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Complete activation of thyroid hormone receptor ? by T3 is essential for normal cochlear function and morphology in mice.

ABSTRACT: BACKGROUND/AIMS:Thyroid hormones (THs) regulate many developmental processes, including the developmental onset of cochlear differentiation and function. TH action is mediated mostly by triiodothyronine (T3) bound to thyroid hormone nuclear receptors (TRs). At positive regulated genes and in the absence of THs, nuclear co-repressors are bound to TRs and decrease basal transcription rate. Ligand (T(3)) binding results in the dissociation of co-repressors and the recruitment of co-activators to the complex, which results in full transcriptional activation. METHODS:We measured cochlear function in two knock-in mouse models: TR?(E457A/E457A), with the TR? co-activator binding surface (AF-2) disrupted to prevent co-activator binding; and TR?(?337T/?337T), which is unable to bind T(3). Cochlear morphology and function were analyzed in 10-week-old normal and mutated mice. Cochlear function was determined by measuring auditory brainstem responses, cochlear tuning and compound action potential (CAP) thresholds. RESULTS:All TR?(?337T/?337T) and 85% of the TR?(E457A/E457A) mice presented elevated CAP thresholds (P < 0.05 or less). Five percent of the TR?(E457A/E457A) mice presented normal CAP thresholds with broadened cochlear tuning. TR?(E457A/E457A) and TR?(?337T/?337T) presented developmental defects that led to a decreased width (P < 0.01) and an increased thickness (P<0.01) of the tectorial membrane. In addition, TR?(?337T/?337T) animals showed an increased tectorial membrane area (P<0.01). CONCLUSION:Both mutations were deleterious to tectorial membrane development and led to important alterations in cochlear morphology and loss of cochlear function.

SUBMITTER: Richter CP

PROVIDER: S-EPMC3709180 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Complete activation of thyroid hormone receptor β by T3 is essential for normal cochlear function and morphology in mice.

Richter Claus-Peter CP Münscher Adrian A Machado Danielle Santana DS Wondisford Fredric E FE Ortiga-Carvalho Tania M TM

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 20111215 5

<h4>Background/aims</h4>Thyroid hormones (THs) regulate many developmental processes, including the developmental onset of cochlear differentiation and function. TH action is mediated mostly by triiodothyronine (T3) bound to thyroid hormone nuclear receptors (TRs). At positive regulated genes and in the absence of THs, nuclear co-repressors are bound to TRs and decrease basal transcription rate. Ligand (T(3)) binding results in the dissociation of co-repressors and the recruitment of co-activato ...[more]

