Biology subjects

Grund, S. C.

Publications and source records attributed to Grund, S. C..

4 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↗

bioRxiv2023

Canonical and noncanonical contribution of thyroid hormone receptor isoforms alpha and beta to cardiac hypertrophy and heart rate in male mice

BackgroundStimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). Aim of this study was to determine in vivo which TH receptor (TR), or {beta}, and which mode of TR action, canonical gene expression or DNA-binding independent noncanonical action, mediate these effects. Material and methodsWe compared global TR and TR{beta} knockout mice (TRKO; TR{beta}KO) with WT mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA- binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRGS; TR{beta}GS). Hearts were studied with echocardiography at baseline and after seven weeks T3-treatment. Gene expression was measured with real-time PCR. Heart rate was recorded with radiotelemetry transmitters for seven weeks in untreated, hypothyroid and T3-treated mice. ResultsT3 induced ventricular hypertrophy in WT and TR{beta}KO mice, but not in TRKO mice. Hypertrophy was also induced in TRGS mice. Thus, hypertrophy is mostly mediated by noncanonical TR action. Similarly, repression of Mhy7 occurred in WT and TRGS mice. Basal heart rate was largely dependent on canonical TR action. But responsiveness to hypothyroidism and T3-treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRKO mice, demonstrating that TR{beta} could compensate for absence of TR. ConclusionT3-induced cardiac hypertrophy could be attributed to noncanonical TR action, whereas heart rate regulation was mediated by canonical TR action. TR{beta} could substitute for canonical, but not noncanonical TR action.

physiology↗

bioRxiv2023

Cardiac recovery from pressure overload is not altered by thyroid hormone status in old mice

1Thyroid hormones (TH) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases are still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Mice at the age of 12 months underwent TAC and after induction of left ventricular pressure overload, received T4 or anti-thyroid medication in the drinking water over the course of 4 weeks. T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis and interstitial fibrosis) and mortality. This is surprising, because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure induced cardiac damage. This suggests that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions.

physiology↗