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Mol Metab. 2013 Oct 23;3(1):29-41. doi: 10.1016/j.molmet.2013.10.005. eCollection 2014 Feb.

Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock.

Author information

1
Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
2
Department of Biomedical Sciences, University of Padova, Italy.
3
Department of Biology, Molecular Integrative Physiology, University of Copenhagen, Denmark.
4
Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
5
Department of Computer Science, Institute for Genomics and Bioinformatics, UC Irvine, USA.
6
Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; CNR Institute of Neuroscience, Padova, Italy.
7
Center for Epigenetics and Metabolism, UC Irvine, USA.
8
Department of Biomedical Sciences, University of Padova, Italy ; CNR Institute of Neuroscience, Padova, Italy.
9
Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; Department of Biomedical Sciences, University of Padova, Italy.

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.

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

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