Aberrant expression of thyroidal hormone receptor α exasperating mitochondrial dysfunction induced sarcopenia in aged mice.

Disrupted mitochondrial dynamics and mitophagy contribute to functional deterioration of skeletal muscle (SM) during aging, but the regulatory mechanisms are poorly understood. Our previous study demonstrated that the expression of thyroid hormone receptor α (TRα) decreased significantly in aged mice, suggesting that the alteration of thyroidal elements, especially the decreased TRα, might attenuate local THs action thus to cause the degeneration of SM with aging, while the underlying mechanism remains to be further explored. In this study, decreased expression of myogenic regulators Myf5, MyoD1, mitophagy markers Pink1, LC3II/I, p62, as well as mitochondrial dynamic factors Mfn1 and Opa1, accompanied by increased reactive oxygen species (ROS), showed concomitant changes with reduced TRα expression in aged mice. Further TRα loss- and gain-of-function studies in C2C12 revealed that silencing of TRα not only down-regulated the expression of above-mentioned myogenic regulators, mitophagy markers and mitochondrial dynamic factors, but also led to a significant decrease in mitochondrial activity and maximum respiratory capacity, as well as more mitochondrial ROS and damaged mitochondria. Notedly, overexpression of TRα could up-regulate the expression of those myogenic regulators, mitophagy markers and mitochondrial dynamic factors, meanwhile also led to an increase in mitochondrial activity and number. These results confirmed that TRα could concertedly regulate mitochondrial dynamics, autophagy, and activity, and myogenic regulators rhythmically altered with TRα expression. Summarily, these results suggested that the decline of TRα might cause the degeneration of SM with aging by regulating mitochondrial dynamics, mitophagy and myogenesis.

TT3, a More Practical Indicator for Evaluating the Relationship Between Sarcopenia and Thyroid Hormone in the Euthyroid Elderly Compared with FT3.

Background and Aims: Sarcopenia is a common disease in the elderly, and the thyroid hormone (TH) might participate in the pathogenesis of sarcopenia. However, the results of previous studies were not completely consistent. We performed this study to investigate the association between THs and sarcopenia in a Chinese elderly euthyroid population. Subjects and Methods: A total of 309 Chinese elderly euthyroid subjects with an average age of 85.19 ± 7.8 years were enrolled. Participants were divided into four groups (non-sarcopenia, possible sarcopenia, sarcopenia and serve sarcopenia) according to the consensus update of AWGS in 2019. Serum levels of TT3, FT3, TT4, FT4, TSH, rT3 and TBG were measured. Muscle mass was measured by multifrequency bioelectrical impedance analysis, hand grip (HG) was represented by spring-type dynamometer, and gait speed (GS) was determined by 6-metre walk test. The FRAIL scale was used to assess frailty. Results: Compared to the non-sarcopenia group, the sarcopenia group showed a significant increase in age and FRIAL score, while FT3 and TT3 levels decreased significantly. Partial correlation analysis (adjusted by age, gender and the scores of FRIAL scale) indicated that FT3, TT3 and TSH had significant positive correlations with HG, and there also was a significant positive correlation between TT3 and GS. In addition, after adjusting for age, gender, BMI, ALT, sCr, and score on the FRAIL scale, the multivariate linear regression analysis showed that TT3 was positively associated with muscle strength and negatively associated with sarcopenia risk. Conclusion: There is an association between the low TT3 level and sarcopenia. Therefore, maintaining higher T3 concentrations within the normal range appears to be beneficial for sarcopenia in the elderly. In addition, due to the fluctuation of FT3, TT3 is a more stable and practical indicator to evaluate the relationship between sarcopenia and thyroid hormone in the elderly euthyroid population.

Distinct response of adipocyte progenitors to glucocorticoids determines visceral obesity via the TEAD1-miR-27b-PRDM16 axis.

