High Glucose-Induced Cardiomyocyte Death May Be Linked to Unbalanced Branched-Chain Amino Acids and Energy Metabolism

Abstract

High glucose-induced cardiomyocyte death is a common symptom in advanced-stage diabetic patients, while its metabolic mechanism is still poorly understood. The aim of this study was to explore metabolic changes in high glucose-induced cardiomyocytes and the heart of streptozotocin-induced diabetic rats by 1H-NMR-based metabolomics. We found that high glucose can promote cardiomyocyte death both in vitro and in vivo studies. Metabolomic results show that several metabolites exhibited inconsistent variations in vitro and in vivo. However, we also identified a series of common metabolic changes, including increases in branched-chain amino acids (BCAAs: leucine, isoleucine and valine) as well as decreases in aspartate and creatine under high glucose condition. Moreover, a reduced energy metabolism could also be a common metabolic characteristic, as indicated by decreases in ATP in vitro as well as AMP, fumarate and succinate in vivo. Therefore, this study reveals that a decrease in energy metabolism and an increase in BCAAs metabolism could be implicated in high glucose-induced cardiomyocyte death.

Salvia miltiorrhiza and the Volatile of Dalbergia odorifera Attenuate Chronic Myocardial Ischemia Injury in a Pig Model: A Metabonomic Approach for the Mechanism Study

“…Creatine is an important indicator for maintaining energy homeostasis, protecting oxidative damage and improving health and survival [ 25 , 26 ]. Creatine can increase creatine phosphate reserves, which can provide energy, protect mitochondria, and reduce cardiomyocyte apoptosis.…”

The role of metabolic syndrome in sudden cardiac death risk: Recent evidence and future directions

“…Hyperglycaemia (HG) has been shown to have different damaging effects on cardiomyocyte (CM) function and survival. Exposure to high glucose environment induces CM death both in vitro and in vivo in different animal models of disease including ischaemic 62–65 and non‐ischaemic ones 66–69 . Lower levels of adenosine triphosphate (ATP), adenosine monophosphate (AMP), fumarate, succinate, aspartate and creatinine, alongside increased branched‐chain amino acids content in CM exposed to HG favour their apoptosis 69 .…”

“…[66][67][68][69] Lower levels of adenosine triphosphate (ATP), adenosine monophosphate (AMP), fumarate, succinate, aspartate and creatinine, alongside increased branched-chain amino acids content in CM exposed to HG favour their apoptosis. 69 Similarly, also oxidative stress through its activating effect on cytochrome c-activated caspase-3 pathway can explain the higher rate of apoptosis in CMs exposed to HG conditions. 66 Moreover, HG was shown to affect the contractile function of CMs by impairing intracellular calcium balance and causing ventricular dilatation and systolic disfunction.…”

Changes in Myocardial Metabolism Preceding Sudden Cardiac Death

“…High glucose alone can promote pathological cardiac development by accelerating hypertrophy, promoting ER stress, increasing ROS production, and ultimately leading to apoptosis (Ng et al, 2018;Zhang X. et al, 2018;Shi et al, 2019). When uncoupled from oxidative phosphorylation, glycolysis produces glycolytic intermediates that can accelerate flux through nonanapleurotic pathways, such as the pentose phosphate pathway (PPP), hexosamine biosynthetic pathway, or lactate shuttling (Gupte et al, 2006;Gibb et al, 2017).…”

“…Li and colleagues recently demonstrated that restoring glucose oxidation by inhibiting pyruvate dehydrogenase kinase (PDK) 4, a rate controlling enzyme of glucose oxidation, improved cardiac function, and glucose uptake post-ischemia reperfusion injury (Li et al, 2017a). Increased glucose exposure over long periods reduces BCAA catabolism, leading to an accumulation of BCAA and BCAA metabolites (Zhang X. et al, 2018). It is well established that leucine, a BCAA, is a potent activator of the mammalian target of rapamycin (mTOR) signaling pathway (Xu and Brink, 2016).…”