title: Gene regulation mediating fiber-type transformation in skeletal muscle cells is partly glucose- and ChREBP-dependent.
abstract: Adaptations in the oxidative capacity of skeletal muscle cells can occur under several physiological or pathological conditions. We investigated the effect of increasing extracellular glucose concentration on the expression of markers of energy metabolism in primary skeletal muscle cells and the C2C12 muscle cell line. Growth of myotubes in 25mM glucose (high glucose, HG) compared with 5.55mM led to increases in the expression and activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a marker of glycolytic energy metabolism, while oxidative markers peroxisome proliferator-activated receptor γ coactivator 1α and citrate synthase decreased. HG induced metabolic adaptations as are seen during a slow-to-fast fiber transformation. Furthermore, HG increased fast myosin heavy chain (MHC) IId/x but did not change slow MHCI/β expression. Protein phosphatase 2A (PP2A) was shown to mediate the effects of HG on GAPDH and MHCIId/x. Carbohydrate response element-binding protein (ChREBP), a glucose-dependent transcription factor downstream of PP2A, partially mediated the effects of glucose on metabolic markers. The glucose-induced increase in PP2A activity was associated with an increase in p38 mitogen-activated protein kinase activity, which presumably mediates the increase in MHCIId/x promoter activity. Liver X receptor, another possible mediator of glucose effects, induced only an incomplete metabolic shift, mainly increasing the expression of the glycolytic marker. Taken together, HG induces a partial slow-to-fast transformation comprising metabolic enzymes together with an increased expression of MHCIId/x. This work demonstrates a functional role for ChREBP in determining the metabolic type of muscle fibers and highlights the importance of glucose as a signaling molecule in muscle.
authors.affiliation: Department of Physiology, Vegetative Physiology 4220, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hanke
authors.forename: Renate J
authors.initials: RJ
authors.lastname: Scheibe
authors.forename: Georgi
authors.initials: G
authors.lastname: Manukjan
authors.forename: David
authors.initials: D
authors.lastname: Ewers
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Umeda
authors.forename: Kin-Chow
authors.initials: KC
authors.lastname: Chang
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kubis
authors.forename: Gerolf
authors.initials: G
authors.lastname: Gros
authors.forename: Joachim D
authors.initials: JD
authors.lastname: Meissner
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D002478:Cells, Cultured; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D000071518:Liver X Receptors; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011817:Rabbits; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071518:Liver X Receptors; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D014157:Transcription Factors; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D054648:Protein Phosphatase 2; D018995:Myosin Heavy Chains; D005947:Glucose