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Alexander Perfilyev

Assistant researcher

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

Author

  • 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
  • Jens U Würthner
  • Klaus Pfeffer
  • Emma Nilsson
  • Allan Vaag
  • Elisabet Stener-Victorin
  • Karolina Pircs
  • Camilla Scheele
  • Charlotte Ling

Summary, in English

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.

Department/s

  • Diabetes - Epigenetics
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Genomics, Diabetes and Endocrinology
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • MultiPark: Multidisciplinary research focused on Parkinson´s disease
  • Wallenberg Neuroscience Centre, Lund
  • Stem Cell Center

Publishing year

2021-04-23

Language

English

Publication/Series

Nature Communications

Volume

12

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Epigenetics
  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 2041-1723