PMID: 22178950

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Project description:The thyroid hormone triiodothyronine (T3) activates thermogenesis by uncoupling electron transport from ATP synthesis in brown adipose tissue (BAT) mitochondria. Although T3 can induce thermogenesis by sympathetic innervation, little is known about its cell autonomous effects on BAT mitochondria. We thus examined effects of T3 on mitochondrial activity, autophagy, and metabolism in primary brown adipocytes and BAT and found that T3 increased fatty acid oxidation and mitochondrial respiration as well as autophagic flux, mitophagy, and mitochondrial biogenesis. Interestingly, there was no significant induction of intracellular reactive oxygen species (ROS) despite high mitochondrial respiration and UCP1 induction by T3. However, when cells were treated with Atg5 siRNA to block autophagy, induction of mitochondrial respiration by T3 decreased, and was accompanied by ROS accumulation, demonstrating a critical role for autophagic mitochondrial turnover. We next generated an Atg5 conditional knockout mouse model (Atg5 cKO) by injecting Ucp1 promoter-driven Cre-expressing adenovirus into Atg5Flox/Flox mice to examine effects of BAT-specific autophagy on thermogenesis in vivo. Hyperthyroid Atg5 cKO mice exhibited lower body temperature than hyperthyroid or euthyroid control mice. Metabolomic analysis showed that T3 increased short and long chain acylcarnitines in BAT, consistent with increased ?-oxidation. T3 also decreased amino acid levels, and in conjunction with SIRT1 activation, decreased MTOR activity to stimulate autophagy. In summary, T3 has direct effects on mitochondrial autophagy, activity, and turnover in BAT that are essential for thermogenesis. Stimulation of BAT activity by thyroid hormone or its analogs may represent a potential therapeutic strategy for obesity and metabolic diseases. Abbreviations: ACACA: acetyl-Coenzyme A carboxylase alpha; AMPK: AMP-activated protein kinase; Acsl1: acyl-CoA synthetase long-chain family member 1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATP: adenosine triphosphate; BAT: brown adipose tissue; cKO: conditional knockout; COX4I1: cytochrome c oxidase subunit 4I1; Cpt1b: carnitine palmitoyltransferase 1b, muscle; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DIO2: deiodinase, iodothyronine, type 2; DMEM: Dulbecco's modified Eagle's medium; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; Fabp4: fatty acid binding protein 4, adipocyte; FBS: fetal bovine serum; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FGF: fibroblast growth factor; FOXO1: forkhead box O1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; Gpx1: glutathione peroxidase 1; Lipe: lipase, hormone sensitive; MAP1LC3B: microtubule-associated protein 1 light chain 3; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; NAD: nicotinamide adenine dinucleotide; Nrf1: nuclear respiratory factor 1; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PPARGC1A: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; Pnpla2: patatin-like phospholipase domain containing 2; Prdm16: PR domain containing 16; PRKA: protein kinase, AMP-activated; RPS6KB: ribosomal protein S6 kinase; RFP: red fluorescent protein; ROS: reactive oxygen species; SD: standard deviation; SEM: standard error of the mean; siRNA: small interfering RNA; SIRT1: sirtuin 1; Sod1: superoxide dismutase 1, soluble; Sod2: superoxide dismutase 2, mitochondrial; SQSTM1: sequestosome 1; T3: 3,5,3'-triiodothyronine; TFEB: transcription factor EB; TOMM20: translocase of outer mitochondrial membrane 20; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); ULK1: unc-51 like kinase 1; VDAC1: voltage-dependent anion channel 1; WAT: white adipose tissue.

Project description:BackgroundThe role of thyroid hormones is crucial in the response to stress and critical illness, which has been reported to be closely associated with a poor prognosis in patients admitted to the intensive care unit (ICU). This study aimed to explore the relationship between thyroid hormone and prognosis in septic shock patients.MethodsA total of 186 patients with septic shock were enrolled in the analytical study between December 2014 and September 2022. The baseline variables and thyroid hormone were collected. The patients were divided into survivor group and non-survivor group according to whether they died during the ICU hospitalization. Among 186 patients with septic shock, 123 (66.13%) were in the survivor group and 63 (33.87%) were in the non-survivor group.ResultsThere were significant differences in the indictors of free triiodothyronine (FT3) (p = 0.000), triiodothyronine (T3) (p = 0.000), T3/FT3 (p = 0.000), acute physiology and chronic health evaluation II score (APACHE II) (p = 0.000), sequential organ failure assessment score (SOFA) (p = 0.000), pulse rate (p = 0.020), creatinine (p = 0.008), PaO2/FiO2 (p = 0.000), length of stay (p = 0.000) and hospitalization expenses (p = 0.000) in ICU between the two groups. FT3 [odds ratio (OR): 1.062, 95% confidence interval(CI): (0.021, 0.447), p = 0.003], T3 (OR: 0.291, 95% CI: 0.172-0.975, p = 0.037) and T3/FT3 (OR: 0.985, 95% CI:0.974-0.996, p = 0.006) were independent risk factors of the short-term prognosis of septic shock patients after adjustment. The areas under the receiver operating characteristic curves for T3 was associated with ICU mortality (AUC = 0.796, p < 0.05) and was higher than that for FT3 (AUC = 0.670, p < 0.05) and T3/FT3 (AUC = 0.712, p < 0.05). A Kaplan-Meier curve showed that patients with T3 greater than 0.48 nmol/L had a significantly higher survival rate than the patients with T3 less than 0.48 nmol/L.ConclusionsThe decrease in serum level of T3 in patients with septic shock is associated with ICU mortality. Early detection of serum T3 level could help clinicians to identify septic shock patients at high risk of clinical deterioration.

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Complete activation of thyroid hormone receptor ? by T3 is essential for normal cochlear function and morphology in mice.

Publications

Complete activation of thyroid hormone receptor β by T3 is essential for normal cochlear function and morphology in mice.

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