Cancer‐induced cardiac atrophy adversely affects myocardial redox state and mitochondrial oxidative characteristics

Abstract

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.

Cardiac myocyte intrinsic contractility and calcium handling deficits underlie heart organ dysfunction in murine cancer cachexia

“…Increased inflammatory signaling leading to proteolytic degradation of sarcomeric proteins 11 , 14 and upregulated autophagy 15 have been proposed as potential mechanisms underlying ventricular atrophy. Fetal gene reactivation 14 , mitochondrial morphological 11 and functional changes 16 , 17 , and aberrant fatty acid oxidation 18 may contribute to both decreased cardiac mass and function, although more work is needed to understand causal relationships.…”

Nutrition challenges of cancer cachexia

“…Muscle loss correlates to tumor burden and is due to an increase in protein‐degradation rate, mainly through ATP‐dependent proteolysis, 34,96 without change in protein synthesis rate. This leads to a decline in muscle and about 5% loss in bone density, 34 as well as cardiac atrophy 97 . Recent studies have revealed alterations of diaphragm function, hepatic metabolism, and the gut microbiome in LLC cachexia.…”

“…This leads to a decline in muscle and about 5% loss in bone density, 34 as well as cardiac atrophy. 97 Recent studies have revealed alterations of diaphragm function, hepatic metabolism, and the gut microbiome in LLC cachexia. This model has revealed important roles for host-derived initiators of cachexia as well as potential therapeutics, in part because of its compatibility with C57BL/6 strains of genetically modified mice.…”

Development and progression of cancer cachexia: Perspectives from bench to bedside

“… 142 Our recent evidence indicates that cardiac tissue from LLC-induced tumor-bearing mice and in vitro models of cardiac cachexia exhibit elevated mitochondria content (likely driven by reduced mitophagy suggesting accumulation of damaged mitochondria), decreased mitochondrial mRNA translation rate, and increased mitochondrial ROS emission with reduced scavenging capacity. 143 Unfortunately, to date cardiac cachexia remains significantly understudied. Therefore, there remains a critical need to identify key underlying mechanisms in development of cardiac cachexia.…”