title: TGF-β Contributes to Impaired Exercise Response by Suppression of Mitochondrial Key Regulators in Skeletal Muscle.
abstract: A substantial number of people at risk of developing type 2 diabetes could not improve insulin sensitivity by physical training intervention. We studied the mechanisms of this impaired exercise response in 20 middle-aged individuals at high risk of developing type 2 diabetes who performed 8 weeks of controlled cycling and walking training at 80% individual Vo2 peak. Participants identified as nonresponders in insulin sensitivity (based on the Matsuda index) did not differ in preintervention parameters compared with high responders. The failure to increase insulin sensitivity after training correlates with impaired upregulation of mitochondrial fuel oxidation genes in skeletal muscle, and with the suppression of the upstream regulators PGC1α and AMPKα2. The muscle transcriptomes of the nonresponders are further characterized by the activation of transforming growth factor (TGF)-β and TGF-β target genes, which is associated with increases in inflammatory and macrophage markers. TGF-β1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells. Activated TGF-β1 signaling downregulates the abundance of PGC1α, AMPKα2, the mitochondrial transcription factor TFAM, and mitochondrial enzymes. Thus, the data suggest that increased TGF-β activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity.
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Böhm
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Department of Sports Medicine, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schneeweiss
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schnauder
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Sailer
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Schmid
authors.affiliation: Department of Sports Medicine, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Hudemann
authors.affiliation: German Center for Diabetes Research (DZD), Neuherberg, Germany Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Machann
authors.affiliation: German Center for Diabetes Research (DZD), Neuherberg, Germany Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Schick
authors.affiliation: German Center for Diabetes Research (DZD), Neuherberg, Germany Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany Institute of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: German Center for Diabetes Research (DZD), Neuherberg, Germany Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany Institute of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.affiliation: Department of Sports Medicine, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Nieß
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany cora.weigert@med.uni-tuebingen.de.
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D015444:Exercise / Q000502:physiology; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood / Q000378:metabolism*
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016212:Transforming Growth Factor beta; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases