Biology subjects

Prinz, A. D.

Publications and source records attributed to Prinz, A. D..

3 recordsLinked to original sources

bioRxiv2025

Short-term but not long-term triiodothyronine treatment improved cardiac function after myocardial infarction in male wild-type mice

ObjectivesThyroid hormone (TH), especially triiodothyronine (T3), plays an important role in cardiac physiology and in the remodeling process following myocardial infarction (MI). We investigated the effects of short-term (until day 5) and long-term (until day 56) post-MI T3 treatment on cardiac function, infarct size, hypertrophy, and gene expression in mice without and with deletion of TR, the main cardiac thyroid hormone receptor (wild-type (WT) and TRKO, respectively) MethodsWT and TRKO mice underwent permanent left anterior descending coronary artery (LAD) ligation or sham surgery followed by either short-term T3 for 5 days post-MI or long-term T3 until day 56, including a subgroup in which T3 treatment commenced 14 days post-MI; all groups were followed up for 4 weeks. T3 was delivered via drinking water at 500 ng/ml. Cardiac function was studied with echocardiography (ejection fraction, EF), infarct size by histology (Sirius red), heart weight normalized to tibia length, and transcriptomic profiling (RNA-seq) in WT hearts. ResultsShort-term T3 improved EF in WT but not in TRKO mice without induction of hypertrophy or changes in infarct size in either genotype. Long-term T3 induced cardiac hypertrophy in both WT and TRKO mice. However, long-term T3 did not improve EF or reduce infarct size. In TRKO mice, baseline EF post-MI was preserved without T3, but T3 treatment decreased EF. RNA-seq in long-term treated WT mice suggested modulation of Rho-GTPase signaling, mitochondrial biogenesis, and immune activation by T3. ConclusionsT3 therapy post-MI improved cardiac function only when applied acutely and for a short term. Long-term exposure led to cardiac hypertrophy without functional improvement and may even worsen cardiac function in TR-deficient settings. Timing, duration, and receptor status are highly relevant for TH-based interventions in MI.

physiology↗

bioRxiv2025

Extrahepatic effects of thyroid hormone and resmetirom override their beneficial hepatic effects in alcohol-associated liver disease in mice

BackgroundAlcohol-associated liver disease (ALD) is a common type of liver disease worldwide. Excessive consumption of ethanol (EtOH) causes fat accumulation leading to hepatic steatosis. Hepatic thyroid hormone (TH) action or liver-specific thyromimetics, e.g. resmetirom, can reduce hepatic triglycerides. We therefore hypothesized that TH treatment could ameliorate ALD. MethodsTo induce ALD, mice were treated with either EtOH or liquid control diet for 10 days followed by a single EtOH or maltose control gavage on day 11. The liquid diets were supplemented with solvent, T3 or Resmetirom. We studied WT and hepatocyte-specific TR{beta} KO mice (hepTR{beta}KO). Effects were measured by clinical chemistry, liver staining, hepatic triglyceride content, and RNA-sequencing. ResultsSurprisingly, resmetirom had no beneficial effect and T3 treatment even aggravated EtOH-induced steatosis (increased liver weight and hepatic triglycerides). The liver phenotype was worsened in hepTR{beta}KO mice, which still suggested beneficial effects of hepatic TR{beta} signaling in WT mice. These seemingly paradoxical results could be explained by extrahepatic effects in WAT: WAT weight and adipocyte size were reduced by EtOH, T3 and resmetirom. These data indicate lipolysis and subsequent fatty acid accumulation in the liver, explaining the more severe ALD phenotype with T3 and attenuated effect of resmetirom. As WAT loss was reduced in hepTR{beta}KO mice, the hepatic TR{beta} mediated the extrahepatic effects of T3 and resmetirom on WAT. ConclusionWe conclude that extrahepatic TH effects in WAT were detrimental in ALD and counteracted beneficial local hepatic TH/TR{beta} action. As WAT loss appeared to originate from the hepatic TR{beta}, this also applied to resmetirom.

pathology↗

bioRxiv2025

ALK Inhibition Prolongs Survival in a Mouse Model of ALK-positive Anaplastic Thyroid Cancer

BackgroundAnaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer with a median survival of about 6 months. So far, no therapies offering a survival benefit are established. Thus, new therapeutic approaches are urgently needed. In general, genetic alterations leading to ATC increase PI3K and MAPK/ERK signalling and include mutations in receptor tyrosine kinases and tumour suppressor genes. They often occur together with the loss of P53, the most prevalent mutation in human ATC. Among such mutations are mutations and rearrangements of the anaplastic lymphoma kinase (ALK) gene. MethodsTo study ATC and potential treatment options, we generated a mouse model with inducible thyrocyte-specific expression of constitutively active mutant ALKF1174L and homozygous deletion of Trp53 due to a Cre recombinase under control of the thyroglobulin promoter (Tg-CreERT2+/0;LSL-ALKF1174L/+;Trp53LoxP/LoxP mice, here referred to as Trp53KO/ALKF1174L mice). Moreover, we established several primary thyroid cancer cell lines harbouring ALKF1174L and Trp53KO and investigated the effects of ALK inhibition in vitro and in vivo. ResultsMedian survival of Trp53KO/ALKF1174L mice was severely reduced and the mice showed massively enlarged thyroids. Histopathology confirmed development of locally invasive and metastatic ATC. Treatment of primary Trp53KO/ALKF1174L ATC cells with the ALK inhibitor TAE-684 decreased AKT and ERK phosphorylation and induced a dose-dependent cytotoxicity. Trp53KO/ALKF1174L mice treated with TAE-684 showed significantly extended median survival compared to the solvent group (66 days vs. 18 days, p < 0.0001). ConclusionOur data demonstrate that the combination of ALKF1174L mutation with Trp53 loss leads to the development of ATC. This study provides first functional data supporting the use of ALK inhibitors in patients with ALK-driven ATC. Our novel ATC mouse model and the derived cell lines offer valuable tools to explore the molecular characteristics of ATC, especially signalling pathway activation and tumour microenvironment, and to test novel therapeutics for the treatment of advanced thyroid cancers.

cancer biology↗