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VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics

Author

Listed:
  • Cajsa Davegårdh

    (Lund University Diabetes Centre, Lund University, Scania University Hospital)

  • Johanna Säll

    (Lund University Diabetes Centre, Lund University, Scania University Hospital)

  • Anna Benrick

    (University of Gothenburg
    University of Skövde)

  • Christa Broholm

    (Diabetes and Bone-metabolic Research Unit, Department of Endocrinology, Rigshospitalet)

  • Petr Volkov

    (Lund University Diabetes Centre, Lund University, Scania University Hospital)

  • Alexander Perfilyev

    (Lund University Diabetes Centre, Lund University, Scania University Hospital)

  • Tora Ida Henriksen

    (Rigshospitalet, University of Copenhagen)

  • Yanling Wu

    (University of Gothenburg)

  • Line Hjort

    (Diabetes and Bone-metabolic Research Unit, Department of Endocrinology, Rigshospitalet
    Department of Obstetrics, Rigshospitalet)

  • Charlotte Brøns

    (Diabetes and Bone-metabolic Research Unit, Department of Endocrinology, Rigshospitalet)

  • Ola Hansson

    (Lund University
    University of Helsinki)

  • Maria Pedersen

    (Rigshospitalet, University of Copenhagen)

  • Jens U. Würthner

    (ADC Therapeutics, Biopole)

  • Klaus Pfeffer

    (Heinrich Heine University Düsseldorf)

  • Emma Nilsson

    (Lund University Diabetes Centre, Lund University, Scania University Hospital)

  • Allan Vaag

    (Steno Diabetes Center Copenhagen)

  • Elisabet Stener-Victorin

    (Karolinska Institutet)

  • Karolina Pircs

    (Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University)

  • Camilla Scheele

    (Rigshospitalet, University of Copenhagen
    University of Copenhagen)

  • Charlotte Ling

    (Lund University Diabetes Centre, Lund University, Scania University Hospital)

Abstract

Insulin resistance and lower muscle quality (strength divided by mass) are hallmarks of type 2 diabetes (T2D). Here, we explore whether alterations in muscle stem cells (myoblasts) from individuals with T2D contribute to these phenotypes. We identify VPS39 as an important regulator of myoblast differentiation and muscle glucose uptake, and VPS39 is downregulated in myoblasts and myotubes from individuals with T2D. We discover a pathway connecting VPS39-deficiency in human myoblasts to impaired autophagy, abnormal epigenetic reprogramming, dysregulation of myogenic regulators, and perturbed differentiation. VPS39 knockdown in human myoblasts has profound effects on autophagic flux, insulin signaling, epigenetic enzymes, DNA methylation and expression of myogenic regulators, and gene sets related to the cell cycle, muscle structure and apoptosis. These data mimic what is observed in myoblasts from individuals with T2D. Furthermore, the muscle of Vps39+/− mice display reduced glucose uptake and altered expression of genes regulating autophagy, epigenetic programming, and myogenesis. Overall, VPS39-deficiency contributes to impaired muscle differentiation and reduced glucose uptake. VPS39 thereby offers a therapeutic target for T2D.

Suggested Citation

  • Cajsa Davegårdh & Johanna Säll & Anna Benrick & Christa Broholm & Petr Volkov & Alexander Perfilyev & Tora Ida Henriksen & Yanling Wu & Line Hjort & Charlotte Brøns & Ola Hansson & Maria Pedersen & Je, 2021. "VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22068-5
    DOI: 10.1038/s41467-021-22068-5
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