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

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 and Charlotte Ling ()
Additional contact information
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
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
Charlotte Brøns: Diabetes and Bone-metabolic Research Unit, Department of Endocrinology, Rigshospitalet
Ola Hansson: Lund University
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
Charlotte Ling: Lund University Diabetes Centre, Lund University, Scania University Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22068-5

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