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Evaluation of changes in body composition and proinflammatory marker levels in ovariectomized rats with induced hyperthyroidism Evaluation of changes in body composition and proinflammatory marker levels in ovariectomized...
Yoon, Jin A; Lee, Young Joo; Lee, Byung-Joo; Kim, In-Joo; Kim, Seong-Jang; Pak, Kyoungjune; Jeon, Yun Kyung; Kim, Jeong Hun; Kim, Ji Min; Kim, Keunyoung; Jun Shin, Myung; Shin, Yong Beom
2020-01-01 00:00:00
ALL LIFE 2020, VOL. 13, NO. 1, 99–107 https://doi.org/10.1080/26895293.2020.1727966 Evaluation of changes in body composition and proinflammatory marker levels in ovariectomized rats with induced hyperthyroidism a∗ b∗ c d e d Jin A Yoon , Young Joo Lee , Byung-Joo Lee ,In-JooKim , Seong-Jang Kim , Kyoungjune Pak , f g g d a a Yun Kyung Jeon , Jeong Hun Kim , Ji Min Kim , Keunyoung Kim , Myung Jun Shin and Yong Beom Shin Department of Rehabilitation Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea; Department of Obstetrics and Gynecology, Biomedical Research Institute Pusan National University School of Medicine, Busan, Republic of Korea; Department of Otorhinolaryngology – Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea; Department of Nuclear Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea; Department of Nuclear Medicine and BioMedical Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea; Department of Internal Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea; Pusan National University Medical Research Institute, Pusan National University School of Medicine, Pusan National University, Busan, Republic of Korea ABSTRACT ARTICLE HISTORY Received 25 November 2019 We examined the effect of TSH-suppressive dose of LT4 on changes in body composition and proin- Accepted 3 February 2020 flammatory markers in ovariectomized rats. Bilateral ovariectomy (OVX) and sham operations (Sham) were performed in female Sprague–Dawley rats at 7 weeks of age. Rats were divided as Sham (n = 6), KEYWORDS Sham + LT4 (n = 6), OVX (n = 8), and OVX + LT4 (n = 8). Eight weeks after surgery, the body com- Body composition; dual position was analyzed using Dual energy X-ray Absorptiometry. The percentage of gain of fat mass energy X-ray absorptiometry; and lean mass of whole body, body trunk and extremities were evaluated. Serum TSH, cholesterol, menopause; creatinine kinase (CK), C-reactive peptide, interleukin (IL)-1β, IL-4, IL-6, IL-10, monocyte chemoattrac- proinflammatory cytokines; well differentiated thyroid tant protein-1 and tumor necrosis factor-α were compared among the four experimental groups. cancer; TSH suppression The middle third of soleus muscle was analyzed with cross-sectional area (CSA), Feret’s diameter (FD) and an area of interstitial space. A Kruskal–Wallis test was used and post-hoc analysis was per- formed using the GRAPHPAD PRISM (ver 8.0, GraphPad Software, Inc.) The fat mass, but not lean mass, was significantly increased in the OVX groups compared with Sham groups, regardless of LT4 treatment. CSA, FD and the area of interstitium were elevated in OVX groups and increased with LT4 treatment. OVX + LT4 group showed the most deteriorated muscle with the lowest serum level of CK and highest level of IL-6. Introduction improves patient survival (Balme 1954;Cadyetal. 1983). Despite studies showing the success of TSH Well differentiated thyroid carcinoma (WDTC), con- suppression therapy, there is an increasing concern sisting both papillary thyroid carcinoma and follic- ular thyroid carcinoma, is one of the most com- regarding the potentially harmful eeff cts of lifelong mon endocrine malignancies. Its prognosis is favor- TSH suppression, especially when WDTC is generally able with an overall survival rate of 80–95% at 10 years an indolent tumor and the cancer-specific mortality (Schlumberger 1998). An initial total thyroidectomy rate is very low (Biondi and Cooper 2010). Becausethyroidhormoneand TSHhavemetabolic and radioiodine ablation using iodine-131, followed effects in determining energy expenditure and body by suppression of thyrotropin (TSH) with exogenous mass, TSH suppressive therapy may affect body com- levothyroxine (LT4), are the traditional and standard position (Mullur et al. 2014). It is reported that the treatments for WDTC (Biondi et al. 2005;Pacini suppressive dose of LT4 has adverse effects on sev- et al. 2006;Cooperetal. 