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Cell Metab. 2017 Jan 10;25(1):182-196. doi: 10.1016/j.cmet.2016.11.003. Epub 2016 Dec 20.

Transcription Factor EB Controls Metabolic Flexibility during Exercise.

Author information

1
Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
2
Department of Biomedical Science, University of Padova, Padova 35121, Italy.
3
MRC Mitochondrial Biology Unit, Cambridge CB2 0XY, UK; Fondazione IRCCS Istituto Neurologico "C. Besta," 20133 Milan, Italy.
4
Fondazione IRCCS Istituto Neurologico "C. Besta," 20133 Milan, Italy.
5
Department of Biomedical Science, University of Padova, Padova 35121, Italy; Venetian Institute of Molecular Medicine, Padova 35129, Italy.
6
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
7
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.
8
Department of Molecular Medicine, University of Padova, Padova 35121, Italy.
9
Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
10
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.
11
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.

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.

KEYWORDS:

PGC1alpha; TFEB; autophagy; diabetes; exercise; glucose; insulin; metabolic flexibility; mitochondria; mitochondrial fusion

PMID:
28011087
PMCID:
PMC5241227
DOI:
10.1016/j.cmet.2016.11.003
[Indexed for MEDLINE]
Free PMC Article

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