title: Metabolic and Transcriptional Changes in Cultured Muscle Stem Cells from Low Birth Weight Subjects.
abstract: Developmental programming of human muscle stem cells could in part explain why individuals born with low birth weight (LBW) have an increased risk of developing type 2 diabetes (T2D) later in life. We hypothesized that immature muscle stem cell functions including abnormal differentiation potential and metabolic function could link LBW with the risk of developing T2D. Design/Settings/Participants: We recruited 23 young men with LBW and 16 age-matched control subjects with normal birth weight. Biopsies were obtained from vastus lateralis, and muscle stem cells were isolated and cultured into fully differentiated myotubes.
  
  
  
  We studied glucose uptake, glucose transporters, insulin signaling, key transcriptional markers of myotube maturity, selected site-specific DNA methylation, and mitochondrial gene expression.
  
  
  
  We found reduced glucose uptake as well as decreased levels of glucose transporter-1 and -4 mRNA and of the Akt substrate of 160-kDa mRNA and protein in myotubes from LBW individuals compared with normal birth weight individuals. The myogenic differentiation markers, myogenin and myosin heavy chain 1 and 2, were decreased during late differentiation in LBW myotubes. Additionally, mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator-1α and cytochrome c oxidase polypeptide 7A were reduced in LBW myotubes. Decreased gene expression was not explained by changes in DNA methylation levels.
  
  
  
  We demonstrate transcriptional and metabolic alterations in cultured primary satellite cells isolated from LBW individuals after several cell divisions, pointing toward a retained intrinsic defect conserved in these myotubes.
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Ninna S
authors.initials: NS
authors.lastname: Hansen
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Line
authors.initials: L
authors.lastname: Hjort
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Christa
authors.initials: C
authors.lastname: Broholm
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Linn
authors.initials: L
authors.lastname: Gillberg
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Maren
authors.initials: M
authors.lastname: Schrölkamp
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Schultz
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Brynjulf
authors.initials: B
authors.lastname: Mortensen
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Sine W
authors.initials: SW
authors.lastname: Jørgensen
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Friedrichsen
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Jørgen F P
authors.initials: JF
authors.lastname: Wojtaszewski
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007230:Infant, Low Birth Weight; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D018008:Myogenin / Q000235:genetics / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D052097:Quadriceps Muscle / Q000166:cytology / Q000378:metabolism*; D013234:Stem Cells; D055815:Young Adult
chemical_list: D051272:Glucose Transporter Type 1; D018008:Myogenin; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt; D018995:Myosin Heavy Chains