2009). This therapeutic eral target organs, especially bone and myocardium approach reduces the risk of tumor recurrence and CONTACT Keunyoung Kim buisket@naver.com; nmpnuh@gmail.com Department of Nuclear Medicine, Pusan National University Hospital, Busan, 49642, Republic of Korea These authors contributed equally to this work as first authors. © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 100 JA. YOON ET AL. (Biondi and Cooper 2010). The recent study reported Materials and methods that the suppressive TSH treatment for female patients Experimental design with WDTC yielded an increased in resting energy expenditure and several cardiovascular risk factors Animal care and all experiments were approved by withoutchangeofbodymassindexorleanbody mass the Institutional Animal Care and Use Committee (Izkhakov et al. 2019). In spite of a few clinical studies of Pusan National University Hospital (Approval No. dealt with the eeff cts of thyroid hormone or TSH sup- PNUH-2017-117) and carried out in compliance with pression on body composition and sarcopenia, it is still university’s scientific research guidelines and regula- less conclusive (Brennan et al. 2006; Johannsen et al. tions. Before designing the experiment, we calculated 2012; Samuels et al. 2016). the sample size using the G Power 3.1.9.4 program. To Postmenopausal women, who are the most com- establish the validity of the OVX model, we measured mon to present WDTC, are prone to the harmful con- serumestrogenlevelsand determinedan eeff ctsize dition of postmenopausal hypogonadism (Greenspan based on difference in serum estrogen levels between and Greenspan 1999). The prevalence of sarcopenia in the Sham groups and OVX groups from our pilot menopausal women varies from 10-40% depending on studydata.Asaresult, theeeff ctsizewas1.86. When the method (Abellan van Kan 2009). The menopause alpha = 0.05, power = 80%, and effect size 1.86 were state, which involves a reduction of estrogen pro- set, six animals per group were required. Consider- duction, may cause major metabolic changes and ing statistical power and 20% mortality during the induce modifications in body composition (Waters OVX operation, eight animals were allocated in the and Baumgartner 2011; Dutra et al. 2017). Advanc- OVX groups. Female Sprague–Dawley virgin rats that ing age with menopause characterized by a progressive were 7-week-old (n = 28) and approximately weigh- decrease in lean mass and increase in fat mass, result- ing 190–210 g were used. The rats were acclimatized ing in obesity and sarcopenia (Aloia et al. 1991;Dutra in individual cages for 7 days prior to experiment in et al. 2017). Majority of the clinical studies have specu- a room with constant temperature of 23 ± 2°C, 55% lated that estrogen deficiency induces sarcopenia with relative humidity, with 14/10 h light and dark cycles. decreased muscle function. However, in spite of mul- Each cage contained two or three animals. Animals tiple lines of evidence, the redistribution of fat and were allowed free access to food and water ad libi- changes in body composition has been poorly charac- tum. The body weight and food intake were monitored terized. weekly. Dual energy X-ray absorptiometry (DXA) is a Rats were anesthetized using thiopental (4 mg/kg) widely used and validated imaging method for body and underwent a bilateral ovariectomy (n = 16, OVX) composition assessment that eeff ctively characterizes or a sham operation (n = 12, Sham). Bilateral ovariec- lean and fat volume and bone mineral density, both in tomy was performed via lower abdominal incision rodents and humans (Brommage 2003;Norcrossand under anesthesia with isou fl orane inhalation vapor- Van Loan 2004;Tanvigetal. 