Open AccessCancer‐induced cardiac atrophy adversely affects myocardial redox state and mitochondrial oxidative characteristics
Author(s) -
Lee David E.,
Brown Jacob L.,
RosaCaldwell Megan E.,
Perry Richard A.,
Brown Lemuel A.,
Haynie Wesley S.,
Washington Tyrone A.,
Wiggs Michael P.,
Rajaram Narasimhan,
Greene Nicholas P.
Publication year - 2020
Publication title -
jcsm rapid communications
Language(s) - English
Resource type - Journals
ISSN - 2617-1619
DOI - 10.1002/rco2.18
Subject(s) - mitophagy , mitochondrial ros , oxidative stress , mitochondrion , medicine , oxidative phosphorylation , endocrinology , nicotinamide adenine dinucleotide phosphate , reactive oxygen species , biology , chemistry , oxidase test , biochemistry , apoptosis , autophagy , enzyme
Background Cachexia presents in 80% of advanced cancer patients; however, cardiac atrophy in cachectic patients receives little attention. This cardiomyopathy contributes to increased occurrence of adverse cardiac events compared with age‐matched population norms. Research on cardiac atrophy has focused on remodelling; however, alterations in metabolic properties may be a primary contributor. The purpose of the study is to determine how cancer‐induced cardiac atrophy alters mitochondrial turnover, mitochondrial mRNA translation machinery, and in vitro oxidative characteristics. Methods Lewis lung carcinoma (LLC) tumours were implanted in C57BL6/J mice and grown for 28 days to induce cardiac atrophy. Endogenous metabolic species and markers of mitochondrial function were assessed. H9c2 cardiomyocytes were cultured in LLC‐conditioned media with (out) the antioxidant MitoTempo. Cells were analysed for reactive oxygen species (ROS), oxidative capacity, and hypoxic resistance. Results LLC heart weights were ~10% lower than controls. LLC hearts demonstrated ~15% lower optical redox ratio [flavin adenine dinucleotide (FAD)/FAD + nicotinamide adenine dinucleotide hydrogen (NADH)] compared with phosphate‐buffered saline controls. When compared with phosphate‐buffered saline, LLC hearts showed ~50% greater Cytochrome‐C oxidase subunit 4 (COX‐IV) and Voltage‐dependent anion channel (VDAC), attributed to ~50% lower mitophagy markers. mt‐mRNA translation machinery was elevated similarly to markers of mitochondrial content. Mitochondrial DNA‐encoded Cytb was ~30% lower in LLC hearts. ROS scavengers GPx‐3 and GPx‐7 were ~50% lower in LLC hearts. Treatment of cardiomyocytes with LLC‐conditioned media resulted in higher ROS (25%), lower oxygen consumption rates (10% at basal and 75% at maximal), and greater susceptibility to hypoxia (~25%), which was reversed by MitoTempo. Conclusions These results substantiate metabolic cardiotoxic effects attributable to tumour‐associated factors and provide insight into interactions between mitochondrial mRNA translation, ROS mitigation, oxidative capacity, and hypoxia resistance.