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.

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.

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.

11ß-hydroxysteroid dehydrogenase type 1 inhibitor attenuates high-fat diet induced cardiomyopathy.

BACKGROUND: High-fat diet (HFD) induces cardiac hypertrophy; however, the underlying cellular and molecular mechanisms are yet unclear. In the present study, we investigated the roles of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an amplifier of local glucocorticoid activity, in the pathogenesis of cardiac dysfunction. METHODS: Male Wistar rats were fed normal chow diet (NC) or HFD and examined the cardiac remolding and functional alteration by echocardiography and histology. Primary neonatal rat ventricular cardiomyocytes (NRCMs) treated with palmitic acid (PA) or infected by lentivirus were used for identifying the role by 11ß-HSD1 in cardiac hypertrophy. Genome microarray of NRCMs was performed to further reveal the mechanism underlying cardiac dysfunction. RESULTS: Palmitic acid induced hypertrophy in NRCMs that upregulated 11ß-HSD1 expression in cardiomyocytes, which led to a significant enlargement in the cell size and expression of cardiac hypertrophy-specific genes. Conversely, a remarkable decrease in cardiomyocytes size was detected in either BVT.2733 (a selective inhibitor of 11ß-HSD1)-treated or 11ß-HSD1-deficient NRCMs. Furthermore, both glucocorticoid receptor (GR) antagonist RU486 and mineralocorticoid receptor (MR) antagonist spironolactone markedly attenuated the 11ß-HSD1-induced cardiomyocytes hypertrophy. Genome microarray revealed that cAMP and calcium signaling pathways are potential downstream signaling pathways regulated by 11ß-HSD1 in cardiomyocytes hypertrophy. Similar to in vitro results, BVT.2733 strikingly attenuated cardiac hypertrophy and improved cardiac function in HFD-fed rats. CONCLUSION: 11ß-HSD1 acts as an important regulator that controls the cardiac remolding via both GR and MR and the pharmacological inhibition of 11ß-HSD1 could be a new therapeutic approach in preventing HFD-induced cardiac hypertrophy.

Molecular mechanisms of human thyrocyte dysfunction induced by low concentrations of polychlorinated biphenyl 118 through the Akt/FoxO3a/NIS pathway.

Polychlorinated biphenyls (PCBs) are typical persistent organic pollutants that can interfere with multiple organ systems of humans. Previously, we concluded that persistent exposure to low doses of PCB118 could severely damage the thyroidal structure, dramatically decrease the concentration of serum thyroid hormones and inhibit the pivotal gene expressions such as sodium/iodide symporter (NIS) and thyroglobulin (Tg). To explore the molecular mechanisms of thyrocyte dysfunction induced by 2,3',4,4',5-pentachlorobiphenyl (PCB118), monolayer cultured human thyroid epithelial cells (HTECs) were treated with PCB118 or dimethyl sulfoxide (DMSO) as a control. Our results indicated that relatively higher concentrations of PCB118 could induce a loss in the viability of HTEC. In cultures with concentrations of PCB118 from 0.025 to 25 nM, which did not affect cell viability or apoptosis, concentrations of Tg and thyroxine (T(4)) were significantly decreased compared with those in the controls. In addition, mRNA and protein levels of Akt were increased significantly in the PCB118-treated groups, whereas FoxO3a expression did not show particular variation. Furthermore, exposure to PCB118 was associated with a significant increase of the protein levels of p-Akt and p-FoxO3a, and these effects were blocked by LY294002. In contrast, mRNA and protein expression levels of NIS were decreased significantly, and this effect was blocked by LY294002. Unlike control cells, a cytoplasmic shift of FoxO3a was observed in the PCB118-treated group. Our research suggests that PCB118 may induce thyrocyte dysfunction through the Akt/FoxO3a/NIS signalling pathway, which provides potential new insights for finding interventions to counteract the damage to the human body caused by PCBs.

The abnormal phenotypes of cartilage and bone in calcium-sensing receptor deficient mice are dependent on the actions of calcium, phosphorus, and PTH.