2014). The basic principle TM izer (Matrix VIP 3000 , Midmark Co., USA). After for measurement of body composition using DXA is surgery, the animals were kept individual cages to based on the attenuation of two dieff rent energy peak recover from anesthesia and rinsed the surgical site of X-ray in tissues (Pietrobelli et al. 1996). Though the daily with povidone-iodine. No signs of infection or use of DXA is not the gold standard tool for measuring stress were evident. Rats were randomized according body composition, it is commonly used in both clinical to their weight and divided into four experimental and research settings because of low cost, short scan groups: (i) Sham (n = 6), (ii) Sham + LT4 (n = 6), time, low radiation exposure, and wide availability (iii) OVX (n = 8), (iv) OVX + LT4 (n = 8). The TSH- (Kim et al. 2002). suppression was induced by the intraperitoneal injec- In this study, we sought to define the role of estro- tion of 0.3 mg/kg of LT4 once per day for 6 weeks. gen deficiency-induced and TSH suppression therapy- The control animals were similarly injected with induced changes in body composition using DXA and 0.9% NaCl. All injections were initiated 7 days after by measuring inflammatory markers in rat models of surgery. ovariectomy and LT4 treatment. ALL LIFE 101 Body composition analysis using dual-energy X-ray Biochemical serum measurements absorptiometry (DXA) After DXA scanning, animals were sacrificed under Animals were scanned using DXA (Lunar Prodigy, CO anesthesia. Blood samples were obtained by car- GE healthcare, Diegem, Belgium). The rats were anes- diac puncture upon euthanasia and were kept at –20°C thetized with isou fl rane, ventrally positioned, and until analysis. The serum levels of C-reactive pep- scanned. The body composition was assessed at base- tide (CRP), interleukin (IL)-1β, IL-4, IL-6, IL-10, line and follow-up analysis was performed 8 weeks monocyte chemoattractant protein-1 (MCP-1) and aftersurgery,using thesmall-animalmodeofthe tumor necrosis factor-alpha (TNF-α)weremeasured encore software (GE Healthcare, v. 13.40, Diegem, Bel- using a Rat premixed Multi-Analyte Kit (R&D Sys- gium). The device was managed with daily quality tems,Minneapolis,USA)withMilliplex (Merck Mil- assurance and calibrated at each study performance. lipore, Darmstadt, Germany) for the determination Forthebodycompositionanalysis, thesoftwarepro- of the role of cytokines. Serum TSH level was mea- vided weight (g), fat mass (g), lean mass (g) and sured using ELISA kit (MBS726442, MyBioSource, San fat free mass (g) of regions of interest as following; Diego, USA). Serum total cholesterol level and cre- wholebody, trunk,bothsidesoflegsand arms.We atine kinase level measured using colorimetric assay adopted the values of total body weight and acquired kit (ECCH-100 and ECPK-100, respectively, BioAssay fat mass and lean mass in trunk and all extremities. Systems, Hayward, USA). Assays for each animal and The changes of body composition were expressed as its correlated control were run in the same lot. percentage (%) of gained mass compared with baseline DXA study. Statistical analyses Histology The variables with non-normal distributions are expressed as medians and interquartile ranges (IQRs; The middle third of soleus muscle (SOL) was removed 25–75%). A Kruskal–Wallis test and was used and and placed in 10% neutral buffered formalin for post-hoc analysis was performed for pairwise compar- 24 h. The tissue samples were embedded in paraf- ison of subgroups to verify differences across