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

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Vis graf over relationer

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.

OriginalsprogEngelsk
Artikelnummer2431
TidsskriftNature Communications
Vol/bind12
Udgave nummer1
Sider (fra-til)2431
ISSN2041-1723
DOI
StatusUdgivet - 23 apr. 2021

Bibliografisk note

Funding Information:
We thank Swegene Center for Integrative Biology at Lund University (SCIBLU) Genomics Facility, and Maria Sterner and Malin Neptin at Lund University Diabetes Center (LUDC) for help with DNA methylation and/or mRNA expression analyses, Anna Hammerberg, and the Cellomics Platform at MultiPark at Lund University for help with HCS analyses, as well as the Transgenic Core Facility at Lund University for help with embryo transfer of Vps39+/− embryos. The LAMP1 and LAMP2 antibodies, developed by August, J.T./Hil-dreth, J.E.K. (The Johns Hopkins University School of Medicine) was obtained from the Developmental Studies Hybridoma Bank (DSHB), created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City (USA). This work was supported by grants from the Swedish Foundation for Strategic Research IRC15-0067, Swedish Research Council, Region Skåne (ALF), Knut and Alice Wallenberg Foundation, Novo Nordisk Foundation, EFSD/Lilly Fellowship, Söderberg Foundation, The Swedish Diabetes Foundation, Diabetes Wellness Sweden, Påhlsson Foundation, The Royal Physiographic Society of Lund, EXODIAB (2009-1039), and Linné grant (B31 5631/2006). The Centre of Inflammation and Metabolism (CIM) is supported by a grant from the Danish National Research Foundation (DNRF55). The Centre for Physical Activity Research (CFAS) is supported by a grant from Trygfonden. Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen (Denmark), and partially funded by an unconditional donation from the Novo Nordisk Foundation (http://www.cbmr.ku.dk/) (Grant number NNF18CC0034900).

Publisher Copyright:
© 2021, The Author(s).

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