OBJECTIVE: Visceral obesity contributes to obesity-related complications; however, the intrinsic mechanism of depot-specific adipose tissue behavior remains unclear. Despite the pro-adipogenesis role of glucocorticoids (GCs) in adipogenesis, the role of GCs in visceral adiposity rather than in subcutaneous adipose tissue is not established. Because adipocyte progenitors display a striking depot-specific pattern, the regulatory pathways of novel progenitor subtypes within different depots remain unclear. This study describes a cell-specific mechanism underlying visceral adiposity. METHODS: A diverse panel of novel depot-specific adipose progenitors was screened in mice and human samples. The transcriptome distinction and various responses of novel progenitor subtypes of GCs were further measured using the GC receptor-chromatin immunoprecipitation assay and RNA sequencing. The mechanism of novel subtypes was identified using transposase-accessible chromatin analysis and bisulfite sequencing and further confirmed using precise editing of CpG methylation. RESULTS: Platelet-derived growth factor receptor α (PDGFRα+ ) progenitors, which were dominant in the visceral adipose tissue, were GC-sensitive beige adipose progenitors, whereas CD137+ progenitors, which were dominant in the subcutaneous adipose tissue, were GC-passive beige adipose progenitors. Expression of miR-27b, an inhibitor of adipocyte browning, was significantly increased in PDGFRα+ progenitors treated with GCs. Using transposase-accessible chromatin analysis, bisulfite sequencing, and precise editing of CpG methylation, TEA domain transcription factor 1 (TEAD1) was discovered to be uniquely hypomethylated in PDGFRα+ progenitors. CONCLUSIONS: GCs inhibited the PDGFRα+ progenitors' browning process via miR-27b, which was transcriptionally activated by the collaboration of TEAD1 with the GC receptor. These data provide insights into the mechanism of depot-specific variations in high-fat diet-induced obesity.

2,3',4,4',5-Pentachlorobiphenyl induced thyroid dysfunction by increasing mitochondrial oxidative stress.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) and are associated with thyroid diseases. Our previous study reported that 2,3',4,4',5-Pentachlorobiphenyl (PCB118) could induce thyroid dysfunction and the rat thyroid tissues exhibit abnormal mitochondrial ultrastructure. However, the more specific effects of PCB118 on mitochondria and the relationship between mitochondria and thyroid dysfunction remain unclear. In this study, Wistar rats were injected with PCB118 intraperitoneally at 0, 10, 100, and 1000 µg/kg/d for 13 weeks and FRTL-5 rat thyroid cells were treated with PCB118 (0, 0.25, 2.5, and 25 nM) for 24 hr, which did not influence the general conditions of rats and FRTL-5 cells viability. The detection of serum levels of thyroid hormones (THs) and the expression of sodium/iodide symporter (NIS) protein demonstrated that thyroid function was impaired after PCB118 exposure. Transmission electron microscopy showed mitochondrial damage in the thyroids of PCB118-treated rats. Biological processes analysis revealed that differentially expressed mRNAs in thyroid tissues induced by PCB118 were enriched in reactive oxygen species (ROS) metabolic process, hydrogen peroxide metabolic process, and hydrogen peroxide catabolic process. Moreover, mRNA expression of mitochondrial respiratory chain genes NDUFB3, UQCRC2, COX17, ATP5I and ATP5E decreased in PCB118-treated groups. In vivo and in vitro data showed that ROS production increased significantly after PCB118 exposure, accompanied by increased levels of phospho-c-Jun N-terminal kinase (P-JNK). Taken together, these results suggest that PCB118 could damage mitochondria by increasing oxidative stress and PCB118-induced thyroid dysfunction may be related to ROS-dependent activation of the JNK pathway.

Muscle Strength, but Not Muscle Mass, Is Associated with Left Ventricular Diastolic Function during Aging in Chinese.