experi- fin in a vertical orientation relative to the longitudi- mental groups. The Mann–Whitney U test was used nal axis of coronary plane. We used automatic tis- to determine the significance of the difference between sue processor for paraffin embedding (Leica, TP1020, two groups. The statistical analyses were performed Semi-enclosed benchtop tissue processor) and dis- using the GRAPHPAD PRISM (ver 8.0, GraphPad pensing (Leica EG1150H, Heated paran ffi embed- Software, Inc.) with P-value < 0.05 was considered ding module). Blocks were cut into 3-μm-thick his- statistically significant. tological sections, stained with hematoxylin-eosin, andplacedonhistology slides.Toavoidrepeated analysis of the same histological area, sections were Results evaluatedinsemi-series,using oneinevery 20sec- Changes in body weight and body composition tions. We selected proper central part on coronary plane of the SOL tissue for representative images All animals gained body weight and those in the OVX taken under 40× objective lens and captured using group showed more rapid weight gain and the amount a light microscope (Leica DM4000/600M, Versatile of weight gain was significantly increased compared upright microscope for materials analysis). At first, with those in control group (median: 104.6; IQR: we analyzed the slide in qualitatively for morphome- 91.267–116.78 vs. median: 66.4; IQR: 61.50–71.20, tric change among the experimental groups. For the P = 0.001; Figure 1). The administration of LT4 did quantitative analyses, four random non-overlapping nothaveaneeff ctonthebodyweight(Figure 1 and areas were analyzed at 10X. The Cross-sectional area Table 1). 2 2 (CSA, μm × 10 ), Feret’s diameter (FD, μm) and an Basedonanalysisofthe body compositionusing 2 4 area of interstitial space (μm × 10 )werequantified DXA, the fat mass was significantly gained in OVX using ImageJ software (National Institutes of Health, group compared with that in the Sham group USA). (median: 11.40; IQR: 10.55–12.42 vs. median: 10.03; 102 JA. YOON ET AL. Figure 1. Serial changes of the body weight during experiment. The ovariectomized (OVX) rats showed more rapid weight gain than sham-operated (Sham) rats. The LT4 treatment has no effect on change of body weight. Table 1. Median values for DXA outcomes and comparisons among the experimental groups. Sham Sham + LT4 OVX OVX + LT4 a a a,c TSH (ng/ml)* 4.392 (4.010) 1.87 (0.824–2.824) 3.06 (2.553–3.928) 2.06 (1.59–2.20) a,b a,b Weight (g)* 267.70 (251.23–269.05) 263.40 (262.00–268.70) 334.20 (312.78–337.13) 332.20 (317.923–340.30) a,b a,b Amount of weight gain (g)* 63.60 (59.50–67.20) 66.45 (65.00–74.70) 106.60 (91.53–119.78) 103.20 (90.325–112.9) a,b a,b Gain of total fat mass (%)* 15.62 (14.94–15.37) 15.79 (15.20–16.00) 17.67 (16.67–19.10) 17.15 (16.92–18.79) a,b a,b Trunk (%)* 9.46 (8.679–10.22) 10.17 (9.67–10.94) 17.67 (16.76–19.08) 17.15 (16.92–18.79) a,b Extremities (%) 7.19 (7.15–7.22) 7.26 (7.15–7.35) 7.08 (7.05–7.34) 7.02 (6.93–7.11) Gain of total lean mass (%) 5.52 (5.115–5.65) 7.24 (6.61–7.48) 5.89 (3.96–7.58) 6.19 (4.829–7.343) Trunk (%) 9.89 (9.23–10.33) 8.79 (8.31–8.79) 10.66 (9.47–10.73) 11.492 (9.46–11.49) Extremities (%) 3.95 (3.02–4.82) 4.17 (4.08–4.21) 4.09 (3.79–5.17) 4.05 (3.39–4.50) DXA, dual X-ray absorptiometry; OVX, ovariectomy; Sham, Sham-operation. Variables are expressed as the median (interquartile range). *, P < 0.05, for comparison among four groups using Kruskal-Wallis test; a, P < 0.05 compared with the sham only operation group; b, P < 0.05, compared with Sham with LT4 treatment; c, P < 0.05 compared with OVX only group. IQR: 9.03–10.37, P < 0.001), without any significant and the Feret’s diameter, however, there was no sig- changes in the lean mass (median: 6.04; IQR: 4.59–7.48 nificance (Figure 2(A, B)). The area of the intersti- vs. median: 6.37; IQR: 5.52–7.44, P = 0.486). Par- tium showed significantly