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
VL - 3
SP - 29
EP - 41
JO - Molecular Metabolism
JF - Molecular Metabolism
SN - 2212-8778
IS - 1
ER -