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Regulation of Skeletal Muscle Function by Amino Acids
Open AccessArticle

A Special Amino-Acid Formula Tailored to Boosting Cell Respiration Prevents Mitochondrial Dysfunction and Oxidative Stress Caused by Doxorubicin in Mouse Cardiomyocytes

1
Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy
2
Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, 20122 Milan, Italy
3
Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
*
Authors to whom correspondence should be addressed.
Nutrients 2020, 12(2), 282; https://doi.org/10.3390/nu12020282
Received: 25 November 2019 / Revised: 23 December 2019 / Accepted: 2 January 2020 / Published: 21 January 2020
(This article belongs to the Special Issue Amino Acids and Health Effects)
Anthracycline anticancer drugs, such as doxorubicin (DOX), can induce cardiotoxicity supposed to be related to mitochondrial damage. We have recently demonstrated that a branched-chain amino acid (BCAA)-enriched mixture (BCAAem), supplemented with drinking water to middle-aged mice, was able to promote mitochondrial biogenesis in cardiac and skeletal muscle. To maximally favor and increase oxidative metabolism and mitochondrial function, here we tested a new original formula, composed of essential amino acids, tricarboxylic acid cycle precursors and co-factors (named α5), in HL-1 cardiomyocytes and mice treated with DOX. We measured mitochondrial biogenesis, oxidative stress, and BCAA catabolic pathway. Moreover, the molecular relevance of endothelial nitric oxide synthase (eNOS) and mechanistic/mammalian target of rapamycin complex 1 (mTORC1) was studied in both cardiac tissue and HL-1 cardiomyocytes. Finally, the role of Krüppel-like factor 15 (KLF15), a critical transcriptional regulator of BCAA oxidation and eNOS-mTORC1 signal, was investigated. Our results demonstrate that the α5 mixture prevents the DOX-dependent mitochondrial damage and oxidative stress better than the previous BCAAem, implying a KLF15/eNOS/mTORC1 signaling axis. These results could be relevant for the prevention of cardiotoxicity in the DOX-treated patients. View Full-Text
Keywords: branched-chain amino acids; cardiomyocytes; doxorubicin; endothelial nitric oxide synthase; Krüppel-like factor 15; mechanistic/mammalian target of rapamycin; mitochondria; oxidative stress; peroxisome proliferator-activated receptor γ coactivator 1 α; tricarboxylic acid cycle branched-chain amino acids; cardiomyocytes; doxorubicin; endothelial nitric oxide synthase; Krüppel-like factor 15; mechanistic/mammalian target of rapamycin; mitochondria; oxidative stress; peroxisome proliferator-activated receptor γ coactivator 1 α; tricarboxylic acid cycle
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Tedesco, L.; Rossi, F.; Ragni, M.; Ruocco, C.; Brunetti, D.; Carruba, M.O.; Torrente, Y.; Valerio, A.; Nisoli, E. A Special Amino-Acid Formula Tailored to Boosting Cell Respiration Prevents Mitochondrial Dysfunction and Oxidative Stress Caused by Doxorubicin in Mouse Cardiomyocytes. Nutrients 2020, 12, 282.

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