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

Kenneth A. Dyar, Stefano Ciciliot, Lauren E. Wright, Rasmus S. 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

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.