Sarcopenia, a progressive and systemic skeletal muscle disorder, is closely related with the incidence of cardiovascular disease (CVD) and CVD-related mortality, but its association with cardiac structure and function during aging remains unclear, particularly in the absence of serious cardiovascular diseases. This study aimed to investigate the correlation of muscle mass and muscle strength, the main components of sarcopenia, with left ventricular mass and function in Chinese subjects.A total of 265 men and 70 women (aged 25-95 years) without serious diseases that could have pronounced impact on muscle and/or cardiovascular system were included. Left ventricular mass and function were assessed by echocardiography and muscle mass and grip strength were evaluated by dual-energy X-ray absorptiometry and a Jamar hand dynamometer, respectively.Grip strength and left ventricular diastolic function, rather than left ventricular mass, demonstrated age-dependent decline in both genders. Muscle mass in males and left ventricular systolic function in females declined with age. In the multivariate-adjusted model, grip strength rather than the relative appendicular skeletal muscle mass (RASM) was positively associated with E/A ratio (r = 0.154, P = 0.019) and e´-av (r = 0.175, P = 0.008), but was negatively correlated with E/e´-av ratio (r = -0.136, P = 0.038). No significant correlation was observed between RASM, grip strength and left ventricular mass, left ventricular ejection fraction or left ventricular fractional shortening. Higher grip strength is independently associated with better left ventricular diastolic function in Chinese during aging.

Estrogen supplementation deteriorates visceral adipose function in aged postmenopausal subjects via Gas5 targeting IGF2BP1.

Increased visceral fat is strongly associated with a series of metabolic complications. Postmenopausal women have an increased risk of visceral fat accumulation, metabolic disorders, and a high incidence of cardiovascular events. However, the effect of estrogen replacement therapy on visceral adipose tissue among postmenopausal women of different ages remains controversial, and the underlying mechanism remains unclear. Hence, it is important to understand when estrogen replacement therapy affects the function of visceral adipose tissue (VAT). Therefore, we collected VAT from pre- and post-menopausal females and we observed increased pro-inflammatory cytokines and insulin resistance-inducing factors, decreased insulin-sensitizing factors, and thermogenic factors in VAT of postmenopausal women. The analysis of adipocytes isolated from the VAT of females of different ages indicated that adiponectin and browning signature genes were significantly decreased with estrogen treatment in postmenopausal women, but were not altered in the young group. Estrogen supplementation in aged female mice (22 m) significantly prevented visceral fat accumulation. However, it deteriorated VAT function by inducing pro-inflammatory cytokines and insulin resistance-inducing factors and decreasing insulin-sensitizing and thermogenic factors. Mechanistically, estrogen induced the expression of long non-coding RNA Gas5 via binding ERα in premenopausal women, which therefore suppressed IGF2BP1 to maintain VAT function. After menopause, with the reversal of ERα/ERß ratio in VAT, estrogen supplementation mainly worked through ERß, which led to low expression levels of Gas5 and eventually caused VAT dysfunction. Our study demonstrated the adverse effects of estrogen supplementation on VAT function in aged postmenopausal population and further elucidated the involved mechanism.

2,3',4,4',5-Pentachlorobiphenyl attenuated fast-twitch fibers and fiber size of skeletal muscle via disturbing thyroid hormone signaling and mitochondrial dynamics.

Polychlorinated biphenyls (PCBs) affect multiple organs, and some of the effects are mediated by interfering with thyroid hormone (TH) signaling that regulates physiological processes in mammals. It remains unclear how PCBs affect skeletal muscle (SM). In our study, wistar rats were injected 2,3',4,4',5-pentachlorobiphenyl (PCB118) intraperitoneally at 0, 10, 100, and 1000 µg/kg/day for 13 weeks, and C2C12 myoblasts were treated PCB118 (0, 0.25, 25, and 50 nM) for 24 h or 48 h. We found that myocyte cross-sectional area (MCSA) was reduced, MyHC IIa and MyHC IIb mRNA levels significantly decreased, and muscle strength was weakened in PCB118-exposed rats. TH receptor α (TRα) and iodothyronine deiodinase type 2 (DIO2) were upregulated after PCB118 exposure both in vivo and in vitro. Transmission electron microscopy showed significant mitochondrial abnormalities in PCB118-treated rats, and the expression of mitochondrial regulators such as PTEN-induced kinase 1 (PINK1) and GTPase dynamin-related protein 1 (DRP1) were altered after PCB118 exposure. These results suggest that PCB118 could weaken muscle strength and attenuate fast-twitch fibers and fiber size of SM in rats. TH signaling, mitochondrial dynamics and mitophagy were also disturbed by PCB118, which may contribute to the alternations of SM structure and function.

Metabolic syndrome and its association with components of sarcopenia in older community-dwelling Chinese.