higher in the OVX + LT4 ticularly, the significant fat changes were found in group compared with other experimental groups the trunk area (median: 11.40; IQR: 10.55–12.42 vs. (Figure 2(C)). The representative hematoxylin-eosin median: 10.02; IQR: 9.03–10.37, P < 0.001) and not staining of coronary section of SOL showed that LT4 in the extremities (median: 7.74; IQR: 7.66–7.79 vs. treatment in OVX group resulted in disorganized mus- median: 7.89; IQR: 7.82–7.95, P = 0.091) The TSH cle b fi ers and widened interstitium, with the rats in the suppressive dose of LT4 did have significant effect on OVX + LT4 group being the worst aeff cted (Figure 3). the accumulated fat or lean mass OVX rats using DXA (Table 1). Difference in biochemical serum parameters AnimalsintheOVXonlygroupshowed signifi- Histomorphologic finding of SOL cantly increased serum total cholesterol levels com- The CSA (median: 25.12, IQR: 20.21–30.39 vs. pared with those in the Sham group. The CK level median: 19.15; IQR: 14.38–23.79, P < 0.001) and FD was significantly lower in the Sham + LT4, OVX and (median: 4.95; IQR: 4.81–5.24 vs. median: 4.16; IQR: OVX + LT4 group than Sham-operation only group. 4.10–4.49, P < 0.001) was significantly larger in OVX Furthermore, treatment of LT4 induced significantly group compared with Sham group. The TSH sup- decrease in CK level compared with both Sham and pressive therapy also induces the increase in CSA OVX only group, respectively (Table 2). Among the ALL LIFE 103 Figure 2. The difference in cross-sectional area (CSA), Feret’s diameter (FD) and area of the interstitium. (A) CSA were significantly higher in ovariectomized (OVX) groups than in Sham-operated (Sham) only group. (B) FD were significantly elevated in OVX groups compared with Sham groups regardless of LT4 treatment. (C) The areas of the interstitium were increasing with OVX and LT4 treatment. OVX with LT treatment showed most widened interstitial space. *, P < 0.05 compared with the Sham only operation group; ˆ, P < 0.05, compared with Sham with LT4 treatment; **, P < 0.05 compared with OVX only group. Figure 3. The representative hematoxylin-eosin staining of coronary section of soleus muscle in light microscope images of hematoxylin-eosin stained section of soleus muscle. Sham operated (Sham) only rats (A) showed most intact and dense morphology of the muscle (A). Sham with LT4 treatment (B) or OVX OVX without LT4 treatment (C) showed disorganized and muscle fibers and widen- ing change of the interstitium compared with Sham group (A). OVX + LT4 rats (D) showed most significant decreased muscle volume, sparsely distributed muscle fibers and widened interstitium of soleus muscle. ageof60years.Sarcopeniaisdefinedasthelossof inflammatory cytokines, CRP, IL-6 and IL-10 were sig- nificantly elevated in the OVX groups compared with skeletal muscle mass and is associated with frailty and the Sham groups. LT4 treatment increased IL-6 levels immobility (Morley et al. 2014;Ooff rd andWitham in both Sham and OVXgroups (Table 2). 2017).Thepathogenesisofsarcopeniaiscausedbysev- eral intrinsic and extrinsic factors, including hormonal changes, nutritional status, oxidative stress, mitochon- Discussion drial dysfunction, insulin resistance, and proinflam- matory cytokine accumulation (Balagopal et al. 1997; The aging process is associated with the development Waters and Baumgartner 2011;Morleyetal. 