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Talking the TORC

A target bulls-eye in a connected network of linked circles

Written by: Peter Williamson, Ph.D. | Issue # 15 | 06 2013

  • Milk provides bioactive molecules that stimulate growth.
  • Nutrients in milk are sensed by the baby’s cells, which turn on mTORC.
  • Inside cells, mTORC initiates the to-do list for making things needed by growing cells.
  • This knowledge could lead to new ways of measuring the health impact of milk.

Milk has evolved to sustain life through supporting the growth and healthy development of infants. A recent article in the prestigious journal Science reported a breakthrough in our understanding of what lies behind the cellular mechanism of the growth “switch”.

In order for the tissues in our body to grow, nutrients need to be converted into structural proteins and lipids, molecules important for energy storage and cell membrane maintenance. Two key events associated with milk production that rely on these critical nutrients are the growth of the mammary gland during pregnancy as it prepares for lactation and, of course, the growth of the baby that consumes the milk. Milk is not only a source of calories, but it also provides bioactive molecules that stimulate growth by switching on the appropriate physiological systems. We refer to this process of activation as an anabolic effect.

What causes growth?

Growth happens at the level of individual cells; growth and proliferation of cells leads to overall developmental growth of organs and tissues. Fundamentally, all cells respond to signals that are generated by nutrients (e.g., milk proteins), hormones (e.g., insulin), and the availability of energy.

We refer to cells as sensors for this purpose, and when there is a demand for growth, and the cells detect that conditions are just right, they switch on the cellular machinery that provides the building blocks for new cells and tissues. The sensing function works because of receptors attached to the outside of the cell that generate a message that travels to the inside of the cell. The “wires” that telegraph these messages are in fact molecules that link with one another. At the heart of this interaction is a molecule called mTOR, and when it is linked with its partners, it is called mTORC1.

How can mTORC1 send a signal?

Much work has focused on the messages that stimulate the formation of mTORC1, and one key element is the amount of the essential amino acid, leucine, that is present in the circulation. Leucine is a key indicator of amino acid “status”, and there are therefore specific receptors that cells use to detect levels of leucine (1). However, the effect that mTORC1 has on other molecules that control the sensor function and complete the messaging system are still emerging.

The missing link

A new study by Robitaille and colleagues from the University of Basel (2) has provided a major step forward in understanding this system. Robitaille et al. used a combination of test tube analysis and laboratory mouse model systems to find the molecules that were activated by mTORC1. First, they identified 1398 proteins that were affected by mTORC1 and then applied a computer-based method to aid some excellent detective work. Just like Sherlock Holmes, they came up with a brilliant deduction! There were groups of phosphoproteins that had not been previously observed, and when they followed the trail of interactions, it provided the missing link to a molecule called CAD. This link we now know plugs the mTORC1 complex into two well-known anabolic mechanisms known as the “de novo pyrimidine synthesis pathway” and the “pentose phosphate pathway”. In other words, mTORC1 initiates the cell’s instructions for making things needed for growth. Interestingly, these are biochemical pathways that we recognise from studies of mammary gland biology and lactation (3-5). By making this connection, Robitaille and colleagues have solved a riddle and for the first time connected nutrient sensing to the switch to anabolic capacity in cells.

Why is this important?

Both maternal and neonatal factors are crucial for the immediate healthy growth of the newborn, and what is becoming abundantly clear is that nutrient quantity and quality during neonatal growth has an impact on lifetime health. The anabolic switch is a key regulator of neonatal growth. Furthermore, the mammary gland itself depends on anabolic growth to achieve a level of production that can generate adequate amounts of milk. Evolutionary determinants of milk composition have provided a tuned and balanced nutrient source for regulating the anabolic switch.

The groundwork has been completed for us to find ways to monitor the cellular proteins at the centre of these events. The development of this approach will provide an efficient tool to measure the health impact of milk.

References

1. Dodd KM & Tee AR. (2012) Leucine and mTORC1: a complex relationship. Am J Physiol Endocrinol Metab 302: E1329-E1342.

2. Robitaille AM, Christen S, Shimobayashi M, Cornu M, Fava LL, Moes S, Prescianotto-Baschong C et al. (2013) Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339: 1320-1323.

3. Lemay DG, Lynn DJ, Martin WF, Neville MC, Casey TM, Rincon G, Kriventseva EV et al. (2009) The bovine lactation genome: insights into the evolution of mammalian milk. Genome Biol 10: R43.

4. Rudolph MC, Russell TD, Webb P, Neville MC, Anderson SM. (2011) Prolactin-mediated regulation of lipid biosynthesis genes in vivo in the lactating mammary epithelial cell. Am J Physiol Endocrinol Metab 300: E1059-E1068.

5. Wei J, Ramanathan P, Martin IC, Moran C, Taylor RM, Williamson P. (2013) Identification of gene sets and pathways associated with lactation performance in mice. Physiol Genomics 45:171-181.

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