Aging and obesity contribute to muscle dysfunction. This study aimed to determine the cross-sectional associations between components of metabolic syndrome (MetS) and sarcopenia in 251 older community-dwelling Chinese. The total fat-free mass was measured by dual-energy X-ray absorptiometry, muscle strength (handgrip strength) by a handheld dynamometer, physical performance by 4-meter walk, 5-time chair stand test, and the short physical performance battery (SPPB). MetS was defined using the International Diabetes Federation (IDF) criteria. The participants with MetS had a higher appendicular skeletal muscle mass (ASM) and relative ASM (RASM). The males with MetS had higher handgrip strength, and the females with MetS had higher SPPB scores. After adjusting for age and body mass index, the participants with an increased waist circumference had a higher ASM, and those with increased diastolic blood pressure (DBP) also had higher handgrip strength. The males with elevated fasting blood glucose (FBG) levels had a lower gait speed. Components of MetS, such as DPB and FBG, were associated with muscle strength and physical performance in older adults. These results suggest that muscle strength and function should be considered in treating older adults with MetS.

Mechanism of thyroid hormone signaling in skeletal muscle of aging mice.

BACKGROUND AND AIM: Skeletal muscle (SM) has been shown as a target of thyroid hormones (THs). However, the status of TH signaling in aged SM remains unclear. This study aimed to explore the mechanism of TH signaling in SM of aging mice. METHODS: Thirty C57BL/6J male mice were divided into 6-, 15- and 22-month (6, 15 and 22M) groups according to different age. Physical parameters were evaluated by analytical balance, grip strength test and histological analysis. Thyroid function was detected by enzyme-linked immunosorbent assay. TH signaling was compared among the three groups by real-time PCR and western blotting analysis. RESULTS: p16, p21, and p53 mRNA levels in SM increased in age-dependent manner. The muscle weight and strength decreased in 22M group compared to 6 and 15M groups. Concentrations of thyroid hormones, including free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) in 22 M mice were not shown significant difference compared to 6M or 15M mice, although FT3 showed slightly decrease and TSH appeared a mild increase accompanying with age. mRNA levels of TH transporters, including MCT8 and MCT10, as well as iodothyronine deiodinase type 2 (DIO2) and type 3 (DIO3), were higher in 22M, while TH receptor α (TRα) mRNA and protein expression was lower in 22M, compared to the other groups. Type-I myosin heavy chain (MyHC I), MyHC IIx, and MyHC IIa were upregulated and Type-IIb MyHC (MyHC IIb) was downregulated in SM with advancing age. CONCLUSIONS: TH signaling in SM changes with aging.

Differential Responses of White Adipose Tissue and Brown Adipose Tissue to Calorie Restriction During Aging.

Age-related adipose tissue dysfunction is potentially important in the development of insulin resistance and metabolic disorder. Caloric restriction (CR) is a robust intervention to reduce adiposity, improve metabolic health, and extend healthy life span. Both white adipose tissue (WAT) and brown adipose tissue (BAT) are involved in energy homeostasis. CR triggers the beiging of WAT in young mice; however, the effects of CR on beiging of WAT and function of BAT during aging are unclear. This study aimed to investigate how age and CR impact the beiging of WAT, the function of BAT, and metabolic health in mice. C57BL/6 mice were fed CR diet (40% less than the ad libitum [AL] diet) for 3 months initiated in young (3 months), middle-aged (12 months), and old (19 months) stage. We found age-related changes in different types of adipose tissue, including adipocyte enlargement, declined beiging of WAT, and declined thermogenic and ß-oxidational function of BAT. Moreover, CR attenuated age-associated adipocyte enlargement and prevented the age-related decline in beiging potential of WAT. These protective effects on the beiging potential were significant in inguinal WAT at all three ages, which were significant in epididymal WAT at young and old age. In contrast, thermogenic and ß-oxidational function of BAT further declined after CR in the young age group. In conclusion, our findings reveal the contribution of WAT beiging decline to age-related metabolic disorder and suggest nutritional intervention, specifically targeting WAT beiging, as an effective approach to metabolic health during aging.

