Down-regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes

Isa M. Lindgren, Rachel R. Drake, Natasha Chattergoon, Kent Thornburg

    Research output: Contribution to journalArticle

    Abstract

    Fetal cardiomyocytes shift from glycolysis to oxidative phosphorylation around the time of birth. Myeloid ecotropic viral integration site 1 (MEIS1) is a transcription factor that promotes glycolysis in hematopoietic stem cells. We reasoned that MEIS1 could have a similar role in the developing heart. We hypothesized that suppression of MEIS1 expression in fetal sheep cardiomyocytes leads to a metabolic switch as found at birth. Expression of MEIS1 was assayed in left ventricular cardiac tissue and primary cultures of cardiomyocytes from fetal (100- and 135-d gestation, term = 145 d), neonatal, and adult sheep. Cultured cells were treated with short interfering RNA (siRNA) to suppress MEIS1. Oxygen consumption rate was assessed with the Seahorse metabolic flux analyzer, and mitochondrial activity was assessed by staining cells with MitoTracker Orange. Cardiomyocyte respiratory capacity increased with advancing age concurrently with decreased expression of MEIS1. MEIS1 suppression with siRNA increased maximal oxygen consumption in fetal cells but not in postnatal cells. Mitochondrial activity was increased and expression of glycolytic genes decreased when MEIS1 expression was suppressed. Thus, we conclude that MEIS1 is a key regulator of cardiomyocyte metabolism and that the normal down-regulation of MEIS1 with age underlies a gradual switch to oxidative metabolism.-Lindgren, I. M., Drake, R. R., Chattergoon, N. N., Thornburg, K. L. Down-regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes.

    Original languageEnglish (US)
    Pages (from-to)7417-7426
    Number of pages10
    JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
    Volume33
    Issue number6
    DOIs
    StatePublished - Jun 1 2019

    Fingerprint

    Virus Integration
    Oxidative Phosphorylation
    Cardiac Myocytes
    Down-Regulation
    Glycolysis
    Metabolism
    Oxygen Consumption
    Small Interfering RNA
    Sheep
    Switches
    Parturition
    Oxygen
    Smegmamorpha
    Hematopoietic Stem Cells
    Stem cells
    Cultured Cells
    Transcription Factors
    Genes

    Keywords

    • development
    • fetal heart
    • glycolysis
    • metabolic shift
    • mitochondrial respiration

    ASJC Scopus subject areas

    • Biotechnology
    • Biochemistry
    • Molecular Biology
    • Genetics

    Cite this

    @article{cfb18b195545434c986d9d1cab51a73e,
    title = "Down-regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes",
    abstract = "Fetal cardiomyocytes shift from glycolysis to oxidative phosphorylation around the time of birth. Myeloid ecotropic viral integration site 1 (MEIS1) is a transcription factor that promotes glycolysis in hematopoietic stem cells. We reasoned that MEIS1 could have a similar role in the developing heart. We hypothesized that suppression of MEIS1 expression in fetal sheep cardiomyocytes leads to a metabolic switch as found at birth. Expression of MEIS1 was assayed in left ventricular cardiac tissue and primary cultures of cardiomyocytes from fetal (100- and 135-d gestation, term = 145 d), neonatal, and adult sheep. Cultured cells were treated with short interfering RNA (siRNA) to suppress MEIS1. Oxygen consumption rate was assessed with the Seahorse metabolic flux analyzer, and mitochondrial activity was assessed by staining cells with MitoTracker Orange. Cardiomyocyte respiratory capacity increased with advancing age concurrently with decreased expression of MEIS1. MEIS1 suppression with siRNA increased maximal oxygen consumption in fetal cells but not in postnatal cells. Mitochondrial activity was increased and expression of glycolytic genes decreased when MEIS1 expression was suppressed. Thus, we conclude that MEIS1 is a key regulator of cardiomyocyte metabolism and that the normal down-regulation of MEIS1 with age underlies a gradual switch to oxidative metabolism.-Lindgren, I. M., Drake, R. R., Chattergoon, N. N., Thornburg, K. L. Down-regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes.",
    keywords = "development, fetal heart, glycolysis, metabolic shift, mitochondrial respiration",
    author = "Lindgren, {Isa M.} and Drake, {Rachel R.} and Natasha Chattergoon and Kent Thornburg",
    year = "2019",
    month = "6",
    day = "1",
    doi = "10.1096/fj.201801330RR",
    language = "English (US)",
    volume = "33",
    pages = "7417--7426",
    journal = "FASEB Journal",
    issn = "0892-6638",
    publisher = "FASEB",
    number = "6",

    }

    TY - JOUR

    T1 - Down-regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes

    AU - Lindgren, Isa M.