Patients with neonatal severe hyperparathyroidism (NSHPT) are homozygous for the calcium-sensing receptor (CaR) mutation and have very high circulating PTH, abundant parathyroid hyperplasia, and severe life-threatening hypercalcemia. Mice with homozygous deletion of CaR mimic the syndrome of NSHPT. To determine effects of CaR deficiency on skeletal development and interactions between CaR and 1,25(OH)(2)D(3) or PTH on calcium and skeletal homeostasis, we compared the skeletal phenotypes of homozygous CaR-deficient (CaR(-/-)) mice to those of double homozygous CaR- and 1α(OH)ase-deficient [CaR(-/-)1α(OH)ase(-/-)] mice or those of double homozygous CaR- and PTH-deficient [CaR(-/-)PTH(-/-)] mice at 2 weeks of age. Compared to wild-type littermates, CaR(-/-) mice had hypercalcemia, hypophosphatemia, hyperparathyroidism, and severe skeletal growth retardation. Chondrocyte proliferation and PTHrP expression in growth plates were reduced significantly, whereas trabecular volume, osteoblast number, osteocalcin-positive areas, expression of the ALP, type I collagen, osteocalcin genes, and serum ALP levels were increased significantly. Deletion of 1α(OH)ase in CaR(-/-) mice resulted in a longer lifespan, normocalcemia, lower serum phosphorus, greater elevation in PTH, slight improvement in skeletal growth with increased chondrocyte proliferation and PTHrP expression, and further increases in indices of osteoblastic bone formation. Deletion of PTH in CaR(-/-) mice resulted in rescue of early lethality, normocalcemia, increased serum phosphorus, undetectable serum PTH, normalization in skeletal growth with normal chondrocyte proliferation and enhanced PTHrP expression, and dramatic decreases in indices of osteoblastic bone formation. Our results indicate that reductions in hypercalcemia play a critical role in preventing the early lethality of CaR(-/-) mice and that defects in endochondral bone formation in CaR(-/-) mice result from effects of the marked elevation in serum calcium concentration and the decreases in serum phosphorus concentration and skeletal PTHrP levels, whereas the increased osteoblastic bone formation results from direct effects of PTH.

Serum metabolome and gut microbiome alterations are associated with low handgrip strength in older adults.

Handgrip strength (HGS), which represents global muscle strength, is a powerful indicator of disability and mortality in older adults; it is also used for the diagnosis of possible- or probable- sarcopenia and physical frailty. This study aimed to explore the metabolic mechanisms and potential biomarkers associated with declining HGS among older adults. We recruited 15 age- and environment-matched inpatients (age, 77-90 years) with low or normal HGS. Liquid chromatography-mass spectrometry (LC-MS) and 16S ribosomal DNA (rDNA) gene sequencing were performed to analyze the metabolome of serum and stool samples and the gut microbiome composition of stool samples. Spearman's correlation analysis was used to identify the potential serum and fecal metabolites associated with HGS. We assessed the levels of serum and fecal metabolites belonging to the class of cinnamic acids and derivatives and reported that the levels of carboxylic acids and their derivatives decreased in the low-HGS group. Serum levels of microbial metabolites, including cinnamoylglycine, 4-methoxycinnamic acid, and (e)-3,4,5-trimethoxycinnamic acid, were positively correlated with HGS. We found that gut microbial α-diversity was significantly higher in the low-HGS group, whereas higher ß-diversity was observed in the normal group. The relative abundances of the genera Parabacteroides and Intestinibacter increased significantly in the low-HGS group and were negatively correlated with the serum levels of cinnamoylglycine. The identified metabolites whose levels were markedly altered, and intestinal flora associated with these metabolites suggest the potential metabolic underpinnings for HGS and provide a basis for the further identification of biomarkers of muscle strength decline in older adults.

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.

11ß-Hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction.

