Ketogenic diet induces expression of the muscle circadian gene Slc25a25 via neural pathway that might be involved in muscle thermogenesis

We recently found that the mRNA expression of Slc25a25, a Ca(2+)-sensitive ATP carrier in the inner mitochondrial membrane, fluctuates in a circadian manner in mouse skeletal muscle. We showed here that the circadian expression of muscle Slc25a25 was damped in Clock mutant, muscle-specific Bmal1-deficient, and global Bmal1-deficient mice. Furthermore, a ketogenic diet (KD) that induces time-of-day-dependent hypothermia (torpor), induced Slc25a25 mRNA expression in skeletal muscle. Hypothermia induced by KD did not affect thermogenic genes such as Sarcolipin and Pgc1a in muscles and Ucp1 in adipose tissues. Sciatic denervation abolished circadian and KD-induced Slc25a25 expression, suggesting that the circadian clock regulates muscle Slc25a25 expression via neural pathways. We measured body temperature (Tb) in sciatic denervated mice fed with KD to determine the functional role of KD-induced Slc25a25 expression. Sciatic denervation abolished Slc25a25 expression and augmented KD-induced hypothermia compared with sham-operated mice, but did not affect Tb in mice given a normal diet. These findings suggest that KD feeding induces expression of the muscle circadian gene Slc25a25 via neural pathways, and that SLC25A25 might be involved in muscle thermogenesis under KD-induced hypothermia in mammals.