A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters

2005 ◽  
Vol 289 (1) ◽  
pp. E75-E81 ◽  
Author(s):  
Robin P. Peeters ◽  
Annewieke W. van den Beld ◽  
Hayat Attalki ◽  
Hans van Toor ◽  
Yolanda B. de Rijke ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Blood Donors ◽  
Muscle Size ◽  
Dependent Manner ◽  
Type Ii ◽  
Elderly Men ◽  
Similar Frequency ◽  
Dose Dependent ◽  
Tsh Levels

Type II deiodinase (D2) is important in the regulation of local thyroid hormone bioactivity in certain tissues. D2 in skeletal muscle may also play a role in serum triiodothyronine (T3) production. In this study, we identified a polymorphism in the 5′-UTR of the D2 gene (D2-ORFa-Gly3Asp). We investigated the association of D2-ORFa-Gly3Asp, and of the previously identified D2-Thr92Ala polymorphism, with serum iodothyronine levels. D2-ORFa-Gly3Asp was identified by sequencing the 5′-UTR of 15 randomly selected individuals. Genotypes for D2-ORFa-Gly3Asp were determined in 156 healthy blood donors (age 46.3 ± 12.2 yr) and 349 ambulant elderly men (age 77.7 ± 3.5 yr) and related to serum iodothyronine and TSH levels. D2-ORFa-Asp3had an allele frequency of 33.9% in blood bank donors and was associated with serum thyroxine (T4; Gly/Gly vs. Gly/Asp vs. Asp/Asp = 7.06 ± 0.14 vs. 6.74 ± 0.15 vs. 6.29 ± 0.27 μg/dl, P = 0.01), free T4(1.22 ± 0.02 vs. 1.16 ± 0.02 vs. 1.06 ± 0.04 ng/dl, P = 0.001), reverse T3( P = 0.01), and T3/T4ratio ( P = 0.002) in a dose-dependent manner, but not with serum T3( P = 0.59). In elderly men, D2-ORFa-Asp3had a similar frequency but was not associated with serum iodothyronine levels. This new polymorphism in the 5′-UTR of D2 is associated with iodothyronine levels in blood donors but not in elderly men. We hypothesize that this might be explained by the decline in skeletal muscle size during aging, resulting in a relative decrease in the contribution of D2 to serum T3production.

scholarly journals Effect of lemon peel flavonoids on anti-fatigue and anti-oxidation capacities of exhaustive exercise mice

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Guili Bao ◽  
Yinglong Zhang ◽  
Xiaoguang Yang
Keyword(s):  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Manganese Superoxide Dismutase ◽  
Fatty Acid Content ◽  
Hepatic Tissue ◽  
Control Group ◽  
Dependent Manner ◽  
Lemon Peel ◽  
Tnf Α ◽  
Dose Dependent

AbstractIn this study, lemon peel flavonoids (LPF) were administered to investigate its effect on the anti-fatigue and antioxidant capacity of mice that undergo exercise until exhaustion. LPF (88.36 min in LPFH group mice) significantly increased the exhaustion swimming time compare to the untreated mice (40.36 min), increased the liver glycogen and free fatty acid content in mice and reduce lactic acid and BUN content in a dose-dependent manner. As the concentration of lemon peel flavonoids increased, the serum creatine kinase, aspartate aminotransferase, and alanine aminotransferase levels of mice gradually decreased. LPF increases superoxide dismutase (SOD) and catalase (CAT) levels in mice and reduces malondialdehyde levels in a dose-dependent manner. And LPF raises hepatic tissue SOD, CAT activities and reduces skeletal muscle tissue iNOS, TNF-α levels of mice compared to the control group. LPF also enhanced the expression of copper/zinc-superoxide dismutase (Cu/Zn-SOD), manganese-superoxide dismutase (Mn-SOD), and CAT mRNA in mouse liver tissue. LPF also enhanced the expression of alanine/serine/cysteine/threonine transporter 1 (ASCT1) mRNA and attenuate the expression of syncytin-1, inducible nitric oxide synthase (iNOS), and tumor necrosis factor (TNF)-α in mouse skeletal muscle. According to high-performance liquid chromatography (HPLC) analysis, it was found that LPF contains flavonoids such as rutin, astragalin, isomangiferin, naringin, and quercetin. Our experimental data show that LPF has good anti-fatigue effects and anti-oxidation ability. In summary, LPF has high prospects to be developed and added to nutritional supplements.

AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle

2001 ◽  
Vol 280 (5) ◽  
pp. E677-E684 ◽  
Author(s):  
Nicolas Musi ◽  
Tatsuya Hayashi ◽  
Nobuharu Fujii ◽  
Michael F. Hirshman ◽  
Lee A. Witters ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Muscle Contractions ◽  
Treadmill Running ◽  
Dependent Manner ◽  
Rat Skeletal Muscle ◽  
Amp Activated Protein Kinase ◽  
Dose Dependent

The AMP-activated protein kinase (AMPK) has been hypothesized to mediate contraction and 5-aminoimidazole-4-carboxamide 1-β-d-ribonucleoside (AICAR)-induced increases in glucose uptake in skeletal muscle. The purpose of the current study was to determine whether treadmill exercise and isolated muscle contractions in rat skeletal muscle increase the activity of the AMPKα1 and AMPKα2 catalytic subunits in a dose-dependent manner and to evaluate the effects of the putative AMPK inhibitors adenine 9-β-d-arabinofuranoside (ara-A), 8-bromo-AMP, and iodotubercidin on AMPK activity and 3- O-methyl-d-glucose (3-MG) uptake. There were dose-dependent increases in AMPKα2 activity and 3-MG uptake in rat epitrochlearis muscles with treadmill running exercise but no effect of exercise on AMPKα1 activity. Tetanic contractions of isolated epitrochlearis muscles in vitro significantly increased the activity of both AMPK isoforms in a dose-dependent manner and at a similar rate compared with increases in 3-MG uptake. In isolated muscles, the putative AMPK inhibitors ara-A, 8-bromo-AMP, and iodotubercidin fully inhibited AICAR-stimulated AMPKα2 activity and 3-MG uptake but had little effect on AMPKα1 activity. In contrast, these compounds had absent or minimal effects on contraction-stimulated AMPKα1 and -α2 activity and 3-MG uptake. Although the AMPKα1 and -α2 isoforms are activated during tetanic muscle contractions in vitro, in fast-glycolytic fibers, the activation of AMPKα2-containing complexes may be more important in regulating exercise-mediated skeletal muscle metabolism in vivo. Development of new compounds will be required to study contraction regulation of AMPK by pharmacological inhibition.

L(+)-Lactate Binding to a Protein in Rat Skeletal Muscle Plasma Membranes

1995 ◽  
Vol 20 (1) ◽  
pp. 112-124 ◽  
Author(s):  
Karl J. A. McCullagh ◽  
Arend Bonen
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membranes ◽  
Mass Range ◽  
Dependent Manner ◽  
Rat Skeletal Muscle ◽  
Lactate Transport ◽  
Sds Page ◽  
Lactate And Pyruvate ◽  
Potential Inhibitors ◽  
Dose Dependent

Biochemical studies were conducted to determine the location of a putative lactate transport protein in rat skeletal muscle plasma membranes (PM). PM (50-100 μg protein) were incubated with [U-14C] L(+)-lactate, in the presence or absence of unlabeled monocarboxylates or potential inhibitors, after which proteins were separated by SDS-PAGE. Gel slices (2 mm) were cut and analyzed for14C. [U-14C] L(+)-lactate was bound to plasma membranes in the 30 to 40 kDa molecular mass range. Binding of [U-14C] L(+)-lactate was inhibited by N-ethylmaleimide, unlabeled L-lactate and pyruvate, and in a dose dependent manner by α-cyano-4-hydroxycinnamate (r = 0.995), but not by cytochalasin-B. The inhibition of [U-14C] L(+)-lactate binding was similar to the inhibition of lactate transport. Therefore the transport of L(+)-lactate across skeletal muscle plasma membranes involves a polypeptide of 30 to 40 kDa. Key words: transport, affinity labeling

scholarly journals Thyroid Hormone Stimulation of Autophagy Is Essential for Mitochondrial Biogenesis and Activity in Skeletal Muscle

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 23-38 ◽  
Author(s):  
Ronny Lesmana ◽  
Rohit A. Sinha ◽  
Brijesh K. Singh ◽  
Jin Zhou ◽  
Kenji Ohba ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Protein Kinase ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Protein ◽  
Adenosine Monophosphate ◽  
Mitochondrial Activity ◽  
Dependent Manner ◽  
In Vivo Models ◽  
Stimulation Of

