Abstract
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.
Highlights
Anthracyclines, such as doxorubicin (DOX), are widely used and highly successful anticancer chemotherapeutics [1]
To protect cardiomyocytes against DOX toxicity, we propose to correct the impaired mitochondrial function and oxidative stress in HL-1 cells exposed to the chemotherapeutic
While α5 (1% w/v) increased the mRNA levels of mitochondrial biogenesis markers in HL-1 cells, including PGC-1α, nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), cytochrome c, and cytochrome c oxidase complex IV (COX IV) over the basal value, only PGC-1α expression was statistically increased by branched-chain amino acid-enriched mixture (BCAAem) (Figure 3A)
Summary
Anthracyclines, such as doxorubicin (DOX), are widely used and highly successful anticancer chemotherapeutics [1]. DOX administration results in dose-dependent side effects to non-cancer tissues, including the development of cardiomyopathy, in addition to dyspnea, exercise intolerance, hepatotoxicity, and nephropathy [2]. The risk of cardiotoxicity is one of the greatest limiting factors to the clinical use of this drug, resulting in both acute and chronic cardiovascular events. Acute cardiac toxicity of DOX can develop within minutes to days after administration. The molecular mechanisms of these side effects are not fully understood, because DOX affects many different intracellular processes, increasing evidence suggests that the primary mediator of cardiac damage by DOX is oxidative stress, with increased reactive oxygen species (ROS)-dependent lipid peroxidation and reduced levels of antioxidants and sulfhydryl groups [1,5].
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