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

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http://hdl.handle.net/10138/335730

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Davegardh , C , Sall , J , Benrick , A , Broholm , C , Volkov , P , Perfilyev , A , Henriksen , TI , Wu , Y , Hjort , L , Brons , C , Hansson , O , Pedersen , M , Wurthner , JU , Pfeffer , K , Nilsson , E , Vaag , A , Stener-Victorin , E , Pircs , K , Scheele , C & Ling , C 2021 , ' VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics ' , Nature Communications , vol. 12 , no. 1 , 2431 . https://doi.org/10.1038/s41467-021-22068-5

Julkaisun nimi: VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics
Tekijä: Davegardh, C; Sall, J; Benrick, A; Broholm, C; Volkov, P; Perfilyev, A; Henriksen, TI; Wu, Y; Hjort, L; Brons, C; Hansson, O; Pedersen, M; Wurthner, JU; Pfeffer, K; Nilsson, E; Vaag, A; Stener-Victorin, E; Pircs, K; Scheele, C; Ling, C
Tekijän organisaatio: Institute for Molecular Medicine Finland
Päiväys: 2021-04
Kieli: eng
Kuuluu julkaisusarjaan: Nature Communications
ISSN: 2041-1723
DOI-tunniste: https://doi.org/10.1038/s41467-021-22068-5
URI: http://hdl.handle.net/10138/335730
Tiivistelmä: 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. Insulin resistance and lower muscle strength in relation to mass are hallmarks of type 2 diabetes. Here, the authors report alterations in muscle stem cells from individuals with type 2 diabetes that may contribute to these phenotypes through VPS39 mediated effects on autophagy and epigenetics.
Avainsanat: MESSENGER-RNA EXPRESSION
WIDE DNA METHYLATION
OPEN-ACCESS DATABASE
SKELETAL-MUSCLE
GENE-EXPRESSION
SATELLITE CELLS
ADIPOSE-TISSUE
REGENERATION
PROTEIN
TRANSCRIPTION
3121 General medicine, internal medicine and other clinical medicine
Vertaisarvioitu: Kyllä
Tekijänoikeustiedot: cc_by
Pääsyrajoitteet: openAccess
Rinnakkaistallennettu versio: publishedVersion


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