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Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model

BACKGROUND: Coronary artery disease is a leading cause of morbidity and mortality among patients with diabetes. Previously, we demonstrated that branched-chain amino acids (BCAAs) showed cardioprotective effects against cardiac ischemia/reperfusion (I/R) injury. A recent study suggested that leucine...

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Autores principales: Morio, Atsushi, Tsutsumi, Rie, Satomi, Shiho, Kondo, Takashi, Miyoshi, Hirotsugu, Kato, Takahiro, Kuroda, Masashi, Kitamura, Tadahiro, Hara, Kenta, Saeki, Noboru, Sakaue, Hiroshi, Tsutsumi, Yasuo M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606064/
https://www.ncbi.nlm.nih.gov/pubmed/34801078
http://dx.doi.org/10.1186/s13098-021-00755-z
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author Morio, Atsushi
Tsutsumi, Rie
Satomi, Shiho
Kondo, Takashi
Miyoshi, Hirotsugu
Kato, Takahiro
Kuroda, Masashi
Kitamura, Tadahiro
Hara, Kenta
Saeki, Noboru
Sakaue, Hiroshi
Tsutsumi, Yasuo M.
author_facet Morio, Atsushi
Tsutsumi, Rie
Satomi, Shiho
Kondo, Takashi
Miyoshi, Hirotsugu
Kato, Takahiro
Kuroda, Masashi
Kitamura, Tadahiro
Hara, Kenta
Saeki, Noboru
Sakaue, Hiroshi
Tsutsumi, Yasuo M.
author_sort Morio, Atsushi
collection PubMed
description BACKGROUND: Coronary artery disease is a leading cause of morbidity and mortality among patients with diabetes. Previously, we demonstrated that branched-chain amino acids (BCAAs) showed cardioprotective effects against cardiac ischemia/reperfusion (I/R) injury. A recent study suggested that leucine (Leu), a BCAA, is a key amino acid involved in mammalian target of rapamycin (mTOR) activity and mitochondrial function. However, whether Leu has cardioprotective effects on diabetic hearts is unclear. In this study, we examined the preconditioning effect of Leu treatment on high-fat diet (HFD)-induced obese mouse which simulate prediabetic heart. METHODS: In vivo mice models of I/R injury were divided into the following groups: control, mTOR(+/−), and high-fat diet (HFD)-induced obese groups. Mice were randomly administered with Leu, the mTOR inhibitor rapamycin (Rap), or Leu with Rap. Isolated rat cardiomyocytes were subjected to simulated I/R injury. Biochemical and mitochondrial functional assays were performed to evaluate the changes in mTOR activity and mitochondrial dynamics caused by Leu treatment. RESULTS: Leu-treated mice showed a significant reduction in infarct size when compared with the control group (34.8% ± 3.8% vs. 43.1% ± 2.4%, n = 7, p < 0.05), whereas Rap-treated mice did not show the protective effects of Leu. This preconditioning effect of Leu was attenuated in mTOR(+/−) mice. Additionally, Leu increased the percentage of fused mitochondria and the mitochondrial volume, and decreased the number of mitochondria per cell in isolated cardiomyocytes. In HFD-induced obese mice, Leu treatment significantly reduced infarct size (41.0% ± 1.1% vs. 51.0% ± 1.4%, n = 7, p < 0.05), which was not induced by ischemic preconditioning, and this effect was inhibited by Rap. Furthermore, we observed enhanced mTOR protein expression and mitochondrial fusion with decreased reactive oxygen species production with Leu treatment in HFD-induced obese mice, but not in mTOR(+/−) mice. CONCLUSIONS: Leu treatment improved the damage caused by myocardial I/R injury by promoting mTOR activity and mitochondrial fusion on prediabetic hearts in mice.
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spelling pubmed-86060642021-11-22 Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model Morio, Atsushi Tsutsumi, Rie Satomi, Shiho Kondo, Takashi Miyoshi, Hirotsugu Kato, Takahiro Kuroda, Masashi Kitamura, Tadahiro Hara, Kenta Saeki, Noboru Sakaue, Hiroshi Tsutsumi, Yasuo M. Diabetol Metab Syndr Research BACKGROUND: Coronary artery disease is a leading cause of morbidity and mortality among patients with diabetes. Previously, we demonstrated that branched-chain amino acids (BCAAs) showed cardioprotective effects against cardiac ischemia/reperfusion (I/R) injury. A recent study suggested that leucine (Leu), a BCAA, is a key amino acid involved in mammalian target of rapamycin (mTOR) activity and mitochondrial function. However, whether Leu has cardioprotective effects on diabetic hearts is unclear. In this study, we examined the preconditioning effect of Leu treatment on high-fat diet (HFD)-induced obese mouse which simulate prediabetic heart. METHODS: In vivo mice models of I/R injury were divided into the following groups: control, mTOR(+/−), and high-fat diet (HFD)-induced obese groups. Mice were randomly administered with Leu, the mTOR inhibitor rapamycin (Rap), or Leu with Rap. Isolated rat cardiomyocytes were subjected to simulated I/R injury. Biochemical and mitochondrial functional assays were performed to evaluate the changes in mTOR activity and mitochondrial dynamics caused by Leu treatment. RESULTS: Leu-treated mice showed a significant reduction in infarct size when compared with the control group (34.8% ± 3.8% vs. 43.1% ± 2.4%, n = 7, p < 0.05), whereas Rap-treated mice did not show the protective effects of Leu. This preconditioning effect of Leu was attenuated in mTOR(+/−) mice. Additionally, Leu increased the percentage of fused mitochondria and the mitochondrial volume, and decreased the number of mitochondria per cell in isolated cardiomyocytes. In HFD-induced obese mice, Leu treatment significantly reduced infarct size (41.0% ± 1.1% vs. 51.0% ± 1.4%, n = 7, p < 0.05), which was not induced by ischemic preconditioning, and this effect was inhibited by Rap. Furthermore, we observed enhanced mTOR protein expression and mitochondrial fusion with decreased reactive oxygen species production with Leu treatment in HFD-induced obese mice, but not in mTOR(+/−) mice. CONCLUSIONS: Leu treatment improved the damage caused by myocardial I/R injury by promoting mTOR activity and mitochondrial fusion on prediabetic hearts in mice. BioMed Central 2021-11-20 /pmc/articles/PMC8606064/ /pubmed/34801078 http://dx.doi.org/10.1186/s13098-021-00755-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Morio, Atsushi
Tsutsumi, Rie
Satomi, Shiho
Kondo, Takashi
Miyoshi, Hirotsugu
Kato, Takahiro
Kuroda, Masashi
Kitamura, Tadahiro
Hara, Kenta
Saeki, Noboru
Sakaue, Hiroshi
Tsutsumi, Yasuo M.
Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model
title Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model
title_full Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model
title_fullStr Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model
title_full_unstemmed Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model
title_short Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model
title_sort leucine imparts cardioprotective effects by enhancing mtor activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606064/
https://www.ncbi.nlm.nih.gov/pubmed/34801078
http://dx.doi.org/10.1186/s13098-021-00755-z
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