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

Davegårdh, Cajsa LU orcid ; Säll, Johanna LU orcid ; Benrick, Anna ; Broholm, Christa ; Volkov, Petr LU ; Perfilyev, Alexander LU orcid ; Henriksen, Tora Ida ; Wu, Yanling ; Hjort, Line LU and Brøns, Charlotte , et al. (2021) In Nature Communications 12.
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
12
article number
2431
publisher
Nature Publishing Group
external identifiers
  • pmid:33893273
  • scopus:85104824362
ISSN
2041-1723
DOI
10.1038/s41467-021-22068-5
language
English
LU publication?
yes
id
47c13da1-a9c1-49a4-897c-6e075ca5692e
date added to LUP
2021-05-08 01:06:37
date last changed
2024-04-20 06:51:35
@article{47c13da1-a9c1-49a4-897c-6e075ca5692e,
  abstract     = {{<p>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.</p>}},
  author       = {{Davegårdh, Cajsa and Säll, Johanna and Benrick, Anna and Broholm, Christa and Volkov, Petr and Perfilyev, Alexander and Henriksen, Tora Ida and Wu, Yanling and Hjort, Line and Brøns, Charlotte and Hansson, Ola and Pedersen, Maria and Würthner, Jens U and Pfeffer, Klaus and Nilsson, Emma and Vaag, Allan and Stener-Victorin, Elisabet and Pircs, Karolina and Scheele, Camilla and Ling, Charlotte}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{04}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-22068-5}},
  doi          = {{10.1038/s41467-021-22068-5}},
  volume       = {{12}},
  year         = {{2021}},
}