Mammalian target of rapamycin (mTOR)

Mammalian target of rapamycin (mTOR) is a cellular signaling protein that integrates a number of different signals from the environment to regulate metabolism and cell growth. Part of mTOR’s role as a master-regulator of metabolism involves regulation of protein synthesis, a point that has been emphasized by the supplement industry for marketing purposes. Although mTOR plays a clear role in the regulation of protein synthesis and muscle growth, there is currently no magical supplement that can coax stubborn muscle cells into unlimited hypertrophy (contrary to some label claims!). To understand mTOR is to understand how cells integrate nutritional cues from the environment to maintain homeostasis. While this does have implications for muscle growth, it is also important for overall health, since dysregulation of mTOR signaling has been implicated in metabolic disorders and chronic disease.

Mammalian target of what?

mTOR got its name in 1964, when a group of microbiologists discovered a new agent with potent antifungal activity. The agent was isolated from bacteria in a soil sample from Easter Island (aka Rapa Nui), and the new compound was named ‘rapamycin’, based on the origin of the sample.^[1] Subsequent research revealed that rapamycin had a number of important properties in including anti-tumor, immunosuppressive, and neuroprotective. It wasn’t until 1994 that the rapamycin mechanism of action was revealed, however, when scientists were able to isolate the cellular protein that it binds to in mammals, the mammalian target of rapamycin, or mTOR.^[2]

Mammalian target of rapamycin (mTOR) was originally identified as the target of the bioactive molecule rapamycin.

How does mTOR control protein synthesis?

The information on how to make any given protein is encoded in the DNA sequence of a gene in the nucleus. To make a new protein, the message encoded in the gene must first be transcribed into messenger RNA (mRNA). The mRNA is then transported out of the nucleus and into the cytosol of the cell, where its encoded message is read by ribosomes. Ribosomes operate at the business end of protein synthesis, binding to and scanning the mRNA sequence as they assemble individual amino acids into polypeptides that form the full-length protein.

Protein synthesis uses a lot of cellular resources in terms of energy and nutrients, so cells tend to be stingy about making new proteins, only doing so under permissive conditions.^[3] This is where mTOR comes in: by integrating signals in terms of energy balance and nutrient availability, it functions as a central control point in the signaling network that regulates protein synthesis. This, in-turn determines whether a given cell is in a catabolic (breaking down cellular components) or anabolic (building cellular components) state.^[4]

mTOR controls protein synthesis in-part by phosphorylating proteins in the 4E-binding protein (4E-BP) family. When not phosphorylated, 4E-BPs sequester another protein called eukaryotic translation initiation factor 4E (eIF4E), preventing mRNAs from interacting with ribosomes to synthesize their encoded proteins.^[5] When phosphorylated by mTOR, 4E-BPs release eIF4E, allowing protein synthesis to proceed. mTOR also phosphorylates the protein p70 S6 kinase, another important control point for protein synthesis. Once turned on by mTOR, p70 S6 kinase phosphorylates and activates the ribosomal protein S6, further promoting protein synthesis.

By integrating cell signals in response to environmental cues such as nutrient availability and energy status, mTOR signaling determines whether protein synthesis is turned on, or off at any given time.

How is mTOR implicated in disease pathology?

When mTOR is activated, it suppresses catabolic processes in the cell such as autophagy. In contrast, when nutrients are scarce mTOR is suppressed, turning on the catabolic program. When in catabolic mode, proteins and lipids are broken down, rather than made, and recycled by autophagy. In happy, healthy cells, mTOR signaling is regulated in such a way that allows the cell to grow and divide when the conditions are appropriate, but also be resilient to poor nutrient availability and stress.

Out of balance mTOR signaling has been implicated in a number of human diseases including obesity, metabolic syndrome, type 2 diabetes, and cancer. It is also becoming increasingly recognized as a major contributing factor to the aging process. Research in a number of different organisms, including mammals, have shown that mTOR inhibition, whether through rapamycin treatment, dietary restriction, or genetic manipulation, can increase lifespan and healthspan. When mTOR signaling is suppressed, protein synthesis is inhibited, and autophagy is activated. Since autophagy is known to decrease with aging, the anti-aging effect of mTOR inhibition may occur in part through activation of autophagy. Although mTOR inhibition is a promising anti-aging strategy, rapamycin is not without side-effects as it is a potent immunosuppressant and can also cause insulin resistance glucose intolerance. Transient or low-dose mTOR inhibition may be a viable strategy as shown by recent studies in mice^[6] and in a randomized controlled trial in elderly humans.^[7]

What are the implications for building muscle?

Given that mTOR is a central control point for protein synthesis, which is required to build new muscle, supplement companies have used the term “mTOR activating” in quite a bit of their product marketing. On one hand, they’re not wrong: mTOR works in part by sensing the availability of amino acids (particularly leucine), so any supplement containing leucine and/or other essential amino acids such as whey protein are technically an mTOR activators. There can be a disconnect between activation of the anabolic signaling that turns on the protein synthesis (mTOR, 4E-BP, S6K, etc) and the actual amount of protein synthesis that occurs, however.^[8] Although increased amounts of leucine or essential amino acids (EAAs) may be able to turn on anabolic signaling more (through increased mTOR, S6K, etc. phosphorylation) this does not necessarily translate to more protein synthesis.

For optimal muscle growth, consuming adequate amounts of high-quality protein is essential. Although mTOR activation may be increased by taking in more leucine or EAAs, this won’t necessarily cause a proportional increase in protein synthesis.