2014; of chronic diseases and inflammation, which induces Cawthon et al. 2015; Dutra et al. 2017). a decline in function of physiological systems includ- Patients diagnosed with WDTC receive lifelong ing age-related sarcopenia (Licastro et al. 2005). The TSH suppression with LT4, followed by total thy- occurrence rate of age-related sarcopenia is up to 10% roidectomy with excellent prognosis. However, there per decade after 50 years of age and 5-15% after the 104 JA. YOON ET AL. Table 2. Effects of ovariectomy and LT4 treatment on cholesterol level and proinflammatory markers. Sham Sham + LT4 OVX OVX + LT4 a,b a,b Cholesterol (mg/dl)* 126.02 (120.96–139.03) 130.97 (120.29–145.04) 148.59 (144.01–159.91) 140.72 (133.53–144.70) a a a,c Creatinine kinase (U/L)* 71.13 (49.75–89.19) 22.85 (15.83–36.32) 29.01 (23.10–38.25) 17.32 (13.36–27.73) a a a C-reactive peptide (ng/ml)* 65.4 (43.98–144.89) 285.50 (90.50–575.40) 326.00 (213.50–349.40) 334.35 (137.72–518.40) Interleukin-1β 6.10 (3.94–9.51) 8.49 (6.76–13.46) 5.42 (3.65–6.49) 6.80 (2.55–10.82) Interleukin-4 17.24 (16.94–18.14) 17.53 (16.96–18.14) 18.14 (17.11–19.01) 19.32 (17.84–20.47) a a a,c Interleukin-6* 83.23 (79.56–86.90) 90.55 (86.90–90.55) 97.99 (31.473–107.25) 109.11 (105.39–110.99) a a Interleukin-10* 0.69 (0.74–1.26) 0.75 (0.65–1.49) 10.99 (3.27–14.57) 2.68 (1.12–6.24) MCP-1 1323.56 (1236.91–1752.64) 1464.45 (1295.06–1517.52) 1317.50 (1293.28–1459.71) 1571.32 (1463.38–1817.14) TNF-α 23.53 (18.13–32.73) 24.58 (18.31–36.40) 25.35 (22.62–32.73) 25.33 (24.44–37.33) OVX, ovariectomy; Sham, Sham-operation; MCP-1, Monocyte chemoattractant protein-1; TNF-α, Tumor Necrosis Factor-α. Variables are expressed as the median (interquartile range). *, P < 0.05, for comparison among four groups using Kruskal-Wallis test; a, P < 0.01 compared with the sham only operation group; b, P < 0.01, compared with Sham with LT4 treatment; c, P < 0.01 compared with OVX only group. have been growing concerns regarding adverse effects Compared with the Sham groups, the OVX groups inducedbytheTSHsuppressivetherapy.Thisismainly showed significantly increased levels of serum choles- because the suppressive dose of LT4 used for prevent- terol, which reduced after additional treatment, albeit ing growth of thyroid cancer has been reported to without showing a statistically significant difference. cause an adverse effect on several organs (Biondi and This result is partly consistent with clinical results Cooper 2010). The aim of this study was to evaluate the that showed no significant difference in the lipid pro- eeff ctofovariectomyon fatmassvariation andmuscle file between low TSH and euthyroidism groups of alterations and examine the additional effects of TSH menopausal women, although patients with TSH sup- suppressive therapy. pression showed lower cholesterol level during follow We observed a significant weight gain in ovariec- up (Heemstra et al. 2006). tomized rats compared with controls. In accordance This study revealed that OVX animals with or with- out LT4 treatment showed higher levels of inflamma- with the literature (Lizcano and Guzman 2014), the tory markers, including CRP, IL-6, and IL-10. IL-6 and majority of weight gain was a result of increased fat mass that was concentrated in the trunk area of the TNF-α were significantly associated with lower mus- ovariectomized rats. Nowadays, a concept of the com- cle and lower muscle strength in a large cohort of older bination ofreducedornochangeofmusclemasswith men and women (Visser et al. 2002). Previous reports increased fat volume, known as obesity-related sar- postulated that the age-related body composition alter- copenia or sarcopenic obesity has emerged (Waters ations are associated with chronic inflammatory con- and Baumgartner 2011). In our study, the weight gain ditionandislinkedtopro-inflammatory cytokines, was mainly due to increased fat mass in trunk area which are extensively produced by adipocytes (Visser was different between the OVX groups and Sham et al. 2002;Cesarietal. 2005;Limaetal. 