Abstract Thyroid hormone (TH) and autophagy share similar functions in regulating skeletal muscle growth, regeneration, and differentiation. Although TH recently has been shown to increase autophagy in liver, the regulation and role of autophagy by this hormone in skeletal muscle is not known. Here, using both in vitro and in vivo models, we demonstrated that TH induces autophagy in a dose- and time-dependent manner in skeletal muscle. TH induction of autophagy involved reactive oxygen species (ROS) stimulation of 5′adenosine monophosphate-activated protein kinase (AMPK)-Mammalian target of rapamycin (mTOR)- Unc-51-like kinase 1 (Ulk1) signaling. TH also increased mRNA and protein expression of key autophagy genes, microtubule-associated protein light chain 3 (LC3), Sequestosome 1 (p62), and Ulk1, as well as genes that modulated autophagy and Forkhead box O (FOXO) 1/3a. TH increased mitochondrial protein synthesis and number as well as basal mitochondrial O2 consumption, ATP turnover, and maximal respiratory capacity. Surprisingly, mitochondrial activity and biogenesis were blunted when autophagy was blocked in muscle cells by Autophagy-related gene (Atg)5 short hairpin RNA (shRNA). Induction of ROS and 5′adenosine monophosphate-activated protein kinase (AMPK) by TH played a significant role in the up-regulation of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), the key regulator of mitochondrial synthesis. In summary, our findings showed that TH-mediated autophagy was essential for stimulation of mitochondrial biogenesis and activity in skeletal muscle. Moreover, autophagy and mitochondrial biogenesis were coupled in skeletal muscle via TH induction of mitochondrial activity and ROS generation.

scholarly journals Evidence that insulin and guanosine triphosphate regulate dephosphorylation of the β-subunit of the insulin receptor in sarcolemma membranes isolated from skeletal muscle

1986 ◽  
Vol 234 (3) ◽  
pp. 527-535 ◽  
Author(s):  
R S Horn ◽  
E Lystad ◽  
A Adler ◽  
O Walaas
Keyword(s):  
Skeletal Muscle ◽  
Membrane Protein ◽  
Insulin Receptor ◽  
Beta Subunit ◽  
Regulatory Proteins ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Insulin Effect ◽  
Phosphoamino Acid Analysis ◽  
Dose Dependent

When sarcolemma membranes isolated from rat skeletal muscle were incubated with [gamma-32P]ATP, a membrane protein of apparent Mr 95,000 was rapidly phosphorylated, with the 32P content reaching a maximum within 2 s. On the basis of immunoprecipitation with anti-insulin-receptor antiserum, phosphoamino acid analysis and Mr, this protein probably represents the beta-subunit of the insulin receptor. Similarly, on incubation of the membrane with adenosine 5′-[gamma-[35S]thio] triphosphate the 95 kDa protein was thiophosphorylated, indicating thiophosphorylation of the beta-subunit of the insulin receptor on the basis of immunoprecipitation studies. The effect of insulin on the phosphorylation of this protein in the membrane was studied. Insulin induced a 20% decrease in the 32P labelling of the protein when the membranes were phosphorylated for 10 s. This insulin effect was dose-dependent, with half-maximal effect obtained at 2-3 nM-insulin. Addition of GTP, but not GDP or guanosine 5′-[beta, gamma-imido]triphosphate, enhanced the effect to 35% inhibition, with half-maximal effect of GTP obtained at 0.5 microM. GTP had no effect on the phosphorylation of the protein in the absence of insulin. Analysis of this insulin effect showed that insulin increased the rate of dephosphorylation of the 95 kDa protein in the membrane. In contrast, insulin had no effect on thiophosphorylation of the 95 kDa membrane protein after incubation with adenosine 5′-[gamma-[35S]thio]triphosphate. Since thiophosphorylated proteins are less sensitive to phosphatase action, these investigations suggest that insulin stimulated a protein phosphatase activity in a GTP-dependent manner. The possibility that GTP-regulatory proteins are involved in the action of insulin on the phosphorylation of the insulin receptor and other membrane proteins is discussed.

scholarly journals Chronic Stress During Adolescence Blunts the Exercise-Induced Expression of Thyroid Hormone-Target Genes in Metabolically Active Tissues of Male and Female Rats

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A974-A974
Author(s):  
Marco Antonio Parra-Montes de Oca ◽  
Karen Lissette Garduño-Morales ◽  
Patricia Joseph-Bravo
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Chronic Stress ◽  
Voluntary Exercise ◽  
Female Rats ◽  
Dependent Manner ◽  
Male And Female ◽  
Male And Female Rats ◽  
Exercise Induced ◽  
Hpt Axis

