title: Transcription Factor EB Controls Metabolic Flexibility during Exercise.
abstract: The transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
authors.forename: Gelsomina
authors.initials: G
authors.lastname: Mansueto
authors.affiliation: Department of Biomedical Science, University of Padova, Padova 35121, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armani
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge CB2 0XY, UK; Fondazione IRCCS Istituto Neurologico "C. Besta," 20133 Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: D'Orsi
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: De Cegli
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Polishchuk
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," 20133 Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," 20133 Milan, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Di Meo
authors.affiliation: Department of Biomedical Science, University of Padova, Padova 35121, Italy; Venetian Institute of Molecular Medicine, Padova 35129, Italy.
authors.forename: Vanina
authors.initials: V
authors.lastname: Romanello
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," 20133 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchet
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Saha
authors.affiliation: Hepatobiliary, Pancreatic, and Intestinal Research Institute, North Sichuan Medical College, Nanchong, Sichuan 637000, China; Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zong
authors.affiliation: Department of Biomedical Science, University of Padova, Padova 35121, Italy.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
authors.affiliation: Department of Biomedical Science, University of Padova, Padova 35121, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Solagna
authors.affiliation: Department of Biomedical Science, University of Padova, Padova 35121, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Tezze
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova 35121, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grumati
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova 35121, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.affiliation: Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge CB2 0XY, UK; Fondazione IRCCS Istituto Neurologico "C. Besta," 20133 Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy; Department of Biomedical Science, University of Padova, Padova 35121, Italy; Venetian Institute of Molecular Medicine, Padova 35129, Italy. Electronic address: marco.sandri@unipd.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy; Medical Genetics, Department of Pediatrics, Federico II University, Via Pansini 5, 80131 Naples, Italy; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: ballabio@tigem.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D050259:Genes, Mitochondrial; D016678:Genome; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D008660:Metabolism / Q000235:genetics; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D010805:Physical Conditioning, Animal; D021381:Protein Transport; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C484068:Tcfeb protein, mouse; D000263:Adenylate Kinase; D005947:Glucose
keywords: PGC1alpha; TFEB; autophagy; diabetes; exercise; glucose; insulin; metabolic flexibility; mitochondria; mitochondrial fusion