    AU - Drake, Rachel R.

    AU - Chattergoon, Natasha

    AU - Thornburg, Kent

    PY - 2019/6/1

    Y1 - 2019/6/1

    N2 - Fetal cardiomyocytes shift from glycolysis to oxidative phosphorylation around the time of birth. Myeloid ecotropic viral integration site 1 (MEIS1) is a transcription factor that promotes glycolysis in hematopoietic stem cells. We reasoned that MEIS1 could have a similar role in the developing heart. We hypothesized that suppression of MEIS1 expression in fetal sheep cardiomyocytes leads to a metabolic switch as found at birth. Expression of MEIS1 was assayed in left ventricular cardiac tissue and primary cultures of cardiomyocytes from fetal (100- and 135-d gestation, term = 145 d), neonatal, and adult sheep. Cultured cells were treated with short interfering RNA (siRNA) to suppress MEIS1. Oxygen consumption rate was assessed with the Seahorse metabolic flux analyzer, and mitochondrial activity was assessed by staining cells with MitoTracker Orange. Cardiomyocyte respiratory capacity increased with advancing age concurrently with decreased expression of MEIS1. MEIS1 suppression with siRNA increased maximal oxygen consumption in fetal cells but not in postnatal cells. Mitochondrial activity was increased and expression of glycolytic genes decreased when MEIS1 expression was suppressed. Thus, we conclude that MEIS1 is a key regulator of cardiomyocyte metabolism and that the normal down-regulation of MEIS1 with age underlies a gradual switch to oxidative metabolism.-Lindgren, I. M., Drake, R. R., Chattergoon, N. N., Thornburg, K. L. Down-regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes.

    AB - Fetal cardiomyocytes shift from glycolysis to oxidative phosphorylation around the time of birth. Myeloid ecotropic viral integration site 1 (MEIS1) is a transcription factor that promotes glycolysis in hematopoietic stem cells. We reasoned that MEIS1 could have a similar role in the developing heart. We hypothesized that suppression of MEIS1 expression in fetal sheep cardiomyocytes leads to a metabolic switch as found at birth. Expression of MEIS1 was assayed in left ventricular cardiac tissue and primary cultures of cardiomyocytes from fetal (100- and 135-d gestation, term = 145 d), neonatal, and adult sheep. Cultured cells were treated with short interfering RNA (siRNA) to suppress MEIS1. Oxygen consumption rate was assessed with the Seahorse metabolic flux analyzer, and mitochondrial activity was assessed by staining cells with MitoTracker Orange. Cardiomyocyte respiratory capacity increased with advancing age concurrently with decreased expression of MEIS1. MEIS1 suppression with siRNA increased maximal oxygen consumption in fetal cells but not in postnatal cells. Mitochondrial activity was increased and expression of glycolytic genes decreased when MEIS1 expression was suppressed. Thus, we conclude that MEIS1 is a key regulator of cardiomyocyte metabolism and that the normal down-regulation of MEIS1 with age underlies a gradual switch to oxidative metabolism.-Lindgren, I. M., Drake, R. R., Chattergoon, N. N., Thornburg, K. L. Down-regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes.

    KW - development

    KW - fetal heart

    KW - glycolysis

    KW - metabolic shift

    KW - mitochondrial respiration

    UR - http://www.scopus.com/inward/record.url?scp=85067267223&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85067267223&partnerID=8YFLogxK

    U2 - 10.1096/fj.201801330RR

    DO - 10.1096/fj.201801330RR

    M3 - Article

    VL - 33

    SP - 7417

    EP - 7426

    JO - FASEB Journal

    JF - FASEB Journal

    SN - 0892-6638

    IS - 6

    ER -