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Lai L.,Sanford Burnham Institute for Medical Research | Leone T.C.,Sanford Burnham Institute for Medical Research | Martin O.J.,Sanford Burnham Institute for Medical Research | Broman A.T.,University of Wisconsin - Madison | And 12 more authors.
Circulation: Heart Failure | Year: 2014

Background-An unbiased systems approach was used to define energy metabolic events that occur during the pathological cardiac remodeling en route to heart failure (HF). Methods and Results-Combined myocardial transcriptomic and metabolomic profiling were conducted in a well-defined mouse model of HF that allows comparative assessment of compensated and decompensated (HF) forms of cardiac hypertrophy because of pressure overload. The pressure overload data sets were also compared with the myocardial transcriptome and metabolome for an adaptive (physiological) form of cardiac hypertrophy because of endurance exercise training. Comparative analysis of the data sets led to the following conclusions: (1) expression of most genes involved in mitochondrial energy transduction were not significantly changed in the hypertrophied or failing heart, with the notable exception of a progressive downregulation of transcripts encoding proteins and enzymes involved in myocyte fatty acid transport and oxidation during the development of HF; (2) tissue metabolite profiles were more broadly regulated than corresponding metabolic gene regulatory changes, suggesting significant regulation at the post-transcriptional level; (3) metabolomic signatures distinguished pathological and physiological forms of cardiac hypertrophy and served as robust markers for the onset of HF; and (4) the pattern of metabolite derangements in the failing heart suggests bottlenecks of carbon substrate flux into the Krebs cycle. Conclusions-Mitochondrial energy metabolic derangements that occur during the early development of pressure overload- induced HF involve both transcriptional and post-transcriptional events. A subset of the myocardial metabolomic profile robustly distinguished pathological and physiological cardiac remodeling. © 2014 American Heart Association, Inc.


Vandal M.,Laval University | White P.J.,Laval University | White P.J.,Duke Molecular Physiology Institute | White P.J.,Faculte Of Medicine Of Luniversite Laval | And 11 more authors.
Diabetes | Year: 2014

Defects in insulin production and signaling are suspected to share a key role in diabetes and Alzheimer disease (AD), two age-related pathologies. In this study, we investigated the interrelation between AD and diabetes using a high-fat diet (HFD) in a mouse model of genetically induced AD-like neuropathology (3xTg-AD). We first observed that cerebral expression of human AD transgenes led to peripheral glucose intolerance, associated with pancreatic human Aβ accumulation. High-fat diet enhanced glucose intolerance, brain soluble Aβ, and memory impairment in 3xTg-AD mice. Strikingly, a single insulin injection reversed the deleterious effects of HFD on memory and soluble Aβ levels, partly through changes in Aβ production and/or clearance. Our results are consistent with the development of a vicious cycle between AD and diabetes, potentiating both peripheral metabolic disorders and AD neuropathology. The capacity of insulin to rapidly break the deleterious effects of this cycle on soluble Aβ concentrations and memory has important therapeutic implications. © 2014 by the American Diabetes Association.


Wong K.E.,Duke Molecular Physiology Institute | Mikus C.R.,Duke Molecular Physiology Institute | Slentz D.H.,Duke Molecular Physiology Institute | Seiler S.E.,Duke University | And 7 more authors.
Diabetes | Year: 2015

This study used mice with muscle-specific overexpression of PGC-1α, a transcriptional coactivator that promotes mitochondrial biogenesis, to determine whether increased oxidative potential facilitates metabolic improvements in response to lifestyle modification. MCK-PGC1α mice and nontransgenic (NT) littermates were fed a high-fat diet (HFD) for 10 weeks, followed by stepwise exposures to voluntary wheel running (HFD+Ex) and then 25% caloric restriction with exercise (Ex/CR), each for an additional 10 weeks with continued HFD. Running and CR improved weight and glucose control similarly in MCK-PGC1α and NT mice. Sedentary MCK-PGC1α mice were more susceptible to diet-induced glucose intolerance, and insulin action measured in isolated skeletal muscles remained lower in the transgenic compared with the NT group, even after Ex/CR. Comprehensive profiling of >200 metabolites and lipid intermediates revealed dramatic group-specific responses to the intervention but did not produce a lead candidate that tracked with changes in glucose tolerance irrespective of genotype. Instead, principal components analysis identified a chemically diverse metabolite cluster that correlated with multiple measures of insulin responsiveness. These findings challenge the notion that increased oxidative capacity defends whole-body energy homeostasis and suggest that the interplay between mitochondrial performance, lipotoxicity, and insulin action is more complex than previously proposed. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.