Abstract Voluntary exercise activates HPT axis1, that contributes to energy mobilization and energy expenditure. Chronic stress in adulthood inhibits HPT response to voluntary wheel running in a sex dependent manner, inhibiting lipolysis of WAT2. We evaluated the effect of chronic stress during adolescence on HPT axis response to voluntary exercise in adulthood3, with emphasis on metabolic response in skeletal muscle and WAT. Wistar male and female rats (N=36 per sex) were divided in an undisturbed group (Control, C; n=18) and one chronic variable stress during adolescence group (CVS; n=18) (males: PND 30-70; females: PND 30-60). As adults (males: PND 84; females: PND: 74) rats were divided in: 1) exercise group: rats placed individually in a cage with a running wheel per 14 nights, 2) sedentary group with ad libitum feeding, 3) sedentary pair-fed group offered the same amount of food consumed by the exercised group, and kept in individual cages during 14 nights (6 rats/group). WAT weight was determined at sacrifice, hormones quantified by RIA and ELISA, gene expression by RT-PCR. Exercise-induced loss of fat mass was not detected in CVS rats. Exercise decreased corticosterone levels in C males and females of both treatments, supporting sex difference on HPA axis reprogramming by CVS. HPT axis response to voluntary exercise is attenuated by CVS also in a sex dimorphic manner: CVS decreased Trh expression in hypothalamic paraventricular nucleus and no changes in thyroid hormones concentration in males, whereas in females, slightly increased TSH, T4 and T3 levels. Sex also influenced the response of skeletal muscle and WAT to CVS. Dio2 and Pgc1a slightly increased expression in skeletal muscle of males, not of females. Adrb3 expression in WAT increased in females, but not in males; exercise-induced stimulation of Hsl expression was not observed in either sex after CVS. These results suggest that CVS imposed during rat adolescence inhibits the responses to voluntary exercise of HPT axis activity of thyroid hormone-targets in WAT and skeletal muscle in sex dependent manner. These changes could lead to reduced mobilization and the utilization of energy fuels coincident with the fatigue observed after exercise in patients with subclinical or clinical hypothyroidism. (Funded: CONACYT 284883, DGAPA IN213419)1Uribe, Endocrinology 155:2020-2030, 2014.2Parra, Front Endocrinol 10(418):1-13, 2019.3Parra, J Endocr Soc 4(Abstract Supp) Abstract SAT-451, 2020.

In Vitro Activity of a Novel Fully Human Anti-CD40 Antibody CHIR-12.12 in Chronic Lymphocytic Leukemia: Blockade of CD40 Activation and Induction of ADCC.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2504-2504 ◽  
Author(s):  
Xia Tong ◽  
Georgios V. Georgakis ◽  
Long Li ◽  
O’Brien Susan ◽  
Younes Anas ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Line ◽  
Blood Donors ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Dose Dependent

Abstract B-cell chronic lymphocytic leukemia (CLL) is characterized by in vivo accumulation of long-lived CD5+ B cells. However when cultured in vitro CLL cells die quickly by apoptosis. Protection from apoptosis in vivo is believed to result from supply of survival signals provided by cells in the microenvironment. We and others have previously reported that CLL cells express CD40 receptor, and that CD40 stimulation of CLL cells may rescue CLL cells from spontaneous and drug-induced apoptosis in vitro. These observations suggested that blocking CD40-CD40L pathway might deprive CLL cells from survival signals and induce apoptosis. To test this hypothesis, we have generated a fully human anti-CD40 blocking monoclonal antibody in XenoMousemice (Abgenix, Inc.). The antibody CHIR-12.12 was first evaluated for its effect on normal human lymphocytes. Lymphocytes from all 10 healthy blood donors did not proliferate in response to CHIR-12.12 at any concentration tested (0.0001 mg/ml to 10 mg/ml range). In contrast, activating CD40 on normal B-lymphocytes by CD40L induced their proliferation in vitro. Importantly, CHIR-12.12 inhibited CD40L- induced proliferation in a dose dependent manner with an average IC50 of 51 ± 26 pM (n=10 blood donors). The antagonistic activity of CHIR-12.12 was then tested in primary CLL samples from 9 patients. CHIR-12.12 alone did not induce CLL cell proliferation. In contrast, primary CLL cells incubated with CD40L, either resisted spontaneous cell death or proliferated. This effect was reversed by co-incubation with CHIR-12.12 antibody, restoring CLL cell death (n=9). CHIR-12.12 was then examined for its ability to lyse CLL cell line EHEB by antibody dependent cell mediated cytotoxicity (ADCC). Freshly isolated human NK cells from normal volunteer blood donors were used as effector cells. CHIR-12.12 showed lysis activity in a dose dependent manner and produced maximum lysis levels at 0.1 mg/ml. When compared with rituximab, CHIR-12.12 mediated greater maximum specific lysis (27.2 % Vs 16.2 %, p= 0.007). The greater ADCC by CHIR-12.12 was not due to higher density of CD40 molecules on CLL cell line compared to CD20 molecules. The CLL target cells expressed 509053 ±13560 CD20 molecules compared to 48416 ± 584 CD40 molecules. Collectively, these preclinical data suggest that CHIR-12.12 monoclonal antibody may have a therapeutic role in patients with CLL.

