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Telomerase reverse transcriptase promotes cardiac muscle hyperplasia, hypertrophy, and survival
TELOMERASE REVERSE TRANSCRIF’TASE PROMOTES CARDIAC MUSCLE HYF’ERPLASIA, HYPERTROPHY, AND SURVlVAL M. Schneider*, H. Oh, G.Taffet, K. Youker, M. Entman, P.Overbeck, L. Michael, Center for Cardiovascular Development and the DeBakey Heart Center Graduate Pro ram in Cardiovascular Sciences, Baylor College of Medicine, Houston, TX, USA Cardiac muscle regeneration after injury is limited by “irreversible” cell cycle exit. Telomere shortening is one postulated basis for teplicative senescence, via down-regulation of telomerase reverse transcnptase (TERT); telomere dysfunction also is associated with greater sensitivitv to anootosis. Here. we have tested the hy othesis that preve%g the normal down-regulation OfpIER T in post-natal mvocardium would delav cardiac m oc e cell cycle exit. As predicted, forced expression Of%!2 RT in cardiac muscle in mice was sufficient to rescue telomerase activity and telomere length. Initially, the ventricle was hypercellular, with increased myocyte densi and DNA synthesis. By 12 weeks, cell cyclmg subs1? ed, instead, cell enlargement (hypertrophy) was seen, without fibrosis or impaired function as potential precipitating factors. Likewise, viral delivery of TERT was sufficient for h ertrophy in cultured cardiac The TE@I virus and transgene also in vitro and in vivo.
hypertrophy, and survival all required active were not seen with a catalytically inactive mutation. Thus, TERT can delay cell cycle exit in cardiac muscle, induce hypertrophy in ost-mitotic cells, and promote cardiac myocyte surv~v 3
HOW IMPORTANT IS MALONYL-COA DECARBOXYLASE AS A REGULATOR OF FATTY ACID OXIDATION IN THE HEART? Jason R. B. Dyck and Gary D. Lopaschuk. University of Alberta, Edmonton, Alberta, Canada. . Malonyl-CoA
is a potent inhibitor of camitine 1 and is important in regulating take into the mitochondria. Althou h the the heart by acetyf -CoA well characterized, less information is available as to how malonvl-CoA is degraded in the heart. Although primaril ‘located in the mitochondria, malonyl CoA decarboxy Yase (MCD) has recently been shownto be primarily responsible for the de adation of myocardial malon 1 CoA. MCD is a 50.7 is a protein, with the cDNA Yor MCD encoding both a initochondrial and peroxisomal targeting seauence. MCD is hiehlv exnressed in heart muscle. and studies from our hboratob and others has an important role in regulating fatty acid For instance, in hearts from newborn rabbits, fatty acid oxidation increases dramatically between l-day and 7day following birth? which is accompanied by a decrease in both ACC activi and malonyl-CoA levels. A parallel increase in M P D activity and expression is also observed. Furthermore, high fatty acid oxidation rates in hearts from adult streptozotocin-diabetic rats is also accompanied by an increase in MCD activity and expression. Recent evidence has also im licated peroxisome proliferator-activated receptor a (P K ARa) as an important transcription factor involved in this upregulation of MCD expression. These and other studies suggest that MCD is an important regulator of fatty acid oxidation. A150
SURVIVING MYOCARDIUM AFTER INFARCTION : DOES IT METABOLICALLY ADAPT 3 Ren6 Lerch, Nathalle Velin-Rosenblatt, Chrlstophe Montessult, Cardiology Center, University Hospital, Geneva, Switzerland The substrate pattern of energy metabolism may influence the outcome of surviving cardiomyocytes after infarction. Recent evidence indicates a shift from fatty acid to glucose metabolism in myocardium undergoing progressive postinfarction remodeling. Metabolic changes are associated with return to a fetal-like expression pattern of “metabolic” genes. We have observed in rats a shift from the insulin-sensitive glucose transporter GLUT4 to the “fetal” isoform GLUTl, both at the mRNA and protein level, 20 weeks after coronary occlusion. Concomitantly, several proteins involved in the regulation of fatty acid metabolism were downregulated. We currently use adult rat cardiomyocytes (ARC) in primary culture to study the signaling pathways involved in altered expression of glucose transporter isoforms. ARC in culture spontaneously undergo morphological changes reminiscent of hypertrophy with upregulation of GLUT1 and downregulation of GLUT4. Initial obsetvations indicate that the GLUT4/GLUTl-ratio is influenced by growth factors, whereby relative differences in activation of the ERKllP and the p38 MAPK pathways seem to play a role. In summary, the metabolic phenotype is altered during myocyte remodeling. Whether molecular changes of metabolic regulation are (( adaptive x remains to be further elucidated.