Improvement of intestinal stem cells and barrier function via energy restriction in middle-aged C57BL/6 mice.

This study aimed to reveal the impact of energy restriction on the intestine via structural and molecular changes in terms of intestinal stem cell (ISC) function, ISC niche, intestinal epithelial barrier function, and intestinal immune function. Female C57BL/6J mice, aged 12 months, fed a commercial chow were used in this study. The ISC function, ISC niche, intestinal epithelial barrier function, and intestinal immune function were assessed. Energy restriction reversed aging-induced intestinal shortening and made the crypts shallower. The intestinal epithelial cells isolated from the intestine showed a significant increase in the expression levels of stem cell-associated genes in small intestinal epithelial cells as detected by flow cytometry. Despite the increase in the number of stem cells and the expression levels of markers, no increase or decrease was found in the enteroid complexity of the small intestine and colonic enteroid formation in vitro. The colonic mucous layer was measured in mice of the energy restricted (ER)-treated group to investigate the epithelial barrier function in the colon. The results revealed that the barrier was more complete. The fluorescence intensity of tight junction markers claudin-2 and zonula occludens-1 increased and the mRNA expression profiles of monocyte chemotactic protein 1 and interleukin-6 decreased in the colon of mice in the ER-treated group. The beneficial effects of ER on the colon in terms of the integrity of the mucosal barrier and alleviation of inflammation were confirmed, thus highlighting the importance of modulating the intestinal function in developing effective antiaging dietary interventions.

2,3',4,4',5-Pentachlorobiphenyl Induced Thyrocyte Autophagy by Promoting Calcium Influx via Store-Operated Ca2+ Entry.

PCB118, a 2,3',4,4',5-pentachlorobiphenyl, has been shown to destroy thyroidal ultrastructure and induce thyrocyte autophagy. Previously, we reported that PCB118 promoted autophagosome formation in vivo and in vitro, but more details remain to be revealed. To explore the underlying mechanism by which PCB118 regulates thyrocyte autophagy, Fischer rat thyroid cell line-5 (FRTL-5) cells were exposed to different doses of PCB118 at 0, 0.25, 2.5, and 25 nM for 0-48 h. Western blot analysis of autophagy-related proteins P62, BECLIN1, and LC3 demonstrated that PCB118 induced autophagy formation in dose- and time-dependent manner. Moreover, laser scanning confocal microscopy and flow cytometry showed PCB118 treatment led to time- and dose-dependent increase in intracellular calcium concentration ([Ca2+]i). Additionally, PCB118 promoted store-operated Ca2+ entry (SOCE) channel followed by significant increase of ORAI1 and STIM1 protein levels. On the other hand, PCB118 induced thyroidal autophagy via class III ß-tubulin (TUBB3)/death-associated protein kinase 2 (DAPK2)/myosin regulatory light chain (MRLC)/autophagy-related 9A (ATG9A) pathway in FRTL-5 cells. Pretreatment with SOCE inhibitor SKF96365 reduced cytosolic Ca2+, ORAI1, STIM1, and BECLIN1 levels as well as LC3 II/LC3 I ratio, while increased P62 expression. SKF96365 also inhibited TUBB3/DAPK2/MRLC/ATG9A pathway in FRTL-5 cells treated by PCB118. Our results provide evidence that PCB118 may induce thyroidal autophagy through TUBB3-related signaling pathway, and these effects are likely to be regulated by calcium influx via SOCE channel.

Correlation of sarcopenia and depressive mood in older community dwellers: a cross-sectional observational study in China.