Pharmacologic glucocorticoids (GCs) inhibit osteoblast function and induce osteoporosis. 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) may play a role in osteoporosis as it regulates GC action at a pre-receptor level by converting inactive GC to its active form. Further, 11ß-HSD1 was found increasingly expressed in bone with age. In spite of these observations, its function in senile osteoporosis remains uncertain. In this study we constructed a lentiviral vector overexpressing mouse 11ß-HSD1 and then MC3T3-E1 preosteoblast cells were infected by the negative control lentivirus and 11ß-HSD1-overexpressing lentivirus, respectively. The mRNA and protein levels of 11ß-HSD1 were significantly increased in MC3T3-E1 cells that were infected by 11ß-HSD1-overexpressing lentivirus compared to the cells infected by the negative control lentivirus. The osteogenic differentiation of MC3T3-E1 preosteoblast cells was dramatically suppressed by 11ß-HSD1 overexpression under the reductase substrate dehydrocorticosterone (DHC). The inhibition effect was similar to the inhibition of osteogenesis by over-dose GCs, including ALP activity, the ultimate calcium nodus formation as well as the expression of the osteogenic genes such as ALP, BSP, OPN and OCN. However, with addition of BVT.2733, a selective inhibitor of 11ß-HSD1, all of the above osteogenic repression effects by 11ß-HSD1 overexpression were reversed. Furthermore, a GC receptor antagonist RU486 also showed the similar effect, preventing inhibition of osteogenesis by 11ß-HSD1 overexpression. These results demonstrated that the specific 11ß-HSD1 inhibitor BVT.2733 can reverse the suppression effect towards osteogenic differentiation in 11ß-HSD1 overexpressed MC3T3-E1 cells. Inhibition of 11ß-HSD1 can be a new therapeutic strategy for senile osteoporosis.

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.

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.

Essential role of ERK activation in neurite outgrowth induced by α-lipoic acid.

BACKGROUND: Neurite outgrowth is an important aspect of neuronal plasticity and regeneration after neuronal injury. Alpha-lipoic acid (LA) has been used as a therapeutic approach for a variety of neural disorders. We recently reported that LA prevents local anesthetics-induced neurite loss. In this study, we hypothesized that LA administration promotes neurite outgrowth. METHODS: To test our hypothesis, we treated mouse neuroblastoma N2a cells and primary neurons with LA. Neurite outgrowth was evaluated by examination of morphological changes and by immunocytochemistry for ß-tubulin-3. ROS production was examined, as were the phosphorylation levels of ERK and Akt. In separate experiments, we determined the effects of the inhibition of ERK or PI3K/Akt as well as ROS production on LA-induced neurite outgrowth. RESULTS: LA promoted significantly neurite outgrowth in a time- and concentration-dependent manner. LA stimulation significantly increased the phosphorylation levels of both Akt and ERK and transiently induced ROS production. PI3K/Akt inhibition did not affect LA-induced neurite outgrowth. However, the inhibition of ERK activation completely abolished LA-induced neurite outgrowth. Importantly, the prevention of ROS production by antioxidants attenuated LA-stimulated ERK activation and completely abolished LA-promoted neurite outgrowth. CONCLUSION: Our data suggest that LA stimulates neurite outgrowth through the activation of ERK signaling, an effect mediated through a ROS-dependent mechanism. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

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.

Frailty's Prevalence and the Association with Aging-Related Health Conditions in Chinese Community Dwelling Elderly.

In this paper, we have investigated the frailty's prevalence and the association with aging-related health conditions in Chinese community dwelling elderly aged ≥60 years in Lianyungang City of China. In this regard, participants were 1,072 adults aged ≥60 years from Houhe Community of Lianyungang City of China. All the enrolled participants were tested for following parameters: (1) the related risk factors of frailty: including economic status, personal health, understanding and communication skills, and mental and psychological status; (2) aging-related health conditions related to frailty: Charlson's comorbidity index (CCI), Mini Nutritional Assessment Short Form (MNA-SF), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder 7-item (GAD-7); (3) body composition, physical strength, and function testing: appendicular skeletal muscle mass index (ASMI), grip strength, five-repetition sit-to-stand test, 6 m walking speed, and strength assistance rise-climb-fall (SARC-F); (4) assessment of the degree and severity of frailty: physical frailty phenotype (PFP), Morse fall scale (MFS), and activities of daily living (ADL). The frailty's prevalence among the elderly aged ≥60 years in the community of Lianyungang City was 13.8%, 55.4% were prefrail, and 30.8% were robust. The independent risk factors of frailty were age, appendicular skeletal muscle mass index, sarcopenia, education, nutrition, and strength assistance rise-climb-fall (P < 0.05). Aging-related health conditions were associated with frailty, including sarcopenia, nutrition, and falls. However, mental and psychological statuses were not significantly associated with frailty.