scholarly journals Regulation of thyroid hormone activation via the liver X-receptor/retinoid X-receptor pathway

2010 ◽  
Vol 205 (2) ◽  
pp. 179-186 ◽  
Author(s):  
Marcelo A Christoffolete ◽  
Márton Doleschall ◽  
Péter Egri ◽  
Zsolt Liposits ◽  
Ann Marie Zavacki ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Liver X Receptor ◽  
Retinoid X Receptor ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Diet Induced Obesity ◽  
Ectopic Liver ◽  
Dose Dependent

Thyroid hormone receptor (TR) and liver X-receptor (LXR) are the master regulators of lipid metabolism. Remarkably, a mouse with a targeted deletion of both LXRα and LXRβ is resistant to western diet-induced obesity, and exhibits ectopic liver expression of the thyroid hormone activating type 2 deiodinase (D2). We hypothesized that LXR/retinoid X-receptor (RXR) signaling inhibits hepatic D2 expression, and studied this using a luciferase reporter containing the human DIO2 (hDIO2) promoter in HepG2 cells. Given that, in contrast to mammals, the chicken liver normally expresses D2, the chicken DIO2 (cDIO2) promoter was also studied. 22(R)-OH-cholesterol negatively regulated hDIO2 in a dose-dependent manner (100 μM, approximately twofold), while it failed to affect the cDIO2 promoter. Truncations in the hDIO2 promoter identified the region −901 to −584 bp as critical for negative regulation. We also investigated if 9-cis retinoic acid (9-cis RA), the ligand for the heterodimeric partner of TR and LXR, RXR, could regulate the hDIO2 promoter. Notably, 9-cis RA repressed the hDIO2 luciferase reporter (1 μM, approximately fourfold) in a dose-dependent manner, while coexpression of an inactive mutant RXR abolished this effect. However, it is unlikely that RXR homodimers mediate the repression of hDIO2 since mutagenesis of a DR-1 at −506 bp did not interfere with 9-cis RA-mediated repression. Our data indicate that hDIO2 transcription is negatively regulated by both 22(R)-OH-cholesterol and 9-cis RA, which is consistent with LXR/RXR involvement. In vivo, the inhibition of D2-mediated tri-iodothyronine (T3) production by cholesterol/9-cis RA could function as a feedback loop, given that T3 decreases hepatic cholesterol levels.

Effects of Insulin on Glucose Metabolism in Skeletal Muscle from Septic and Endotoxaemic Rats

1989 ◽  
Vol 77 (1) ◽  
pp. 61-67 ◽  
Author(s):  
Brendan Leighton ◽  
George D. Dimitriadis ◽  
Mark Parry-Billings ◽  
Jane Bond ◽  
Paulo R. L. de Vasconcelos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Soleus Muscle ◽  
Glycogen Synthesis ◽  
Dependent Manner ◽  
H 26 ◽  
Lactate Formation ◽  
Dose Dependent

1. The effects of non-lethal bacteraemia or endotoxaemia on insulin-stimulated glucose metabolism were studied in isolated, incubated soleus muscle of rats after 24 and 48 h. 2. The insulin-stimulated rates of lactate formation and glycogen synthesis were similar in muscles isolated from control and bacteraemic rats. 3. Endotoxaemia increased the rates of lactate formation, at all levels of insulin, both at 24 h (∼ 32%) and 48 h (∼ 26%). Endotoxaemia did not alter the sensitivity of glycolysis to insulin. 4. Endotoxaemia decreased the rates of glycogen synthesis at all concentrations of insulin both at 24 h (∼ 39%) and 48 h (∼ 23%). 5. The increase in the rate of glycolysis was related in a dose-dependent manner to the amount of endotoxin given to the animals. 6. Endotoxaemia decreased plasma tri-iodothyronine levels (41%). However, the effects of endotoxaemia (48 h) on glucose metabolism in muscle are similar to those caused by hyperthyroidism. In hypothyroid rats, endotoxin administration increased the rates of glycolysis in muscle in vitro. 7. It is concluded that there are enhanced basal and insulin-stimulated rates of glycolysis in soleus muscle from endotoxaemic rats. This may be due to both increased glucose transport and decreased glycogen synthesis.

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