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.
Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock
K. Dyar,Stefano Ciciliot,L. Wright,R. Biensø,G. Tagliazucchi,Vishal R. Patel,M. Forcato,Marcia I.P. Paz,Anders Gudiksen,Francesca Solagna,M. Albiero,Irene Moretti,Kristin L. Eckel-Mahan,P. Baldi,P. Sassone-Corsi,R. Rizzuto,S. Bicciato,H. Pilegaard,B. Blaauw,S. Schiaffino
Published 2013 in Molecular Metabolism
ABSTRACT
PUBLICATION RECORD
- Publication year
2013
- Venue
Molecular Metabolism
- Publication date
2013-10-23
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- bmal1
A core circadian clock gene and transcription factor expressed in skeletal muscle.
- glut4
The insulin-responsive glucose transporter that mediates glucose entry into muscle cells.
- muscle-specific bmal1 knockout
A conditional and inducible mouse model in which Bmal1 is ablated selectively in skeletal muscle.
- pdk4
A gene encoding pyruvate dehydrogenase kinase 4, a regulator of PDH activity.
- pdp1
A gene encoding pyruvate dehydrogenase phosphatase 1, a regulator of PDH activity.
- pyruvate dehydrogenase
The enzyme complex that links glycolysis to oxidative metabolism by converting pyruvate toward acetyl-CoA.
Aliases: PDH
- rest/fasting phase to active/feeding phase
The daily metabolic transition from the resting and fasting period to the active and feeding period in which skeletal muscle changes fuel use.
- skeletal muscle clock
The circadian timekeeping system operating within skeletal muscle tissue.
- tbc1d1
A Rab-GTPase regulatory protein involved in GLUT4 translocation in muscle.
REFERENCES
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