2009). Few groups regardless of the TSH suppressive therapy. The studies reported that age-related body composition reduced lean body mass and increased fat mass in OVX alterations including progression of sarcopenia are rats might indicate that menopause induces obesity- mediated by prolonged inflammation that is mainly related sarcopenic changes. attributed to aggravation of muscle loss. These are evi- Although total mass increased, we did not find a sig- denced by significant correlations between loss of mus- nificant change in the lean body mass, and the decreas- cle mass and pro-inflammatory cytokines and related ing trend of lean mass in the extremities due to TSH parameters (Visser et al. 2002;PhillipsandPerry 2013; suppressive LT4 treatment using DXA. However, we Dutra et al. 2017). Reduced and weakened muscle quality in meno- confirmed that enlargement of CSA and FD induced pause state is inevitable because estrogen functions to by ovariectomy and these results are concordant with previous studies (Pighon et al. 2010;NgoSocket al. resolve the inflammatory response and to accelerate 2013). In the studies performed Ngo Sock et al. and muscle healing through proliferation and activation Pighonetal., OVXinducedincreased in legmuscleof of themusclefibersatellite cells(Enns andTiidus the rats, which was speculated to be an adaptation to 2008). The postmenopausal period shows marked ele- body weight gain induced by ovariectomy. vated levels of inflammatory indexes, such as IL-6, ALL LIFE 105 TNF- α and IL-1 (Weitzmann and Pacifici 2006). It atherosclerosis and cardiovascular disease (Zhu et al. is assumed that inflammatory markers increase with 2018). advancing age and age-related inflammation could be In conclusion, TSH suppression and estrogen defi- involved in the pathogenesis of incident cardiovas- ciency could result in the accumulation of harmful cular disease and mortality (Rea et al. 2018). In this eeff cts in the progression of obesity-related sarcopenia, regard, age-associated changes in body composition however, the underlying mechanism for menopause – might be aeff cted by markers of inflammation such as and TSH suppression therapy-associated loss of skele- IL-6, TNF-α,and CRP(Walrandetal. 2011). tal muscle and changes in body composition is com- In addition, there was significant change of the plex. The results of our study have clinical implications increased interstitial space based on the histologic for considering TSH suppressive therapy as a latent analysis which means the deteriorated quality of mus- riskfactor foroverall survival.Wepropose that body clefiberand thelower levelofCKinserumwhich composition and muscular function need to be eval- implies the systemic sarcopenia with suppressive LT uated in menopausal patients being considered for treatment in both OVX and Sham groups. The sig- long-term TSH-suppressive therapy. nificanthighserum levelofIL-6inLT4 treatment groups suggested that more inflammatory condition Acknowledgement could induce the histologic change in the skeletal mus- The levothyroxine sodium hydrate were generously provided cle. The elevated level of inflammatory cytokines in by Bukwang Pharmaceutical (South Korea). OVX + LT4 group indirectly suggests that menopause and TSH suppressive therapy might raise the risk of Disclosure statement obesity related sarcopenia. Ourfindings showed thatthechangeinbodycom- No potential conflict of interest was reported by the author(s). position, characterized as a combination of no signif- icantchangeofmusclemassandexcess body fat,was Funding associated with elevated inflammatory markers, which This research was supported by the Bio & Medical Technology was associated with sarcopenic obesity-related phe- Development Program of the National Research Foundation notypes in postmenopausal women. The significant (NRF) [grant number NRF-2018R1D1A1B07050719] funded differences in histological changes with inflammatory by the Korean Government (MSIT). parameter were higher in the groups of LT4 treatment in our study. In addition, these results reflect that TSH References suppressive condition could further induce proinflam- Abellanvan KanG. 2009 Oct. 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