mTOR signaling regulates central and peripheral circadian clock function

Abstract

The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators. Using a combination of genetic and pharmacological approaches we show that mTOR regulates intrinsic clock properties including period and amplitude. In peripheral clock models of hepatocytes and adipocytes, mTOR inhibition lengthens period and dampens amplitude, whereas mTOR activation shortens period and augments amplitude. Constitutive activation of mTOR in Tsc2–/–fibroblasts elevates levels of core clock proteins, including CRY1, BMAL1 and CLOCK. Serum stimulation induces CRY1 upregulation in fibroblasts in an mTOR-dependent but Bmal1- and Period-independent manner. Consistent with results from cellular clock models, mTOR perturbation also regulates period and amplitude in the ex vivo SCN and liver clocks. Further, mTOR heterozygous mice show lengthened circadian period of locomotor activity in both constant darkness and constant light. Together, these results support a significant role for mTOR in circadian timekeeping and in linking metabolic states to circadian clock functions.

Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

“…However, the same timekeeping mechanisms, rhythms in mTORC activity, and daily variation in ion transport have been observed in other cellular contexts, both ex vivo and in vivo [8][9][10][11]26,64 . Based on our similar recent findings in human, algal and fungal cells 9,65 , we predict that rhythms in ion transport will be observed in any eukaryotic cell with oscillations in mTORC activity, circadian or otherwise.…”

“…Between 6% and 20% of cellular proteins are under circadian control, and the expression of most oscillating proteins peaks during translational "rush hours" that typically coincide with the organism's habitual active phase [1][2][3][4][5][6][7] . Daily regulation of mechanistic target-of-rapamycin complexes (mTORC) partitions phases of increased protein production (increased mTORC activity) from those of increased catabolism (decreased mTORC activity) [8][9][10][11] . This temporal organisation of protein homeostasis (proteostasis) permits the most efficient use of bioenergetic resources, both in vivo and in cultured mammalian cells [8][9][10][12][13][14] .…”

“…Daily regulation of mechanistic target-of-rapamycin complexes (mTORC) partitions phases of increased protein production (increased mTORC activity) from those of increased catabolism (decreased mTORC activity) [8][9][10][11] . This temporal organisation of protein homeostasis (proteostasis) permits the most efficient use of bioenergetic resources, both in vivo and in cultured mammalian cells [8][9][10][12][13][14] . How cellular protein concentration varies over circadian time in different intracellular compartments is currently unknown.…”

Emerging Roles of Translational Control in Circadian Timekeeping

“…used a variety of pharmacological and genetic mTOR gain-and loss-of-function models, as well as different cell and tissue types, to demonstrate that activation of mTOR shortens period and augments amplitude [82]. Through which specific clock protein(s) and mechanisms these effects are mediated is, however, still an outstanding question.…”

“…Through which specific clock protein(s) and mechanisms these effects are mediated is, however, still an outstanding question. Initially identified candidates are CRY1, CLOCK and 425 BMAL1, whose abundances all increase when mTOR is constitutively activated [82,83]. Recent findings that place mTORC1-mediated translational regulation of Period mRNAs downstream of feeding-mediated insulin signaling make the mechanism even more complex [84].…”