Rationale: Metabolic and structural remodeling is a hallmark of heart failure. This remodeling involves activation of the mTOR (mammalian target of rapamycin) signaling pathway, but little is known on how intermediary metabolites are integrated as metabolic signals. Objective: We investigated the metabolic control of cardiac glycolysis and explored the potential of glucose 6-phosphate (G6P) to regulate glycolytic flux and mTOR activation. Methods and Results: We developed a kinetic model of cardiomyocyte carbohydrate metabolism, CardioGlyco , to study the metabolic control of myocardial glycolysis and G6P levels. Metabolic control analysis revealed that G6P concentration is dependent on phosphoglucose isomerase (PGI) activity. Next, we integrated ex vivo tracer studies with mathematical simulations to test how changes in glucose supply and glycolytic flux affect mTOR activation. Nutrient deprivation promoted a tight coupling between glucose uptake and oxidation, G6P reduction, and increased protein-protein interaction between hexokinase II and mTOR. We validated the in silico modeling in cultured adult mouse ventricular cardiomyocytes by modulating PGI activity using erythrose 4-phosphate. Inhibition of glycolytic flux at the level of PGI caused G6P accumulation, which correlated with increased mTOR activation. Using click chemistry, we labeled newly synthesized proteins and confirmed that inhibition of PGI increases protein synthesis. Conclusions: The reduction of PGI activity directly affects myocyte growth by regulating mTOR activation.

The present work aims to identify the microbial diversity associated with six Indian Drosophila species using next generation sequencing (NGS) technology and to discover the nature of their distribution across species and eco-geographic regions. Whole fly gDNA of six Drosophila species were used to generate sequences in an Illumina platform using NGS technology. De novo based assembled raw reads were blasted against the NR database of NCBI using BLASTn for identification of their bacterial loads. We have tried to include Drosophila species from different taxonomical groups and subgroups and from three different eco-climatic regions India; four species belong to Central India, while the rest two, D. melanogaster and D. ananassae, belong to West and South India to determine both their species-wise and region-wide distribution. We detected the presence of 33 bacterial genera across all six study species, predominated by the class Proteobacteria. Amongst all, D. melanogaster was found to be the most diverse by carrying around 85% of the bacterial diversity. Our findings infer both species-specific and environment-specific nature of the bacterial species inhabiting the Drosophila host. Though the present results are consistent with most of the earlier studies, they also remain incoherent with some. The present study outcome on the host-bacteria association and their species specific adaptation may provide some insight to understand the host-microbial interactions and the phenotypic implications of microbes on the host physiology. The knowledge gained may be importantly applied into the recent insect and pest population control strategy going to implement through gut microflora in India and abroad.

This article documents the whole genome sequence information of the Indian Zaprionus indianus, a member of the fruit fly family Drosophilidae. The sequences were generated on an Illumina platform and reads and whole genome sequence submitted to NCBI to the SRA and BioProject databases, respectively. This is the first Indian Z. indianus whole genome (draft) submitted to the sequence repository with SRA reads. The details of methodology, assembly statistics and functional annotation are presented in this work.

The cardiovascular effects of marijuana have been shown to be a result of the activation of the CB1 and CB2 receptors located in the myocardium and coronary vasculatures. Adverse cardiovascular consequences of recreational use of marijuana and synthetic cannabinoids include stroke, artery dissection, vasospasm, vasculitis, coronary artery thrombosis, myocarditis/pericarditis, postural hypotension, arrhythmias, and acute heart failure. With marijuana being legalized for medicinal purposes and recreational use in more and more states in the United States, physicians should have a low threshold for the possibility of marijuana being the underlying cause of adverse cardiovascular events. Marijuana has been established to increase sympathetic tone and cause blood pressure elevations and severe coronary artery spasm (CAS). Some studies have even indicated that the risks of heart attack, atrial fibrillation, and ischemic stroke are several times higher within an hour of marijuana use. This case series discusses three female patients, aged 27, 39, and 53 years, who were known to smoke marijuana consistently. These patients all presented with signs and symptoms of acute coronary syndrome (ACS) less than 12 hours after smoking recreational marijuana. All patients endorsed smoking marijuana a few hours prior to the onset of chest pain and less than 12 hours prior to the presentation, which was confirmed by a positive urine drug screen (UDS). Coronary artery angiograms revealed coronary artery dissection in the proximal left circumflex (LCX) artery, the mid-distal left anterior descending (LAD) artery, and mid-LAD in the 27 y/o, 39 y/o, and 53 y/o patients respectively. The average age of spontaneous coronary artery dissection (SCAD) cases ranges between 35-40 years. Women account for more than 70% of cases; it is thought to be due to higher levels of estrogen in women, which alters the normal arterial wall architecture. Additionally, the excessive use of marijuana resulting in CAS further increases the susceptibility to spontaneous dissection in female patients.

Comparative analysis of multiple genomes of closely or distantly related Drosophila species undoubtedly creates excitement among evolutionary biologists in exploring the genomic changes with an ecology and evolutionary perspective. We present herewith the de novo assembled whole genome sequences of four Drosophila species, D. bipectinata, D. takahashii, D. biarmipes and D. nasuta of Indian origin using Next Generation Sequencing technology on an Illumina platform along with their detailed assembly statistics. The comparative genomics analysis, e.g. gene predictions and annotations, functional and orthogroup analysis of coding sequences and genome wide SNP distribution were performed. The whole genome of Zaprionus indianus of Indian origin published earlier by us and the genome sequences of previously sequenced 12 Drosophila species available in the NCBI database were included in the analysis. The present work is a part of our ongoing genomics project of Indian Drosophila species.