OBJECTIVE: Whether sarcopenia is detrimental to depression is still controversial, which may be due to the three components of the sarcopenia. Our objective was to define the correlation between depression and sarcopenia in older Chinese community dwellers. DESIGN: The study has a cross-sectional design. SETTING: The study was conducted in Jiangsu, China. PARTICIPANTS: A total of 101 men and 149 women aged 60 years or older were recruited. OUTCOME MEASURES: Lean tissue mass was measured by dual-energy X-ray absorptiometry. Muscle strength in the upper and lower limbs was measured by a handheld dynamometer and a chair stand test, respectively. Physical performance was assessed by gait speed and standing balance tests. Depressive mood was assessed using the Geriatric Depression Scale-30 (range 0-30). RESULTS: Participants in the sarcopenia group had a higher mean depression score than the normal group (p=0.002). Pearson's correlation analysis showed that depression was negatively associated with muscle strength (handgrip strength: R=-0.170, p=0.028 for women, R=-0.196, p=0.048 for men; chair stand test performance: R=0.252, p=0.002 for women, R=0.311, p=0.001 for men) and physical performance (gait speed: R=-0.200, p=0.009, standing balance test performance: R=-0.224, p=0.006, Short Physical Performance Battery (SPPB): R=-0.218, p=0.007 for women; SPPB: R=-0.252, p=0.01 for men). Multiple linear regression models revealed that depressive mood was inversely associated with chair stand test (ß=0.325, p<0.001), gait speed (ß=-0.009, p=0.041) and standing balance test (ß=-0.24, p=0.016) after adjusting for confounding factors, while no significant correlation was observed between depressive mood and muscle mass. CONCLUSION: The diagnostic components of sarcopenia-strength of the leg muscles (chair stand test) and physical performance (gait speed and standing balance test)-were associated with depressive mood.

Impact of a high­fat diet on intestinal stem cells and epithelial barrier function in middle­aged female mice.

A high­fat diet (HFD) or obesity­promoting diet is closely associated with metabolic diseases and intestinal tumors, particularly in middle­aged individuals (typically 45­64 years old). The intestinal epithelium constitutes a barrier that separates the host from the food and microbiota in the gut, and thus, a dysfunctional epithelium is associated with a number of diseases. However, the changes caused to the function of intestinal epithelium in response to an HFD have not been well­studied to date. In the present study, middle­aged female mice (12 months old) fed an HFD for a period of 14 weeks were used to determine the effects of HFD on the intestine. Characteristics including the body weight, fat deposition, glucose metabolism, inflammatory state and intestinal morphology were assessed, while the intestinal stem cell (ISC) counts and the ability of isolated intestinal crypts to form organoid bodies in 3D culture were examined. Intestinal epithelial barrier function, including secretory defense, tight junctions and cell apoptosis, were also studied. Morphologically, the HFD resulted in a mild reduction in the length of villi of the small intestine, the colon length and the depth of colon crypts. In addition, the ISC counts were increased in the small intestine and colon in HFD­fed mice. The ability of crypts to grow into organoids (mini­guts) was also increased in crypts obtained from mice fed an HFD, while HFD compromised the epithelial barrier function of the colon. These results demonstrated how an HFD affects the intestinal epithelium and highlighted the need to carefully consider dietary patterns.

Bone mineral density and trabecular bone score in Chinese subjects with sarcopenia.

BACKGROUND: As the general population is aging worldwide, the incidence of sarcopenia and osteoporosis is also rapidly increasing. Studies have found the link between sarcopenia and osteoporosis, but the relationship between sarcopenia and osteoporosis, especially bone microarchitecture, remains unclear. AIMS: To investigate the relationship between components of sarcopenia (muscle mass, handgrip strength, and gait speed) and components of osteoporosis [bone mass measured by bone mineral density (BMD) and bone microarchitecture measured by trabecular bone score (TBS)] in Chinese subjects. METHODS: 318 Chinese men and 203 Chinese women were included in our study. Muscle mass and BMD were measured by dual-energy X-ray absorptiometry (DXA). TBS iNsight® software was used for TBS. Jamar hydraulic hand dynamometer was used to assess muscle strength, and gait speed was used to assess physical performance. RESULTS: We found that the relative appendicular skeletal muscle mass (RASM) in both genders and handgrip strength in women correlated positively with TBS, RASM in men and handgrip strength in women correlated positively with BMDs. In the multiple linear regression model, RASM was positively associated with TBS in both genders, but no significant association was observed between RASM and BMDs. Interestingly, handgrip strength showed positive association with all evaluated BMDs and TBS in women, but not in men. Women with sarcopenia had lower TBS and BMDs at all evaluated sites. Men with sarcopenia had lower BMDs only at femur neck and total hip. CONCLUSIONS: The reduction of muscle mass and strength was significantly associated with decreased bone mass and deteriorated bone microarchitecture. More importantly, low muscle mass is an independent risk factor for bone microarchitecture in Chinese subjects.

