 11.0. Numerical data were shown with mean ± SD. The relative mRNA expression and protein expression were shown in mean ± SE. Comparisons used the two-tailed paired (within group) and unpaired t test (between groups). Correlations were determined by linear regression. There was a significant difference if the P value was less than 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the patients are shown in Table 1Go. The duration of the treatment of hyperthyroid to reach the euthyroid status ranged from 10–24 months (mean = 13.3 months).


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  		TABLE 1. The clinical features and thyroid hormones in eight Graves’ disease patients and 10 control subjects

 
In hyperthyroid patients, the relative mRNA expression of the {alpha}2 subunit of the Na+-K+-ATPase was increased approximately 3-fold in pretreatment compared with posttreatment (2.98 ± 0.52 vs. 0.95 ± 0.40, P < 0.01) and was different compared with the normal controls (2.98 ± 0.52 vs. 1.0 ± 0.23, P = 0.02) (Fig. 1Go). There was no difference in the relative mRNA expression of the {alpha}2 subunit between the posttreatment patients (euthyroid) and the control subjects (0.95 ± 0.40 vs. 1.0 ± 0.23, P = 0.95). For the ß1 subunit, the relative mRNA expression in hyperthyroid patients was also increased approximately 2.8-fold before treatment (2.83 ± 0.38 vs. 1.10 ± 0.27, P < 0.01) and was also different compared with the normal controls (2.83 ± 0.38 vs. 1.0 ± 0.28, P < 0.01). There was no difference in the relative mRNA expression of the ß1 subunit between euthyroid patients and control subjects (1.10 ± 0.27 vs. 1.0 ± 0.28, P = 0.74) (Fig. 1Go).


Figure 1
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  		FIG. 1. The changes of the relative mRNA abundance of the {alpha}1 (A), {alpha}2 (B), ß1 (C), and ß2 (D) isoforms of the Na+-K+-ATPase to the housekeeping gene (GAPDH) in skeletal muscles of hyperthyroid patients (Hyper, n = 8) and euthyroid patients (Eu, n = 8) compared with the control subjects (Con, n = 10). The expression level obtained in control samples was set as 1 for comparison. The values are shown in mean ± SE (bars). Paired t tests were used for comparison (P values) between hyperthyroid and euthyroid patients, and unpaired t tests were used for comparison between control and hyperthyroid or euthyroid patients. *, P < 0.05 greater than euthyroid; #, P < 0.05 greater than control. Dark gray box, Hyperthyroid patients; light gray box, euthyroid patients; white box, control subjects.

 
For the {alpha}1, {alpha}3, ß2, and ß3 subunits, there were no differences in the relative mRNA expression between pretreatment and posttreatment in hyperthyroid patients. There were also no differences in the relative mRNA expression of the {alpha}1, {alpha}3, ß2, or ß3 subunits between hyperthyroid patients and control subjects (Fig. 1Go).

Correlations between thyroid hormone and the relative mRNA expression of the Na+-K+-ATPase

In hyperthyroid patients and control subjects, the relative mRNA expression of the {alpha}2 and ß1 subunits were positively correlated to serum T3 (r = 0.75, P = 0.001 for {alpha}2 and r = 0.66, P = 0.003 for ß1), T4 (r = 0.63, P = 0.006 for {alpha}2 and r = 0.48, P = 0.04 for ß1), and free T4 (r = 0.64, P = 0.005 for {alpha}2 and r = 0.58, P = 0.01 for ß1). No correlation was found between the relative mRNA expression of the {alpha}1, {alpha}3, ß2, or ß3 subunits and serum T3, T4, or free T4.

Effects of thyroid hormone on human skeletal muscle membrane Na+-K+-ATPase expression

The immunofluorescent staining of the {alpha}1, {alpha}2, ß1, and ß2 subunits of the Na+-K+-ATPase using antibody recognized human skeletal muscle Na+-K+-ATPase protein largely in the plasma membranes of muscle fibers. However, there was also some nonspecific fluorescein isothiocyanate and tetramethylrhodamine isothiocyanate labeling (observed as bright yellow and bright orange staining) as this was also present in muscle sections incubated with secondary antibody alone (Fig. 2Go, A, E, I, and M). The plasma membrane staining was negative using only secondary antibody in control muscle fibers (Fig. 2Go, A, E, I, and M). The membrane protein abundance of the {alpha}2 and ß1 subunits were increased in muscle fibers of hyperthyroid patients (Fig. 2Go, G and K) and decreased after treatment (euthyroid) (Fig. 2Go, H and L). There was no difference in membrane protein abundance of the {alpha}2 and ß1 subunits in muscle fibers of euthyroid patients and control subjects (Fig. 2Go, H vs. F and L vs. J). In contrast, there was no difference in membrane protein abundance of both {alpha}1 and ß2 subunits in muscle fibers between hyperthyroid and euthyroid patients (Fig. 2Go, C vs. D and O vs. P). There was also no difference in membrane protein abundance of both {alpha}1 and ß2 subunits in muscle fibers between hyperthyroid patients and control subjects (Fig. 2Go, C vs. B and O vs. N). These results were consistent with the results from Western blot analysis that showed the increase in the expression of the {alpha}2 (~100–105 kDa) and ß1 (~45–52 kDa), but not {alpha}1 (~100–105 kDa) or ß2 (~45–52 kDa), subunits in hyperthyroid patients and decrease after treatment (Fig. 3Go). There was no difference in protein abundance of the {alpha}2 and ß1 subunits in muscle fibers of euthyroid patients and control subjects.