Caloric restriction delays age-related muscle atrophy by inhibiting 11ß-HSD1 to promote the differentiation of muscle stem cells.

Introduction: Calorie restriction (CR) is an important direction for the delay of sarcopenia in elderly individuals. However, the specific mechanisms of CR against aging are still unclear. Methods: In this study, we used a CR model of elderly mice with muscle-specific 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) knockout mice and 11ß-HSD1 overexpression mice to confirm that CR can delay muscle aging by inhibiting 11ß-HSD1 which can transform inactive GC(cortisone) into active GC(cortisol). The ability of self-proliferation and differentiation into muscle fibers of these mouse muscle stem cells (MuSCs) was observed in vitro. Additionally, the mitochondrial function and mitochondrial ATP production capacity of MuSCs were measured by mitochondrial oxygen consumption. Results: It was found that the 11ß-HSD1 expression level was increased in age-related muscle atrophy. Overexpression of 11ß-HSD1 led to muscle atrophy in young mice, and 11ß-HSD1 knockout rescued age-related muscle atrophy. Moreover, CR in aged mice reduced the local effective concentration of glucocorticoid (GC) through 11ß-HSD1, thereby promoting the mitochondrial function and differentiation ability of MuSCs. Conclusions: Together, our findings highlight promising sarcopenia protection with 40% CR in older ages. Furthermore, we speculated that targeting an 11ß-HSD1-dependent metabolic pathway may represent a novel strategy for developing therapeutics against age-related muscle atrophy.

Application of Muscle Thickness and Quality Measured by Ultrasound in Frailty Assessment in China.

To explore the correlation between Fried Frailty Phenotype (FFP) and the muscle thickness and quality of local muscle, and to provide a reasonable basis for the application of ultrasound measurement in the frailty assessment. A total of 150 people (age ≥ 65 years, 58 women, 92 men) were included from the First Hospital Affiliated to Nanjing Medical University. They were divided into Normal group (40 cases), Prefrailty group (69 cases) and Frailty group (41 cases). The thickness and the quality of local muscle were detected by ultrasound. Participants in the prefrailty group had a higher grayscale value of the vastus lateralis muscle, indicating the deterioration of muscle quality. At the frailty stage, the muscle thickness and quality of the vastus lateralis muscle and the anterior tibialis muscle decreased significantly compared with the normal and the prefrailty group. Pearson's correlation analysis also showed FFP was negatively correlated with muscle thickness and quality of the lower limbs. In multiple regression model, FFP was positively associated with gray value (Vastus lateralis muscle:ß =0.457, p < 0.001; Anterior tibialis muscle: ß = 0.220, p = 0.037) and inversely associated with muscle thickness (Vastus lateralis muscle:ß = -0.973, p = 0.031; Anterior tibialis muscle: ß = -4.551, p = 0.004) in the frailty stage. Together, FFP was closely related to muscle thickness and quality, especially vastus lateralis muscle. Moreover, Muscle quality has deteriorated in the prefrailty stage, which is earlier than muscle thickness.

Distinct Serum and Fecal Metabolite Profiles Linking With Gut Microbiome in Older Adults With Frailty.