McDonnell E.,Duke Molecular Physiology Institute | Peterson B.S.,Duke Molecular Physiology Institute | Bomze H.M.,Duke Molecular Physiology Institute | Hirschey M.D.,Duke Molecular Physiology Institute | Hirschey M.D.,Duke University
Trends in Endocrinology and Metabolism | Year: 2015

The mitochondrial sirtuin SIRT3 is a protein deacylase that influences almost every major aspect of mitochondrial biology, including nutrient oxidation, ATP generation, reactive oxygen species (ROS) detoxification, mitochondrial dynamics, and the mitochondrial unfolded protein response (UPR). Interestingly, mice lacking SIRT3 (SIRT3KO), either spontaneously or when crossed with mouse models of disease, develop several diseases of aging at an accelerated pace, such as cancer, metabolic syndrome, cardiovascular disease, and neurodegenerative diseases, and, thus, might be a valuable model of accelerated aging. In this review, we discuss functions of SIRT3 in pathways involved in diseases of aging and how the lack of SIRT3 might accelerate the aging process. We also suggest that further studies on SIRT3 will help uncover important new pathways driving the aging process. © 2015 Elsevier Ltd.


Olson S.A.,Duke University | Furman B.D.,Duke University | Kraus V.B.,Duke Molecular Physiology Institute | Kraus V.B.,Duke University | And 2 more authors.
Journal of Orthopaedic Research | Year: 2015

An estimated 12% of patients seeking surgical intervention for symptomatic arthritis have an etiology of post-traumatic arthritis (PTA). The onset of PTA is rapid in the setting of articular fracture (AF). The investigation began with development of a murine model of a closed AF that develops PTA. In the process of characterizing this model a technique was developed for assessing quantitative synovial fluid biomarker concentrations. The work began with observations of the natural history of PTA development in the C57BL/6 strain of mice. A species of mice (MRL/MpJ) was found that is protected from PTA after AF. Further work identified key differences between mouse strains that did and did not develop PTA. This knowledge led to an intervention based on anti-cytokine (interleukin 1 receptor antagonist, (IL-1Ra) delivery in the C57BL/6 strain of mice that successfully prevented PTA following AF. This success in preventing PTA in the murine model has elucidated several important clinical implications: 1) Pro-inflammatory cytokines play an important role in the development of PTA after joint injury, 2) Pharmacologic intervention can lessen the severity of PTA after an AF, and 3) The murine AF model of joint injury provides a novel means of studying mechanisms of PTA development. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.


Todor H.,Duke University | Dulmage K.,Duke University | Gillum N.,Duke University | Bain J.R.,Duke University | And 3 more authors.
Molecular Microbiology | Year: 2014

Co-ordinating metabolism and growth is a key challenge for all organisms. Despite fluctuating environments, cells must produce the same metabolic outputs to thrive. The mechanisms underlying this 'growth homeostasis' are known in bacteria and eukaryotes, but remain unexplored in archaea. In the model archaeon Halobacterium salinarum, the transcription factor TrmB regulates enzyme-coding genes in diverse metabolic pathways in response to glucose. However, H. salinarum is thought not to catabolize glucose. To resolve this discrepancy, we demonstrate that TrmB regulates the gluconeogenic production of sugars incorporated into the cell surface S-layer glycoprotein. Additionally, we show that TrmB-DNA binding correlates with instantaneous growth rate, likely because S-layer glycosylation is proportional to growth. This suggests that TrmB transduces a growth rate signal to co-regulated metabolic pathways including amino acid, purine, and cobalamin biosynthesis. Remarkably, the topology and function of this growth homeostatic network appear conserved across domains despite extensive alterations in protein components. © 2014 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.


Orlowsky E.W.,Duke Molecular Physiology Institute | Orlowsky E.W.,Duke University | Kraus V.B.,Duke Molecular Physiology Institute | Kraus V.B.,Duke University
Journal of Rheumatology | Year: 2015

Although osteoarthritis (OA) has existed since the dawn of humanity, its pathogenesis remains poorly understood. OA is no longer considered a "wear and tear" condition but rather one driven by proteases where chronic low-grade inflammation may play a role in perpetuating proteolytic activity. While multiple factors are likely active in this process, recent evidence has implicated the innate immune system, the older or more primitive part of the body's immune defense mechanisms. The roles of some of the components of the innate immune system have been tested in OA models in vivo including the roles of synovial macrophages and the complement system. This review is a selective overview of a large and evolving field. Insights into these mechanisms might inform our ability to identify patient subsets and give hope for the advent of novel OA therapies. The Journal of Rheumatology Copyright © 2015. All rights reserved.


Siska P.J.,Duke Molecular Physiology Institute | Rathmell J.C.,Duke Molecular Physiology Institute
Trends in Immunology | Year: 2015

T cell metabolism has a central role in supporting and shaping immune responses and may have a key role in antitumor immunity. T cell metabolism is normally held under tight regulation in an immune response of glycolysis to promote effector T cell expansion and function. However, tumors may deplete nutrients, generate toxic products, or stimulate conserved negative feedback mechanisms, such as through Programmed Cell Death 1 (PD-1), to impair effector T cell nutrient uptake and metabolic fitness. In addition, regulatory T cells are favored in low glucose conditions and may inhibit antitumor immune responses. Here, we review how the tumor microenvironment modifies metabolic and functional pathways in T cells and how these changes may uncover new targets and challenges for cancer immunotherapy and treatment. © 2015 Elsevier Ltd.