The correlation of muscle thickness and pennation angle assessed by ultrasound with sarcopenia in elderly Chinese community dwellers.

Background: Sarcopenia is typically defined as the loss of muscle mass, strength and low physical performance with aging. Ultrasound is a safe and easy method for evaluating muscle mass and quality by muscle thickness (MT) and pennation angle (PA), respectively. Although the positive correlations between MT and muscle mass and handgrip strength were observed, the relationship between MT, PA and physical performance remains unclear. Purpose: This study aimed to investigate the correlation of aforementioned ultrasound parameters with muscle mass, muscle strength and physical performance and explore the utility of ultrasound in predicting sarcopenia. Patients and methods: A total of 265 elderly Chinese community dwellers were included. MT of both forearm and lower leg as well as PA of gastrocnemius was assessed by ultrasound. Muscle mass was assessed by dual-energy X-ray absorptiometry. Muscle strength was measured by a Jamar hand dynamometer. Physical performance was assessed by the Short Physical Performance Battery (SPPB). Results: Anterior radial MT in men and regional MTs except posterior fibula in women were negatively correlated with the age. No significant correlation was observed between PA and the age in both genders. Posterior tibial MT and posterior fibula MT were positively correlated with the relative appendicular skeletal muscle mass in men and women, respectively. Anterior ulnar MT was positively correlated with grip strength in both genders. Moreover, gastrocnemius medialis PA showed a positive association with gait speed and SPPB in women but not in men. Conclusion: A combination of posterior fibula MT, anterior ulnar MT and gastrocnemius medialis PA measured by muscle ultrasound is helpful for the assessment of sarcopenia in Chinese elderly women. In addition, a combination of posterior tibial MT and anterior ulnar MT measured by muscle ultrasound is helpful for the assessment of sarcopenia in Chinese elderly men.

2,3',4,4',5-Pentachlorobiphenyl induced autophagy of the thyrocytes via DAPK2/PKD/VPS34 pathway.

2,3',4,4',5-Pentachlorobiphenyl (PCB118) has been shown to cause thyroidal ultrastructure lesions, but the underlying mechanism remains elusive. This study aimed to elucidate the mechanism by which PCB118 induces the abnormalities of the thyrocytes. Wistar rats were injected intraperitoneally with PCB118 (0, 10, 100 and 1000 µg/kg/d) for 13 weeks, and FRTL-5 cells were treated with PCB118 (0, 0.25, 2.5 and 25 nM). Transmission electron microscopy showed typical autophagosomes in the thyroid of PCB118-treated rats. Immunofluorescence staining showed dose-dependent increase of autophagy in FRTL-5 cells exposed to PCB118. In vivo and vitro studies found that Tubulin beta 3 class III (Tubb3) mRNA and protein levels decreased significantly, while Death-associated protein kinase 2 (DAPK2) increased after PCB118 exposure, and the binding between Tubb3 and DAPK2 was enhanced by PCB118 in a dose-dependent manner. Moreover, PCB118 resulted in the upregulation of Protein kinase D (PKD) and downregulation of Phosphatidylinositol 3-kinase (VPS34) in mRNA levels, and the activation of PKD and VPS34 phosphorylation. Additionally, Tubb3 small interfering RNA (siTubb3) suppressed DAPK2 protein expression and PKD phosphorylation in FRTL-5 cells, while VPS34 phosphorylation was inhibited by siPKD. Furthermore, DAPK2, PKD and VPS34 were upregulated by Tubb3 overexpression following PCB118 exposure. Our results demonstrate that low concentrations of PCB118 could promote thyroid autophagy formation and cause the abnormalities in thyroidal ultrastructure, and these effects are likely to be mediated by DAPK2/PKD/VPS34 dependent pathway.

MiR-27b-3p Inhibition Enhances Browning of Epididymal Fat in High-Fat Diet Induced Obese Mice.

