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

Kenneth A. Dyar; Stefano Ciciliot; Lauren E. Wright; Rasmus Sjørup Biensø; Guidantonio M. Tagliazucchi; Vishal R. Patel; Mattia Forcato; Marcia I.P. Paz; Anders Gudiksen; Francesca Solagna; Mattia Albiero; Irene Moretti; Kristin L. Eckel-Mahan; Pierre Baldi; Paolo Sassone-Corsi; Rosario Rizzuto; Silvio Bicciato; Henriette Pilegaard; Bert Blaauw; Stefano Schiaffino

doi:10.1016/j.molmet.2013.10.005

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

Kenneth A. Dyar^*, Stefano Ciciliot, Lauren E. Wright, Rasmus Sjørup Biensø, Guidantonio M. Tagliazucchi, Vishal R. Patel, Mattia Forcato, Marcia I.P. Paz, Anders Gudiksen, Francesca Solagna, Mattia Albiero, Irene Moretti, Kristin L. Eckel-Mahan, Pierre Baldi, Paolo Sassone-Corsi, Rosario Rizzuto, Silvio Bicciato, Henriette Pilegaard, Bert Blaauw, Stefano Schiaffino

^*Corresponding author for this work

Molecular Integrative Physiology

202 Citations (Scopus)

675 Downloads (Pure)

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.

Original language	English
Journal	Molecular Metabolism
Volume	3
Issue number	1
Pages (from-to)	29-41
Number of pages	13
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2013.10.005
Publication status	Published - 2014

Keywords

Bmal1
Circadian rhythms
Glucose metabolism
Glucose uptake
Muscle insulin resistance
Skeletal muscle

Access to Document

10.1016/j.molmet.2013.10.005

Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clockFinal published version, 2.36 MB

Cite this

Dyar, K. A., Ciciliot, S., Wright, L. E., Biensø, R. S., Tagliazucchi, G. M., Patel, V. R., Forcato, M., Paz, M. I. P., Gudiksen, A., Solagna, F., Albiero, M., Moretti, I., Eckel-Mahan, K. L., Baldi, P., Sassone-Corsi, P., Rizzuto, R., Bicciato, S., Pilegaard, H., Blaauw, B., & Schiaffino, S. (2014). Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock. Molecular Metabolism, 3(1), 29-41. https://doi.org/10.1016/j.molmet.2013.10.005

Dyar, KA, Ciciliot, S, Wright, LE, Biensø, RS, Tagliazucchi, GM, Patel, VR, Forcato, M, Paz, MIP, Gudiksen, A, Solagna, F, Albiero, M, Moretti, I, Eckel-Mahan, KL, Baldi, P, Sassone-Corsi, P, Rizzuto, R, Bicciato, S, Pilegaard, H, Blaauw, B & Schiaffino, S 2014, 'Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock', Molecular Metabolism, vol. 3, no. 1, pp. 29-41. https://doi.org/10.1016/j.molmet.2013.10.005

@article{c17d6bb301d3452082c785b1df437ae7,

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.",

keywords = "Bmal1, Circadian rhythms, Glucose metabolism, Glucose uptake, Muscle insulin resistance, Skeletal muscle",

author = "Dyar, {Kenneth A.} and Stefano Ciciliot and Wright, {Lauren E.} and Biens{\o}, {Rasmus Sj{\o}rup} and Tagliazucchi, {Guidantonio M.} and Patel, {Vishal R.} and Mattia Forcato and Paz, {Marcia I.P.} and Anders Gudiksen and Francesca Solagna and Mattia Albiero and Irene Moretti and Eckel-Mahan, {Kristin L.} and Pierre Baldi and Paolo Sassone-Corsi and Rosario Rizzuto and Silvio Bicciato and Henriette Pilegaard and Bert Blaauw and Stefano Schiaffino",

year = "2014",

doi = "10.1016/j.molmet.2013.10.005",

language = "English",

volume = "3",

pages = "29--41",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier",

number = "1",

}

TY - JOUR

T1 - Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock

AU - Dyar, Kenneth A.

AU - Ciciliot, Stefano

AU - Wright, Lauren E.

AU - Biensø, Rasmus Sjørup

AU - Tagliazucchi, Guidantonio M.

AU - Patel, Vishal R.

AU - Forcato, Mattia

AU - Paz, Marcia I.P.

AU - Gudiksen, Anders

AU - Solagna, Francesca

AU - Albiero, Mattia

AU - Moretti, Irene

AU - Eckel-Mahan, Kristin L.

AU - Baldi, Pierre

AU - Sassone-Corsi, Paolo

AU - Rizzuto, Rosario

AU - Bicciato, Silvio

AU - Pilegaard, Henriette

AU - Blaauw, Bert

AU - Schiaffino, Stefano

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Bmal1

KW - Circadian rhythms

KW - Glucose metabolism

KW - Glucose uptake

KW - Muscle insulin resistance

KW - Skeletal muscle

U2 - 10.1016/j.molmet.2013.10.005

DO - 10.1016/j.molmet.2013.10.005

M3 - Journal article

C2 - 24567902

AN - SCOPUS:84895128336

SN - 2212-8778

VL - 3

SP - 29

EP - 41

JO - Molecular Metabolism

JF - Molecular Metabolism

IS - 1

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this