PubMed | Indiana University, Duke University, Duke Molecular Physiology Institute, Harvard University and George Washington University
Type: Journal Article | Journal: Arthritis research & therapy | Year: 2017

To identify molecular alterations in skeletal muscle in rheumatoid arthritis (RA) that may contribute to ongoing disability in RA.Persons with seropositive or erosive RA (n=51) and control subjects matched for age, gender, race, body mass index (BMI), and physical activity (n=51) underwent assessment of disease activity, disability, pain, physical activity and thigh muscle biopsies. Muscle tissue was used for measurement of pro-inflammatory markers, transcriptomics, and comprehensive profiling of metabolic intermediates. Groups were compared using mixed models. Bivariate associations were assessed with Spearman correlation.Compared to controls, patients with RA had 75% greater muscle concentrations of IL-6 protein (p=0.006). In patients with RA, muscle concentrations of inflammatory markers were positively associated (p<0.05 for all) with disease activity (IL-1, IL-8), disability (IL-1, IL-6), pain (IL-1, TNF-, toll-like receptor (TLR)-4), and physical inactivity (IL-1, IL-6). Muscle cytokines were not related to corresponding systemic cytokines. Prominent among the gene sets differentially expressed in muscles in RA versus controls were those involved in skeletal muscle repair processes and glycolytic metabolism. Metabolic profiling revealed 46% higher concentrations of pyruvate in muscle in RA (p<0.05), and strong positive correlation between levels of amino acids involved in fibrosis (arginine, ornithine, proline, and glycine) and disability (p<0.05).RA is accompanied by broad-ranging molecular alterations in skeletal muscle. Analysis of inflammatory markers, gene expression, and metabolic intermediates linked disease-related disruptions in muscle inflammatory signaling, remodeling, and metabolic programming to physical inactivity and disability. Thus, skeletal muscle dysfunction might contribute to a viscous cycle of RA disease activity, physical inactivity, and disability.


News Article | September 23, 2016
Site: www.biosciencetechnology.com

While searching for  a non-invasive way to detect prostate cancer cells circulating in blood, Duke Cancer Institute researchers have identified some blood markers associated with tumor resistance to two common hormone therapies. In a study published online this month in the journal Clinical Cancer Research, the Duke-led team reported that they isolated multiple key gene alterations in the circulating prostate tumor cells of patients who had developed resistance to abiraterone or enzalutamide. Enzalutamide is a drug that blocks the male androgen receptor, and abiraterone is a drug that lowers testosterone levels. Both drugs are approved to treat hormone-resistant prostate cancer, but the tumors typically develop resistance within a few years. The study, focusing on a small number of patients and using sophisticated blood analysis technology, demonstrated that circulating tumor cells detected in blood have the potential to reveal important genetic information that could guide treatments selection in the future, and suggest targets for new therapies. “We have developed a method that allows us to examine the whole genome of rare circulating cancer cells in the blood, which is unique in each patient, and which can change over time during treatment,” said senior author Andrew Armstrong, M.D., a medical oncologist and co-director of Genitourinary Clinical-Translational Research at the Duke Cancer Institute (DCI). “Among the genomic changes in the patients’ individual cancers, we were able to find key similarities between the cancer cells of men who have hormone-resistant prostate cancer,” Armstrong said. “Our goal is to develop a ‘liquid biopsy’ that would be non-invasive, yet provide information that could guide clinical decisions.” Armstrong and colleagues from the DCI and the Duke Molecular Physiology Institute used a process called array-based comparative genomic hybridization to analyze the genome of the circulating tumor cells of 16 men with advanced, treatment-resistant prostate cancer. The technique enabled them to determine which genes had extra copies and which regions were deleted. Focusing both on genes that have previously been implicated in tumor progression, plus other genes important to cancer biology, the researchers found changes in multiple genetic pathways that appear to be in common among the men’s circulating tumor cells. “Our research provides evidence supporting the ability to measure gains and losses of large scale sections of the circulating tumor cells genome in men with prostate cancer,” said co-author Simon Gregory, Ph.D., director of the Section of Genomics and Epigenetics in the Duke Molecular Physiology Institute. “We are now evaluating this method combined with higher resolution DNA mutational studies and measurements of RNA splice variants in CTCs to determine their clinical relevance to patients and treatment resistance.” Should these common alterations be similarly identified in larger studies, they could be used as biomarkers as part of a blood-based liquid biopsy to help determine what treatments would be most effective. The findings could also point to new targets for drug development. One such large prospective clinical validation study is underway now at the Duke Cancer Institute, which is examining how the mutations develop in the context of enzalutamide or abiraterone therapy, and how the mutations relate to other key genetic events. The study received support from the Robert B. Goergen Prostate Cancer Foundation and the Department of Defense. Authors reported no conflicts of interest.

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