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         headline:Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression
         description:The neonatal mammalian heart is capable of regeneration for a brief window of time after birth. However, this regenerative capacity is lost within the first week of life, which coincides with a postnatal shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty-acid utilization. Despite the energy advantage of fatty-acid beta-oxidation, cardiac mitochondria produce elevated rates of reactive oxygen species when utilizing fatty acids, which is thought to play a role in cardiomyocyte cell-cycle arrest through induction of DNA damage and activation of DNA-damage response (DDR) pathway. Here we show that inhibiting fatty-acid utilization promotes cardiomyocyte proliferation in the postnatal heart. First, neonatal mice fed fatty-acid-deficient milk showed prolongation of the postnatal cardiomyocyte proliferative window; however, cell-cycle arrest eventually ensued. Next, we generated a tamoxifen-inducible cardiomyocyte-specific pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse model to selectively enhance oxidation of glycolytically derived pyruvate in cardiomyocytes. Conditional PDK4 deletion resulted in an increase in pyruvate dehydrogenase activity and consequently an increase in glucose relative to fatty-acid oxidation. Loss of PDK4 also resulted in decreased cardiomyocyte size, decreased DNA damage and expression of DDR markers and an increase in cardiomyocyte proliferation. Following myocardial infarction, inducible deletion of PDK4 improved left ventricular function and decreased remodelling. Collectively, inhibition of fatty-acid utilization in cardiomyocytes promotes proliferation, and may be a viable target for cardiac regenerative therapies. Proliferation of cardiomyocytes typically ceases shortly after birth. Here the authors show that decreasing fatty-acid oxidation extends the perinatal cardiomyocyte proliferative window and can reintroduce cell-cycle activity in adult cardiomyocytes.
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      headline:Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression
      description:The neonatal mammalian heart is capable of regeneration for a brief window of time after birth. However, this regenerative capacity is lost within the first week of life, which coincides with a postnatal shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty-acid utilization. Despite the energy advantage of fatty-acid beta-oxidation, cardiac mitochondria produce elevated rates of reactive oxygen species when utilizing fatty acids, which is thought to play a role in cardiomyocyte cell-cycle arrest through induction of DNA damage and activation of DNA-damage response (DDR) pathway. Here we show that inhibiting fatty-acid utilization promotes cardiomyocyte proliferation in the postnatal heart. First, neonatal mice fed fatty-acid-deficient milk showed prolongation of the postnatal cardiomyocyte proliferative window; however, cell-cycle arrest eventually ensued. Next, we generated a tamoxifen-inducible cardiomyocyte-specific pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse model to selectively enhance oxidation of glycolytically derived pyruvate in cardiomyocytes. Conditional PDK4 deletion resulted in an increase in pyruvate dehydrogenase activity and consequently an increase in glucose relative to fatty-acid oxidation. Loss of PDK4 also resulted in decreased cardiomyocyte size, decreased DNA damage and expression of DDR markers and an increase in cardiomyocyte proliferation. Following myocardial infarction, inducible deletion of PDK4 improved left ventricular function and decreased remodelling. Collectively, inhibition of fatty-acid utilization in cardiomyocytes promotes proliferation, and may be a viable target for cardiac regenerative therapies. Proliferation of cardiomyocytes typically ceases shortly after birth. Here the authors show that decreasing fatty-acid oxidation extends the perinatal cardiomyocyte proliferative window and can reintroduce cell-cycle activity in adult cardiomyocytes.
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               type:PostalAddress
            type:Organization
      name:Salim Abdisalaam
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Aroumougame Asaithamby
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Chao Xing
      url:http://orcid.org/0000-0002-1838-0502
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:McDermontt Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Mohammed Kanchwala
      url:http://orcid.org/0000-0001-6035-2970
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:McDermontt Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Gonçalo Vale
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Kaitlyn M. Eckert
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Matthew A. Mitsche
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Jeffrey G. McDonald
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
            name:University of Texas Southwestern Medical Center
            address:
               name:Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Joseph A. Hill
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Linzhang Huang
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Philip W. Shaul
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Luke I. Szweda
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Hesham A. Sadek
      url:http://orcid.org/0000-0002-4745-366X
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
            name:University of Texas Southwestern Medical Center
            address:
               name:Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, USA
      name:Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Radiology, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Chemistry, University of Texas at Dallas, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Radiology, University of Texas Southwestern Medical Center, Dallas, USA
      name:Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Radiology, University of Texas Southwestern Medical Center, Dallas, USA
      name:Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA
      name:Cardiovascular Research Institute, National University Singapore; Genome Institute of Singapore, Singapore, Singapore
      name:Cardiovascular Research Institute, National University Singapore; Genome Institute of Singapore, Singapore, Singapore
      name:Cardiovascular Research Institute, National University Singapore; Genome Institute of Singapore, Singapore, Singapore
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Pediatric Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
      name:NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, USA
      name:McDermontt Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, USA
      name:McDermontt Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, USA
      name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
      name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
      name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
      name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA
      name:Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
      name:Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, USA
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