AN OVERVIEW OF THE CENTRAL ROLE OF CPT I IN THE REGULATION OF METABOLISM J. Denis McGarry-Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas The pivotal role of mitochondrial camitine almitoyltransferase I (CPT I) in fatty acid metabolism ed in 1977 when this enzyme was found to I-CoA, the product of ) reaction. Since that time, it has emerged at CPT I exists as at least two isoforms, the liver (L) and muscle (M) variants, with very different kinetic and regulato 7 properties and a tissue distribution that was not readi y predictable. The malonyl-CoA/CPT I partnership, in conjunction with the more recently discovered AMP-activated kinase (which appears to play a major role in the regulation of ACC), is now viewed as a central element in glucosefatty acid cross-talk in a variet of tissues. In addition, it has been implicated in x e regulation of insulin secretion from the pancreatic p-celi and as a possible player in the genesis of obesity/Type 2 diabetes syndromes. A recent and very provocative suggestion is that the fuel sensin function of malonyl-CoA might also be at work in f e central nervous system as a component of a etite control. Equally intriguing is the fact that M-& I is strongly expressed in the developing sperm, but what function it serves in these cells remams unclear. An overview of how this field has evolved in the past thirty years will be presented.
hypertrophy, and survival all required active were not seen with a catalytically inactive mutation. Thus, TERT can delay cell cycle exit in cardiac muscle, induce hypertrophy in ost-mitotic cells, and promote cardiac myocyte surv~v 3
HOW IMPORTANT IS MALONYL-COA DECARBOXYLASE AS A REGULATOR OF FATTY ACID OXIDATION IN THE HEART? Jason R. B. Dyck and Gary D. Lopaschuk. University of Alberta, Edmonton, Alberta, Canada. . Malonyl-CoA
is a potent inhibitor of camitine 1 and is important in regulating take into the mitochondria. Althou h the the heart by acetyf -CoA well characterized, less information is available as to how malonvl-CoA is degraded in the heart. Although primaril ‘located in the mitochondria, malonyl CoA decarboxy Yase (MCD) has recently been shownto be primarily responsible for the de adation of myocardial malon 1 CoA. MCD is a 50.7 is a protein, with the cDNA Yor MCD encoding both a initochondrial and peroxisomal targeting seauence. MCD is hiehlv exnressed in heart muscle. and studies from our hboratob and others has an important role in regulating fatty acid For instance, in hearts from newborn rabbits, fatty acid oxidation increases dramatically between l-day and 7day following birth? which is accompanied by a decrease in both ACC activi and malonyl-CoA levels. A parallel increase in M P D activity and expression is also observed. Furthermore, high fatty acid oxidation rates in hearts from adult streptozotocin-diabetic rats is also accompanied by an increase in MCD activity and expression. Recent evidence has also im licated peroxisome proliferator-activated receptor a (P K ARa) as an important transcription factor involved in this upregulation of MCD expression. These and other studies suggest that MCD is an important regulator of fatty acid oxidation. A150
SURVIVING MYOCARDIUM AFTER INFARCTION : DOES IT METABOLICALLY ADAPT 3 Ren6 Lerch, Nathalle Velin-Rosenblatt, Chrlstophe Montessult, Cardiology Center, University Hospital, Geneva, Switzerland The substrate pattern of energy metabolism may influence the outcome of surviving cardiomyocytes after infarction. Recent evidence indicates a shift from fatty acid to glucose metabolism in myocardium undergoing progressive postinfarction remodeling. Metabolic changes are associated with return to a fetal-like expression pattern of “metabolic” genes. We have observed in rats a shift from the insulin-sensitive glucose transporter GLUT4 to the “fetal” isoform GLUTl, both at the mRNA and protein level, 20 weeks after coronary occlusion. Concomitantly, several proteins involved in the regulation of fatty acid metabolism were downregulated. We currently use adult rat cardiomyocytes (ARC) in primary culture to study the signaling pathways involved in altered expression of glucose transporter isoforms. ARC in culture spontaneously undergo morphological changes reminiscent of hypertrophy with upregulation of GLUT1 and downregulation of GLUT4. Initial obsetvations indicate that the GLUT4/GLUTl-ratio is influenced by growth factors, whereby relative differences in activation of the ERKllP and the p38 MAPK pathways seem to play a role. In summary, the metabolic phenotype is altered during myocyte remodeling. Whether molecular changes of metabolic regulation are (( adaptive x remains to be further elucidated.
AN OVERVIEW OF THE CENTRAL ROLE OF CPT I IN THE REGULATION OF METABOLISM J. Denis McGarry-Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas The pivotal role of mitochondrial camitine almitoyltransferase I (CPT I) in fatty acid metabolism ed in 1977 when this enzyme was found to I-CoA, the product of ) reaction. Since that time, it has emerged at CPT I exists as at least two isoforms, the liver (L) and muscle (M) variants, with very different kinetic and regulato 7 properties and a tissue distribution that was not readi y predictable. The malonyl-CoA/CPT I partnership, in conjunction with the more recently discovered AMP-activated kinase (which appears to play a major role in the regulation of ACC), is now viewed as a central element in glucosefatty acid cross-talk in a variet of tissues. In addition, it has been implicated in x e regulation of insulin secretion from the pancreatic p-celi and as a possible player in the genesis of obesity/Type 2 diabetes syndromes. A recent and very provocative suggestion is that the fuel sensin function of malonyl-CoA might also be at work in f e central nervous system as a component of a etite control. Equally intriguing is the fact that M-& I is strongly expressed in the developing sperm, but what function it serves in these cells remams unclear. An overview of how this field has evolved in the past thirty years will be presented.