title: Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock.
abstract: Circadian rhythms control metabolism and energy homeostasis, but the role of the skeletal muscle clock has never been explored. We generated conditional and inducible mouse lines with muscle-specific ablation of the core clock gene Bmal1. Skeletal muscles from these mice showed impaired insulin-stimulated glucose uptake with reduced protein levels of GLUT4, the insulin-dependent glucose transporter, and TBC1D1, a Rab-GTPase involved in GLUT4 translocation. Pyruvate dehydrogenase (PDH) activity was also reduced due to altered expression of circadian genes Pdk4 and Pdp1, coding for PDH kinase and phosphatase, respectively. PDH inhibition leads to reduced glucose oxidation and diversion of glycolytic intermediates to alternative metabolic pathways, as revealed by metabolome analysis. The impaired glucose metabolism induced by muscle-specific Bmal1 knockout suggests that a major physiological role of the muscle clock is to prepare for the transition from the rest/fasting phase to the active/feeding phase, when glucose becomes the predominant fuel for skeletal muscle.
authors.affiliation: Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Dyar
authors.affiliation: Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ciciliot
authors.affiliation: Department of Biomedical Sciences, University of Padova, Italy.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Wright
authors.affiliation: Department of Biology, Molecular Integrative Physiology, University of Copenhagen, Denmark.
authors.forename: Rasmus S
authors.initials: RS
authors.lastname: Biensø
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Guidantonio M
authors.initials: GM
authors.lastname: Tagliazucchi
authors.affiliation: Department of Computer Science, Institute for Genomics and Bioinformatics, UC Irvine, USA.
authors.forename: Vishal R
authors.initials: VR
authors.lastname: Patel
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Forcato
authors.affiliation: Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
authors.forename: Marcia I P
authors.initials: MI
authors.lastname: Paz
authors.affiliation: Department of Biology, Molecular Integrative Physiology, University of Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Gudiksen
authors.affiliation: Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Solagna
authors.affiliation: Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Albiero
authors.affiliation: Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; CNR Institute of Neuroscience, Padova, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Moretti
authors.affiliation: Center for Epigenetics and Metabolism, UC Irvine, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Eckel-Mahan
authors.affiliation: Department of Computer Science, Institute for Genomics and Bioinformatics, UC Irvine, USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Baldi
authors.affiliation: Center for Epigenetics and Metabolism, UC Irvine, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Sassone-Corsi
authors.affiliation: Department of Biomedical Sciences, University of Padova, Italy ; CNR Institute of Neuroscience, Padova, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: Department of Biology, Molecular Integrative Physiology, University of Copenhagen, Denmark.
authors.forename: Henriette
authors.initials: H
authors.lastname: Pilegaard
authors.affiliation: Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; Department of Biomedical Sciences, University of Padova, Italy.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
authors.affiliation: Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; CNR Institute of Neuroscience, Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Schiaffino
keywords: 2-DG, 2-Deoxyglucose; BSA, bovine serum albumin; Bmal1; Circadian rhythms; GSEA, Gene Set Enrichment Analysis; Glucose metabolism; Glucose uptake; HK2, hexokinase 2; KHB, Krebs–Henseleit buffer; Muscle insulin resistance; PDH, pyruvate dehydrogenase; PDK, PDH kinase; PDP, PDH phosphatase; SCN, suprachiasmatic nucleus; Skeletal muscle; ZT, Zeitgeber time; imKO, inducible muscle-specific Bmal1 knockout; mKO, muscle-specific Bmal1 knockout