Metabolic reprogramming is a hallmark in both cancer and heart failure. Mutations of the isocitrate deyhydrogenase (IDH) 1 and 2 cause metabolic dysfunction in cancer cells through overproduction of the oncometabolite D-2-hydroxyglutarate (D2-HG) and are associated with cardiomyopathy. We recently discovered that alpha-Ketoglutarate dehydrogenase inhibition by D2-HG redirects Krebs cycle flux. This implies a central role for IDH and ATP citrate lyase (ACL) in regulating reductive formation of citrate and histone acetylation in response to mitochondrial impairment in heart and skeletal muscle. Elucidating how metabolic rewiring promotes changes in gene expression and remodeling in heart muscle holds the promise for development of metabolic strategies to support the failing heart. We tested whether modulation of ACL activity reverses D2-HG-mediated metabolic changes using adult rat ventricular cardiomyocytes and L6 myocytes. The ACL inhibitor BMS303141 (BMS) decreased ATP provision in cultured myocytes in a concentration-dependent manner. There was an inverse relation between alpha-KG and ACL activities. Conversely, co-culture with both BMS (0.5 μM) and D2-HG (1 mM) increased ATP provision suggesting that ACL inhibition in presence of D2-HG may be beneficial for energy provision. Next, we conducted isolated working rat heart perfusions with BMS (0.5 μM) and/or D2-HG (1 mM). Cardiac power rapidly declined (by 25%) in the presence of BMS or D2-HG. Simultaneous perfusion with D2-HG and BMS improved cardiac power, suggesting that ACL inhibition protects the heart from metabolic dysfunction by D2-HG. Further, D2-HG elevation mediated structural remodeling in the heart by activating authophagy through increased acetylation of p300, increased phosphorylation of AMPK, and a corresponding decrease in activation and phosphorylation of mTOR. Parallel tracer studies using labeled glucose and glutamine allowed us to conduct computational flux rate analysis by applying the metabolic network CardioNet. We identified major metabolic pathways that are up- and downregulated by D2-HG. Our findings suggest an “oncometabolic axis” in the heart and underscore the potential application of ACL inhibitors to protect the heart from failing.

Autophagy “scavenges” proteins and yields amino acids under conditions of metabolic stress to support cell survival and growth. In isocitrate dehydrogenase 1 and 2 mutant tumors, increased plasma levels of the oncometabolite D-2-hydroxyglutarate (D2-HG) are associated with systemic effects, including dilated cardiomyopathy. Our recent in vivo work showed that increased D2-HG supply by IDH2-mutant hematopoetic stem cells causes heart and skeletal muscle atrophy, and decreases cellular ATP and NADH. While heart failure in cancer is commonly associated with chemotherapy, cancer survivors have a five-fold increased risk of heart failure independent of any cytostatic treatment. The connection between metabolic changes and proteomic remodeling in this context remain poorly understood. We hypothesize that D2-HG-mediated alpha-ketoglutarate dehydrogenase inhibition in myocytes results in metabolomic pertubations, proteomic remodeling, and increased autophagy. We measured autophagic flux and remodeling of the stable proteome upon D2-HG treatment in vivo using wild-type C57BL/J6 mice, and in vitro using both cultured L6 myocytes and adult mouse ventricular cardiomyocytes. We observed increases in the LC3-II/LC3-I ratio and p62 expression in heart and skeletal muscle from mice treated with D2-HG, indicating activation of autophagy. Live cell imaging with GFP-tagged LC3 indicated that D2-HG (1 mM) increased LC3-II lipidation and flux within 24 h. Furthermore, we observed increased phosphorylation and activation of AMPK, while phosphorylation of mTOR and p70S6K were decreased in presence of D2-HG. In vitro exposure to D2-HG resulted in the formation of a molecular complex between Sirt1 and LC3, indicating that increased NAD+ in presence of D2-HG promotes Sirt1 activation in myocytes. Finally, we used LC-MS/MS to assess the effect of D2-HG on the stable proteome and metabolome in heart and skeletal muscle. Myocytes exposed to D2-HG showed proteomic remodeling and metabolomic changes within 24 h. Integrating multi-omics data in a network-level context revealed upregulation of glycolysis and the pentose phosphate pathway. In short, autophagy activation may support proteome remodeling in muscle cells during IDH-mutant leukemia.

Cardiac masses are a rare finding, with most masses found being thrombi or vegetations. Still, some masses are suspected to be a tumor based on multiple characteristics such as size, location, mobility, and the tumor's hemodynamic effects. Cardiovascular magnetic resonance (CMR) and CT have been shown to differentiate a tumor from a thrombus based on tissue characteristics of the mass. Here we highlight the role of contrast perfusion imaging on echocardiography in identifying the malignant potential of a cardiac mass. This case report demonstrates the effectiveness of contrast imaging with a transesophageal echocardiogram in identifying the etiology of cardiac masses without the need of CMR or cardiac CT, which helps save between $100-1207 of hospital costs. Besides the cost-benefit, the use of non-invasive and easily accessible imaging like echocardiogram enables smaller facilities with limited resources to diagnose and hence further manage patients with cardiac masses.