Figure 2
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  		FIG. 2. Immunohistochemistry of the {alpha}1, {alpha}2, ß1, and ß2 subunits of the Na+-K+-ATPase in 10-µm transverse sections of the vastus lateralis muscle samples from Graves’ disease patients and control subjects. Muscle sections were fixed and treated either with no primary antibody (negative control) or with specific antibody followed by secondary antibody. The specific antibodies included anti-{alpha}1, anti-{alpha}2, anti-ß1, and anti-ß2 antibodies as described in Subjects and Methods. All images were visualized at a magnification of x200. Neg, Skeletal muscle samples from control subjects treated with only secondary antibody (no primary antibody). Con, Skeletal muscle samples from control subjects treated with specific primary antibody. Hyper, Skeletal muscle samples from hyperthyroid patients treated with specific primary antibody. Eu, Skeletal muscle samples from euthyroid patients treated with specific primary antibody.

 

Figure 3
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  		FIG. 3. The representative of immunoblotting analysis and the relative protein expression of the {alpha}1, {alpha}2, ß1, and ß2 subunits of the Na+-K+-ATPase in skeletal muscles of hyperthyroid patients (Hyper), euthyroid patients (Eu), and control subjects (Con). Arrows indicated the molecular weight of the protein. The bars on the right show the relative protein expression in each group. Data are mean ± SE (bars); n = 8 for hyperthyroid and euthyroid patients, n = 10 for control subjects. All results were normalized against controls. *, P < 0.05 greater than euthyroid group; #, P < 0.05 greater than control group. Dark gray box, Hyperthyroid patients; light gray box, euthyroid patients; white box, control subjects.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrated, for the first time, that thyroid hormone up-regulates Na+-K+-ATPase {alpha}2- and ß1-mRNA and protein expression in human skeletal muscles of hyperthyroid patients and the expression of the Na+-K+-ATPase returns to normal level after treatment of hyperthyroidism. In this study, the expression of the {alpha}2 and ß1 mRNA correlated well with thyroid hormone levels, especially T3 levels. In hyperthyroid patients, the average T3 level increased 3-fold in pretreatment compared with posttreatment, whereas the average relative mRNA expression of the {alpha}2 and ß1 subunits increased approximately 3- and 2.8-fold, respectively. The elevation of mRNA expression of the {alpha}2 and ß1 subunits was confirmed in protein levels by both immunoblotting and immunohistochemical studies. Immunohistochemical study showed that the intensity of plasma membrane staining of the {alpha}2 and ß1 subunits were higher in pretreatment and decreased after treatment. The correlation of thyroid hormone and both mRNA and protein abundance of the {alpha}2 and ß1 subunits of the Na+-K+-ATPase implied that thyroid hormone up-regulates the Na+-K+-ATPase protein expression at least, in part, at mRNA level. These results were in agreement with previous studies by Horowitz et al. (21) and Azuma et al. (10), who reported the increase in the {alpha}2, not {alpha}1, mRNA and protein abundance during transition from hypothyroid to hyperthyroid state in rat skeletal muscles (10, 21). For the ß-subunit, we observed an increase in ß1, not ß2, mRNA and protein abundance when patients were hyperthyroid, and a decrease to normal level after treatment. These results contrasted to the previous study by Azuma et al. (10), who reported the coordinate increase in ß2, not ß1, mRNA and protein abundance with that of {alpha}2 isoform in transition from hypothyroid to hyperthyroid in rat skeletal muscles. In the previous study, the investigators used the skeletal muscle from the whole hind limb, whereas vatus lateralis was used in this study. It is known that ß-subunit in rat skeletal muscles is muscle-type specific (15, 24, 25). Hundal et al. (24) reported that pooled membrane from muscle enriched in slow twitch oxidative fibers express ß1, not ß2, whereas pooled membranes from muscles composed of fast twitch glycolytic fibers express ß2, not ß1. It is possible that the difference in the results of ß-subunit expression in this study and the previous one might be due to the difference in the tissue used in the particular experiment (26, 27) or related to the difference in isoform expression of the muscles between rodents and humans.

In human skeletal muscle disease, thyrotoxic periodic paralysis (TPP) is typically seen in hyperthyroid males developing hypokalemia due to shift of K+ from extracellular water space and paralysis during the disease attacks (28). Thyroid hormone up-regulates the number of the Na+-K+-ATPase pump in human skeletal muscles (20). However, most of the hyperthyroid patients, except TPP, do not have hypokalemia. It is possible that there might be some defects related to the quantity or quality of the pump in muscles of TPP patients. Studies on the effect of thyroid hormone on the Na+-K+-ATPase in muscles of TPP patients may provide knowledge to answer the above questions.

In summary, our study demonstrates that thyroid hormone up-regulates mRNA and protein expression of the {alpha}2 and ß1 subunits of the Na+-K+-ATPase in human skeletal muscles and this regulation is operated at least, in part, at mRNA level.


   Acknowledgments
 
Our grateful appreciation is extended to all patients who participated in our studies. We thank Prof. Rajata Rajatanavin and Dr. Chagriya Kitiyakara for many helpful discussions, and Dr. Atiporn Ingsathit for statistical analysis in this manuscript.


   Footnotes
 
This work was supported by The Thailand Research Fund and a Mahidol University Grant.

Disclosure Statement: All of the authors have nothing to declare.

First Published Online October 10, 2006

Abbreviations: GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; TPP, thyrotoxic periodic paralysis.

Received March 13, 2006.

Accepted October 3, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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