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

Davegårdh, Cajsa (author)
Lund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital,Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
Säll, Johanna (author)
Lund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital,Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
Benrick, Anna, 1979 (author)
Högskolan i Skövde,University of Gothenburg,Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology,Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden,Institutionen för hälsovetenskaper,Forskningsmiljön hälsa, hållbarhet och digitalisering,Translationell medicin TRIM, Translational Medicine
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Broholm, C. (author)
Copenhagen University Hospital,Diabetes and Bone-metabolic Research Unit, Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark
Volkov, Petr (author)
Lund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital,Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
Perfilyev, Alexander (author)
Lund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital,Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
Henriksen, T. I. (author)
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark
Wu, Yanling, 1985 (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology,Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden
Hjort, Line (author)
Copenhagen University Hospital,Diabetes and Bone-metabolic Research Unit, Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark ; Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark
Brons, C. (author)
Copenhagen University Hospital,Diabetes and Bone-metabolic Research Unit, Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark
Hansson, Ola (author)
Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups,Institute for Molecular Medicine Finland (FIMM),Genomics, Diabetes and Endocrinology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden ; Finnish Institute of Molecular Medicine, University of Helsinki, Finland
Pedersen, M. (author)
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark
Wurthner, J. U. (author)
ADC Therapeutics, Biopole, Epalinges, Switzerland
Pfeffer, K. (author)
Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Germany
Nilsson, Emma (author)
Lund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital,Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
Vaag, Allan (author)
Steno Diabetes Center Copenhagen, Gentofte, Denmark
Stener-Victorin, E. (author)
Karolinska Institutet,Karolinska Institute,Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Pircs, Karolina (author)
Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Wallenberg Neurocentrum, Lund,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Wallenberg Neuroscience Centre, Lund,Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Sweden
Scheele, C. (author)
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark ; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
Ling, Charlotte (author)
Lund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital,Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden
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 (creator_code:org_t)
2021-04-23
2021
English.
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
Related links:
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https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Keyword

messenger-rna expression
wide DNA methylation
open-access database
skeletal-muscle
gene-expression
satellite cells
adipose-tissue
regeneration
protein
transcription
Science & Technology - Other Topics
Translationell medicin TRIM

Publication and Content Type

ref (subject category)
art (subject category)

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