Crosstalk dynamics between the circadian clock and the mTORC1 pathway

Abstract

Crosstalk between the circadian clock clockwork and cellular metabolic regulatory networks is crucial to ensure an adequate response of an organism to the day/night cycle. mTOR (mammalian/mechanistic target of rapamycin) is a master growth regulator and sensor of nutrient status, which is part of the mTOR complex 1 (mTORC1). While the circadian clock confers rhythmicity to the mTOR protein by regulating its degradation rate, mTORC1 activity diminishes period and augments amplitude of circadian oscillations at the cellular level by a currently unknown mechanism. Here, we develop a mathematical deterministic DAE (differential–algebraic equation) model, to explore the possible interactions that allow mTORC1 to display such regulation of the core circadian clock. Our results suggest that mTORC1 is capable of regulating amplitude by exerting translational control on core the clock protein BMAL1, and that period-tuning is achieved by controlling post-translational localization of BMAL1. Since, in our model, mTORC1 control of BMAL1 localization greatly diminishes the ability of the clock to oscillate, and regulation of BMAL1 translation reduces this effect, our results also suggest that both levels of regulation must be present to ensure the robustness of oscillations. Together, the above results emphasize the importance of the influence of mTORC1 on the circadian rhythms.