Frailty is a critical aging-related syndrome but the underlying metabolic mechanism remains poorly understood. The aim of this study was to identify novel biomarkers and reveal potential mechanisms of frailty based on the integrated analysis of metabolome and gut microbiome. In this study, twenty subjects consisted of five middle-aged adults and fifteen older adults, of which fifteen older subjects were divided into three groups: non-frail, pre-frail, and frail, with five subjects in each group. The presence of frailty, pre-frailty, or non-frailty was established according to the physical frailty phenotype (PFP). We applied non-targeted metabolomics to serum and feces samples and used 16S rDNA gene sequencing to detect the fecal microbiome. The associations between metabolites and gut microbiota were analyzed by the Spearman's correlation analysis. Serum metabolic shifts in frailty mainly included fatty acids and derivatives, carbohydrates, and monosaccharides. Most of the metabolites belonging to these classes increased in the serum of frail older adults. Propylparaben was found to gradually decrease in non-frail, pre-frail, and frail older adults. Distinct changes in fecal metabolite profiles and gut microbiota were also found among middle-aged adults, non-frail and frail older subjects. The relative abundance of Faecalibacteriu, Roseburia, and Fusicatenibacter decreased while the abundance of Parabacteroides and Bacteroides increased in frailty. The above altered microbes were associated with the changed serum metabolites in frailty, which included dodecanedioic acid, D-ribose, D-(-)-mannitol, creatine and indole, and their related fecal metabolites. The changed microbiome and related metabolites may be used as the biomarkers of frailty and is worthy of further mechanistic studies.

Age-Related Changes in Trabecular Bone Score and Bone Mineral Density in Chinese Men: A Cross-Sectional and Longitudinal Study.

Purpose: This study was designed to explore age-related changes in trabecular bone score (TBS) and bone mineral density (BMD) in Chinese men through cross-sectional and longitudinal studies. Patients and Methods: We included adult men who had at least twice TBS and BMD examinations in our hospital between January 2013 and December 2020. All men were divided into an age subgroup per 10 years, comparing differences in baseline lumbar spine (LS) TBS and BMD at various parts between each age group and analyzing age-related changes in TBS and BMD during follow-up. Results: Baseline data showed that in men aged 36 to 85 years, BMD in the hip region showed a decreasing trend with age (P for trend < 0.01). However, TBS reached a high value around the age of 50, after which it decreased with age (P for trend = 0.03). During a mean follow-up of 3 years, the average annual change rate at TBS was -0.17% in men aged 36 to 85 years, with the fastest decrease rate -1.08% at 66 to 75 years (P < 0.05). The mean annual rate of change in LS BMD in different age subgroups increased with age (P for trend = 0.001). There was no significant decrease in mean annual change in BMD in hip regions. Conclusion: In men aged 36~85 years, the trend of TBS was inconsistent with BMD. Men experience a high value of LS TBS around age 50, later than the commonly believed age of peak BMD, which may reflect developmental differences between bone microstructure and bone minerals. The TBS may be used as a better indicator of changes in bone strength than BMD in adult men at short-term follow-up. The rapid loss of TBS at age 66 to 75 may have implications for the prevention and medication of osteoporosis in men.

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.

Jwa participates the maintenance of intestinal epithelial homeostasis via ERK/FBXW7-mediated NOTCH1/PPARγ/STAT5 axis and acts as a novel putative aging related gene.

The intestinal epithelium is a rapid self-renewal and regenerated tissue of which the structural integrity is beneficial for maintaining health. The integrity of intestinal epithelium depends on the balance of cell proliferation, differentiation, migration, and the function of intestinal stem cells, which declines due to genetic defect or aging. Jwa participates in multiple cellular processes; it also responds to oxidative stress and repairs DNA damage. However, whether Jwa plays a role in maintaining the homeostasis of intestinal renewal and regeneration is not clear. In the present study, we firstly described that the deletion of Jwa disturbed the homeostasis of intestinal epithelial renewal and regeneration. Jwa deficiency promoted NOTCH1 degradation in the ERK/FBXW7-mediated ubiquitin-proteasome pathway, thus disturbing the PPARγ/STAT5 axis. These mechanisms might partially contribute to the reduction of intestinal stem cell function and alteration of intestinal epithelial cell lineage distribution, finally suppressing the renewal and regeneration of intestinal epithelium. Moreover, our results also revealed that Jwa was a novel putative aging related gene.