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We began analyzing https://www.nature.com/articles/s42255-020-0169-x, but it redirected us to https://www.nature.com/articles/s42255-020-0169-x. The analysis below is for the second page.

Title[redir]:
Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression | Nature Metabolism
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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Keywords {🔍}

pubmed, google, scholar, cas, nature, data, mice, heart, central, pdk, cardiomyocyte, performed, regeneration, center, usa, independent, university, analysis, cell, control, texas, biologically, dallas, article, cardiac, pyruvate, access, fig, medical, myocardial, res, experiments, southwestern, research, postnatal, dehydrogenase, extended, protein, supported, regenerative, fatty, proliferation, cardiomyocytes, ventricular, adult, development, department, group, content, information,

Topics {✒️}

nature portfolio journals permissions reprints nature portfolio privacy policy peroxisome-proliferator-activated receptor alpha advertising cardiomyocyte cell-cycle arrest roger sik-yin foo metabolism research program camp-response element-binding protein social media tools endoplasmic-reticulum-resident kinase fatty-acid beta-oxidation tissue-specific gene manipulations electron transport chain-dependent myocardial substrate utilization research institute tamoxifen-inducible cre protein nature+ nature 497 nature 248 nature 464 nature 492 nature 397 nature fatty-acid utilization fatty acid-supported respiration mitochondrial h2o2 emission pyruvate dehydrogenase kinase sun yat-sen university 3 rna-seq analysis induce cardiomyocyte proliferation cell cycle reentry low-density lipoprotein cholesterol fatty-acid oxidation research extended data fig springerlink instant access permissions acute myocardial infarction myocardial infarction surgeries cardiomyocytes promotes proliferation fatty acid biosynthesis pyruvate dehydrogenase activity pyruvate dehydrogenase complex selectively enhance oxidation mammary gland development mitochondrial oxidative phosphorylation neonatal mammalian heart

Schema {🗺️}

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         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.
         datePublished:2020-02-20T00:00:00Z
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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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         Cardiac regeneration
         Cell-cycle exit
         Metabolism
         Life Sciences
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      url:http://orcid.org/0000-0002-8079-4618
      affiliation:
            name:Cardiovascular Research Institute, National University Singapore; Genome Institute of Singapore
            address:
               name:Cardiovascular Research Institute, National University Singapore; Genome Institute of Singapore, Singapore, Singapore
               type:PostalAddress
            type:Organization
      name:Ngoc Uyen Nhi Nguyen
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            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:Shujuan Li
      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:The First Affiliated Hospital, Sun Yat-sen University
            address:
               name:Department of Pediatric Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
               type:PostalAddress
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            name:NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University)
            address:
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               type:PostalAddress
            type:Organization
      name:Mahmoud Salama Ahmed
      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:Waleed M. Elhelaly
      affiliation:
            name:University of Texas Southwestern Medical Center
            address:
               name:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
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            address:
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      affiliation:
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            address:
               name:Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
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            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
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            name:University of Texas Southwestern Medical Center
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               name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
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            address:
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            name:University of Texas Southwestern Medical Center
            address:
               name:Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, USA
               type:PostalAddress
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            name:University of Texas Southwestern Medical Center
            address:
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      name:Joseph A. Hill
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            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
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            name:University of Texas Southwestern Medical Center
            address:
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            type:Organization
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            address:
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            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
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      email:[email protected]
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      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
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      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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