Metabolic Suppression by 3-Iodothyronamine Induced Muscle Cell Atrophy &lt;i&gt;via&lt;/i&gt; Activation of FoxO–Proteasome Signaling and Downregulation of Akt1–S6K Signaling

Kim, Tae‐Wan; Chung, C.; Junsoo, Park; Nikawa, Takeshi; Park, Kyoungsook; Choi, Inho

doi:10.1248/bpb.b16-00653

Cited by 6 publications

(3 citation statements)

References 32 publications

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“…Evidence was reported suggesting that T1AM treatment decreased the OCR of muscle cells [27]. Notably, our study is the first to demonstrate that T1AM treatment decreases the OCR of AC-16 cells in vitro, suggesting a hypometabolic effect of T1AM in AC-16 cells, which indicates that T1AM affects cardiomyocytes by metabolic function.…”

Section: Discussionsupporting

confidence: 65%

Thyroid Hormone Metabolite 3-Iodothyronamine (T1AM) Alleviates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via Akt/FoxO1 Pathway

Zhou

Liu

2020

Med Sci Monit

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Background: The thyroid hormone metabolite 3-iodothyronamine (T1AM) is rapidly emerging as promising compound of decreasing heart rate and lowering cardiac output. The aim of our study was to fully understand the molecular mechanism of T1AM on cardiomyocytes and its potential targets in cardiovascular diseases. Material/Methods: We developed an in vitro myocardial ischemia-reperfusion injury model of AC-16 cells by hypoxia-reoxygenation injury. Cell viability of AC-16 cells was detected using CCK-8 assay and apoptosis was detected by flow cytometry. RNA-seq was used to characterize the gene expression in H/R-induced AC-16 cells after T1AM treatment. The mRNA levels of FoxO1, PPARa, Akt, and GCK and the protein levels of PPARa, GCK, and components of the Akt/FoxO1 pathway were detected by qRT-PCR and Western blotting, respectively. Results: Exogenous T1AM increased the H/R-induced AC-16 cell viability in a relatively low concentration. A total of 210 DEGs, including 142 upregulated and 68 downregulated genes, were determined in H/R-induced AC-16 cells treated with or without T1AM. A Venn diagram showed 135 common DEGs. The FoxO signaling pathway was identified via KEGG enrichment analysis of these 135 DEGs. Moreover, T1AM mediated hypometabolism and reduced the apoptosis of H/R-induced AC-16 cells via the Akt/FoxO1 pathway. Conclusions: Exogenous T1AM protects against cell injury induced by H/R in AC-16 cells via regulation of the FoxO signaling pathway. Our results suggest that T1AM can play a preventive role in myocardial H/R injury and also provide new insight for clinical management of AMI patients.

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Section: Discussionsupporting

confidence: 65%

Thyroid Hormone Metabolite 3-Iodothyronamine (T1AM) Alleviates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via Akt/FoxO1 Pathway

Zhou

Liu

2020

Med Sci Monit

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“…Recently, T1AM decreased oxygen consumption and cell diameter in cultured C2C12 myotubes. Suppression of AKT phosphorylation and mTOR activation together with increased catabolic pathways, such as ubiquitin E3 ligase, were demonstrated after T1AM treatment ( 115 ).…”

Section: Thyroid Hormones Metabolites and The Skeletal Musclementioning

confidence: 99%

Similarities and Differences in the Peripheral Actions of Thyroid Hormones and Their Metabolites

Louzada

Carvalho

2018

Front. Endocrinol.

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Thyroxine (T4) and 3,5,3'-triiodothyronine (T3) are secreted by the thyroid gland, while T3 is also generated from the peripheral metabolism of T4 by iodothyronine deiodinases types I and II. Several conditions like stress, diseases, and physical exercise can promote changes in local TH metabolism, leading to different target tissue effects that depend on the presence of tissue-specific enzymatic activities. The newly discovered physiological and pharmacological actions of T4 and T3 metabolites, such as 3,5-diiodothyronine (3,5-T2), and 3-iodothyronamine (T1AM) are of great interest. A classical thyroid hormone effect is the ability of T3 to increase oxygen consumption in almost all cell types studied. Approximately 30 years ago, a seminal report has shown that 3,5-T2 increased oxygen consumption more rapidly than T3 in hepatocytes. Other studies demonstrated that exogenous 3,5-T2 administration was able to increase whole body energy expenditure in rodents and humans. In fact, 3,5-T2 treatment prevents diabetic nephropathy, hepatic steatosis induced by high fat diet, insulin resistance, and weight gain during aging in Wistar male rats. The regulation of mitochondria is likely one of the most important actions of T3 and its metabolite 3,5-T2, which was able to restore the thermogenic program of brown adipose tissue (BAT) in hypothyroid rats, just as T3 does, while T1AM administration induced rapid hypothermia. T3 increases heart rate and cardiac contractility, which are hallmark effects of hyperthyroidism involved in cardiac arrhythmia. These deleterious cardiac effects were not observed with the use of 3,5-T2 pharmacological doses, and in contrast T1AM was shown to promote a negative inotropic and chronotropic action at micromolar concentrations in isolated hearts. Furthermore, T1AM has a cardioprotective effect in a model of ischemic/reperfusion injury in isolated hearts, such as occurs with T3 administration. Despite the encouraging possible therapeutic use of TH metabolites, further studies are needed to better understand their peripheral effects, when compared to T3 itself, in order to establish their risk and benefit. On this basis, the main peripheral effects of thyroid hormones and their metabolites in tissues, such as heart, liver, skeletal muscle, and BAT are discussed herein.

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“…In the skeletal muscle, Ju et al. (2017) reported T1AM activated catabolic pathways involved in sarcopenia including AMPK activation ( 22 ).…”

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confidence: 99%

Commentary: Euthyroid Sick Syndrome in Patients With COVID-19

et al. 2021

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Metabolic Suppression by 3-Iodothyronamine Induced Muscle Cell Atrophy <i>via</i> Activation of FoxO–Proteasome Signaling and Downregulation of Akt1–S6K Signaling

Cited by 6 publications

References 32 publications

Thyroid Hormone Metabolite 3-Iodothyronamine (T1AM) Alleviates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via Akt/FoxO1 Pathway

Thyroid Hormone Metabolite 3-Iodothyronamine (T1AM) Alleviates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via Akt/FoxO1 Pathway

Similarities and Differences in the Peripheral Actions of Thyroid Hormones and Their Metabolites

Commentary: Euthyroid Sick Syndrome in Patients With COVID-19

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