title: Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach.
abstract: 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).
  
  
  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.
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Ling
authors.initials: L
authors.lastname: Lai
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Ola J
authors.initials: OJ
authors.lastname: Martin
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Aimee T
authors.initials: AT
authors.lastname: Broman
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Nigro
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Kapil
authors.initials: K
authors.lastname: Kapoor
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Robert
authors.initials: R
authors.lastname: Stevens
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Rick B
authors.initials: RB
authors.lastname: Vega
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.).
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.affiliation: From the Diabetes and Obesity Research Center (J.N., K.K.), Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (L.L., T.C.L., O.J.M., R.B.V., D.P.K.); Department of Biochemistry (M.P.K., A.D.A.), and Department of Biostatistics and Medical Informatics (A.T.B.), University of Wisconsin-Madison, Madison, WI; and Duke Molecular Physiology Institute (T.R.K., R.S., O.R.I., D.M.M.), Departments of Medicine (T.R.K., D.M.M.), Pharmacology and Cancer Biology (D.M.M.), Duke University, Durham, NC (T.R.K., R.S., O.R.I., D.M.M.). dkelly@sanfordburnham.org.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D050356:Lipid Metabolism / Q000235:genetics; D055442:Metabolome; D051379:Mice; D015854:Up-Regulation / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D000596:Amino Acids
keywords: energy metabolism; heart failure; metabolomics; mitochondria; transcriptome profiling