Objective: Long-term dysregulation of energy balance is the key component of the obesity epidemic. Given the harm of central obesity and the discovery that beige cells appear within white adipose tissue (WAT), enhancing the energy-expending or "browning" ability of visceral adipose tissue (VAT) has become of therapeutic interest. In this study, we focused on the regulating role of microRNA (miRNA)-27b-3p in mice epididymal white adipose tissue (eWAT) browning. Methods: High-fat diet (HFD) induced obese mice model was constructed. Expression of miR-27b-3p and Ucp1 in eWAT was measured during the course of HFD. Through tail vein injection of antimiR-27b-3p, miR-27b-3p expression was inhibited to analyze the potential role of miR-27b-3p in fat browning and metabolism. Results: miR-27b-3p was predominantly expressed in eWAT and browning ability of eWAT in HFD induced obese mice was impaired. Inhibition of miR-27b-3p enhanced browning capacity of eWAT in mice fed an HFD and led to weight loss and insulin sensitivity improvement. Conclusions: High expression of miR-27b-3p in eWAT inhibits browning ability and leads to visceral fat accumulation. It is suggested miR-27b-3p may become a potential therapeutic option for visceral obesity and its associated diseases.

A High Efficient Method to Isolate Exosomes from Small Intestinal Epithelium.

The intestinal epithelium is an important receptor that is not only exposed to nutrients but also to pathogens, such as ingested toxins, bacterial flora, and their metabolites. The sensory information is communicated to extensive endocrine, neural, immune systems, and the exosomes acts as carriers of communication from cell-to-cell. Isolation of exosomes from small intestinal epithelium remains more complex to obtain as a source of exosomes, as it contains varying proportions of exosomes derived from many different cells. Current studies on exosomes have been largely performed using supernatants of cultured cells. This is because, in a cell culture, the origin of exosomes can be determined and isolation of exosomes devoid of 'contaminating' proteins, lipids, and sugars involves relatively simple composition of most culture media facilitates. However, this is hard to achieve in intestinal epithelial cells (IECs) due to several technical issues, including recapitulation of in vivo physiology, operational simplicity, culture stability over time, and assay throughput. Meanwhile, separation of exosomes from a specific cell type remains to be a considerable problem, as the isolated supernatant exosomal fraction may represent only a small fraction of the total instead of reflecting the overall situation. Herein, we proposed an efficient protocol for enrichment of exosomes from the interstitial space of small intestinal epithelium. This method maintains the integrity of the vesicles as well as their contents. Also, it may help to better understand the properties of exosomes and explore their role in cell-to-cell communication of small intestinal epithelium.

Association of thyroid function with sarcopenia in elderly Chinese euthyroid subjects.

OBJECTIVES: With the increase in aging population worldwide, the incidence of sarcopenia is also increasing. Thyroid hormones are important regulators that can affect body composition and physical function. The association between thyroid hormone levels and sarcopenia in susceptible elderly euthyroid subjects remains unclear. In this study, we investigated the effect of thyroid hormone concentrations on body muscle mass, muscle strength and physical function related to sarcopenia in elderly Chinese euthyroid subjects. METHODS: A total of 94 elderly Chinese euthyroid subjects (73 men, 21 women) without medications or diseases which obviously affected muscle metabolism or thyroid function were included in our study. Concentrations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were determined by immunoassays. Appendicular skeletal muscle mass (ASM) was assessed by dual-energy X-ray absorptiometry. Handgrip strength was measured using a Jamar hand dynamometer, and physical function was assessed by the Short Physical Performance Battery (SPPB). RESULTS: Muscle function, both handgrip strength and SPPB, was negatively associated with age, and FT3 demonstrated age-dependent decline. Pearson's correlation analysis showed positive associations of FT3 with ASM, handgrip strength and SPPB. Neither FT4 nor TSH was associated with these parameters of sarcopenia in euthyroid subjects. Significantly positive correlations between FT3 and ASM, handgrip strength and SPPB were also observed in multiple linear regression analysis adjusted for age, gender and BMI, while no significant correlations were found between FT4 or TSH and aforementioned four parameters of sarcopenia. Subjects with sarcopenia had lower level of FT3. CONCLUSIONS: Higher FT3 concentration within normal range was correlated to muscle mass and muscle function in elderly subjects.