Fig. 5

Simplified scheme of glucose uptake and metabolism in muscle cells, highlighting two crucial steps controlled by the intrinsic muscle clock: insulin-dependent glucose uptake and pyruvate conversion to acetyl-CoA. Insulin promotes glucose uptake by activating the kinase AKT that phosphorylates the Rab-GTPase-activating protein TBC1D1, thus promoting the translocation of GLUT4 to the plasma membrane. Pyruvate, upon entry into mitochondria (mito), is metabolized to acetyl-CoA by pyruvate dehydrogenase (PDH), whose activity is inhibited by the PDH kinase PDK4 and stimulated by the PDH phosphatase PDP1. The protein expression of GLUT4, and both mRNA and protein levels of TBC1D1, PDK4, and PDP1 vary across the day-night cycle (0, lights on; 12, lights off) and are drastically affected by Bmal1 mKO. Under normal conditions, PDK4 has a peak of expression in the fasting phase (around ZT4), whereas PDP1 peaks around the transition from the fasting to the feeding/active phase (around ZT12). Note that PDK4 starts to decrease and PDP1 to increase during the fasting phase, before awakening, supporting the notion of the anticipatory role of the muscle clock, which prepares the muscles to the upcoming activity period. These circadian adaptations are completely disrupted by Bmal1 mKO, with downregulation of PDP1 and a rightward shift in the peak of PDK4, leading to decrease in PDH activity at awakening (data from [27])