Insulin signaling regulates heart size in postnatal development

INSULIN SIGNALING REGULATES HEART SIZE IN POSTNATAL DEVELOPMENT I, Shiojima*,Div of Cardio Res, St.Elizabeth’s Med Center,Boston,MA,M,Yefremashvili,E.D.Abel,Prog inHuman Molecular Biology Genetics, Univ of Utah, Salt Lake City,UT, K.Walsh,Div of Cardio Res, St. Elizabeth’s Med Center,Boston,MA Insulin mediates a wide variety of biological responses includine regulation of elucose metabolism and urotein synthesis. Although eaylier studies have shown that insulin activates mRNA translation and stimulates global protein synthesis in the heart, the physiological role of insulin signaling in cardiac growth control is not well understood. To explore the role of insulin signaling in the heart, cardiac-specific insulin receptor knockout (CIRKO) mice were generated bv Cre/loxP recombination. No metabozc disorders ’ or growth retardation was observed in CIRKO mice. However, the heart weight/body weight ratio was significantly reduced in CIRKO mice, demonstrating that the loss of insulin signaling in cardiomyocytes attenuates physiological cardiac growth. Activities of Akt/PKB and S6K, two serine/threonine kinases that are thought to mediate insulin-induced protein synthesis, were downregulated in the hearts of CIRKO mice, suggesting that these molecules are the downstream effecters of insulinmediated cardiac growth. In support of this hypothesis, adenovirus-mediated delivery of constitutivelv active Akt was sufficient to induce cardiac growth in vi&. Although it is established that IGF regulates organ growth and body size, our results indicate that insulin is an important regulator of postnatal cardiac growth and suggest that insulin signaling regulates heart size in response to external nutritional condition.

ISCHAEMIAAND REPERFUSION INCREASE SARCOLEMMALGLUT4BUTDECREASE 2-FLUORO2-DEOXYGLUCOSE-BP (FDGBP)ACCUMULATlON RichardSouthworth,Roddfo A. Medina, WilliamFuller 8 PamelaB. Garlick.Guy’s,King’sand St Thomas’Schoolof Medicine,LondonSE19RT,UK. We have determinedthe effectsof regionalischaemiaand reperfusbnon glucosetransporter(GLUT)disfributionand 18FDG6Paccumulation(by PEf). Hearts(n=3/group)from fed or fasted Wistarrats were ‘dualperfused’ for 2 hours with Krebsbuffer(plus1lmM glucose+ 200MBq1sFDG)at 37oC.Total ischaemia(ISCH)of one of the coronarybeds was inducedfor 40 min. After60 min reperfusion(REP),the heartswere frozenin liquidNPand the distributionof GLUT1 and GLUT4 determinedin each coronarybed by Western blotting. ISCHand REPcausedtranslocationof GLUT4to the samolemmain fed (24 -+3% to 59 -+5%; PcO.01)and fasted(34-+5%to 41-+3%; P
LOW TOTAL CREATINE IN HYPERTHYROID HEARTS: MOLECULAR BASIS AND PHYSIOLOGICAL CONSEQUENCES Mercia Sifva Queiroz’, Yvonne Shao”, Deborah A. Berkich’, E. Douglas Lewandowokf’, Faraman I. Beigi*, Kathryn F. LaNoue’, Dept. of ‘C&M Physiology, Penn State Univ. College of Medicine, Hershey, PA; ‘Medicine and Physiology and Biophysics, Case Western Research Center, Cfevefand, OH and ‘Dept. of Physiology and Biophysics, Univ. of Illinois at Chicago Hearts from T;treated rats were studied to understand the basis for their lower maximal work capacity. The hypothesis was tested that diminished levels of creatine, typically found in hyperthyroid hearts, limit work capacity. Hearts of euthyroid and hyperthyroid rats were isolated and perfused isovolumicafly at low and high workloads. 0, consumption at high work was 4-fold higher than at low work. Increased perfusion pressures and 10 nM isoproterenol in the perfusate induced the work increase. Heads of hyperthyroid rats had only 53% of the total creatine of euthyroid hearts. The Na’icreatine transporter mRNA levels in hyperthyroid hearts were 3.0 + 0.5-fold lower than that in euthyroid hearts, while, in contrast, mRNA encoding uncoupling protein-3 (UCP-3) was 3.6 f 0.6-fold higher in hyperthyroid hearts. ATP levels of hyperthyroid hearts were lower than those of euthyroid hearts (18%) and decreased as workload increased. Free ADP (fADP) was higher (35%) in hyperthyroid hearts. Mitochondrial membrane potentials (AYm) measured in situ were lower in hearts of hyperthyroid rats at low but not high workloads. Since perfusion with fatty acids did not alter AYm in euthyroid or hyperthyroid hearts the conclusion was drawn that UCP’s are not responsible for the low AYm or high fADP of T,treated heads. The data suggest that diminished creatine may limit the capacity of the hyperthyroid hearts to sustain high ratios of cytosolic ATPMDP and thereby may limit the capacity of the heart for sustained high work output.

METABOLIC CHANGES IN TI-IE DIABETIC HEART UNDER ISCHEMIC CONDITIONS

William C. Stanley, De t. of Physiology and Biophysics, Case Western Reserve 8. mversity, Cleveland, Ohio, USA. Diabetic patients have a greater incidence of coronary artery disease, myocardial infarction, and heart failure than nondiabetic people. The poorer prognosis is largely due to derangements specific to the diabetic myocardium. The primary metabolic abnormality in the diabetic heart is impaired pymvate oxidation. Our studies in diabetic swine showed that diabetes causes a decrease in myocardial GLUT 1 and GLUT 4 protein expression, and a decrease in glucose uptake under normal and ischemic conditions (60% decrease in coronary flow). The activity of pyruvate dehydrogenase was lower in the diabetic myocardium, as was the rate of lactate uptake. When the work of the heart was doubled by infusing dobutamine, the rate of glucose uptake was not effected by diabetes, however pyruvate dehydrogenase activity was depressed in the diabetic animals. Nondiabetic animals had a significant increase in net lactate uptake during dobutamine infusion, while diabetic animals switched to net lactate output. This metabolic lesion appears to be largely secondary to high circulating free fatty acid and ketone body concentrations in the plasma, resulting in greater ace@-CoAJCoA and NADWNAD+ ratios in cardiac mitochondria, and subsequent inhibition of pyruvate dehydrogenase. Clinical studies demonstrate that therapies that reduce fatty acid oxidation and stimulating pyruvate oxidation (i.e. with glucose and insulin, or partial inhibitors of fatty acid oxidation) will improve clinical outcome in diabetic patients with ischemic heart disease.