Trait: Muscle Hypertrophy (mTOR)
Dr Haran Sivapalan
February 3, 2020
What is mTOR?
mTOR stands for Mammalian Target of Rapamycin.
It is a key molecule that regulates the growth of cells in response to various stimuli, including: the availability of nutrients, changes in energy balance, hormones, changes in blood flow and oxygen delivery, and mechanical load on muscles (e.g. as part of resistance training).
mTOR controls the growth and production (or ‘synthesis’) of protein in various types of cells, including muscle cells (muscle fibers). Enlargement of muscle fibers (hypertophy) relies upon mTOR signalling. It therefore plays an important role in muscle gains following exercise.
mTOR also regulates a process called autophagy - the breakdown and recycling of old, faulty and damaged cell components. This process helps to rejuvenate cells and influences how quickly our cells age. mTOR is therefore crucially involved in the ageing process.
- mTOR is an important molecule that regulates protein synthesis, cell growth and ageing.
- Activity of mTOR influences muscle gains following exercise.
What is hypertrophy?
If you’ve ever worked out consistently over a period of time, you may have noticed that your muscles gradually became bigger. This is due to a process called hypertrophy.
Hypertrophy generally describes an increase in size of an organ due to enlargement of its constituent cells. * When applied to skeletal muscle, hypertrophy refers to an increase in muscle volume or mass resulting from a rise in the cross-sectional area of individual muscle fibers.
Muscle hypertrophy is an adaptive response to what we term progressive overload – a gradual increase in the stress placed upon the musculoskeletal system. When it comes to strength training, progressive overload might, for example, involve gradually stepping up the maximum amount of weight you lift over consecutive training sessions.
*Note: this is in contrast to hyperplasia – which refers to an increase in the number of constituent cells.
- Hypertrophy is the enlargement of muscles due to the increase in size of individual muscle fibers.
How do muscles grow in size?
Basic muscle anatomy
Before we describe hypertrophy in greater detail, it’s worth quickly going over the basic anatomy of our skeletal muscles. Our skeletal muscles (e.g. our biceps) are made up of lots of different types of tissue (collections of cells), including: blood vessels, nerves, connective tissue, and muscle fibers. It is our muscle fibers that are ultimately responsible for muscle contraction.
Muscle fibers are basically long, cylindrical muscle cells. Within a muscle (e.g. the biceps), groups of muscle fibers are organised into bundles called fascicles.
Muscle fibers themselves are made up of bundles of smaller thread-like structures called myofibrils. Myofibrils are the parts of muscle fibers that contract. They’re composed of thick and thin filaments, which are made, respectively, out of the contractile proteins myosin and actin. When our muscles contract, the thin actin filaments slide over the thick myosin filaments, generating a force.
Myofibrils are surrounded by a matrix similar to cell cytoplasm, called sarcoplasm. The sarcoplasm contains various fluids, stores of glycogen, non-contractile proteins and organelles (e.g. the mitochondria we encountered in your Mitochondrial Biogenesis trait).
Finally, each individual muscle fiber, containing both myofibrils and sarcoplasm, is enclosed by a membrane called the sarcolemma.
- Muscle fibers are composed of myofibrils, which contract, and sarcoplasm, which does not contract.
Types of hypertrophy
As explained earlier, hypertrophy of an entire muscle (e.g. the biceps) results from an increase in cross-sectional area of its individual muscle fibers.
Muscle fibers can increase cross-sectional area in two main ways:
1) Myofibrillar hypertrophy - an increase in the number and size of myofibrils.
Myofibrils are the thread like structures within muscle fibers that are responsible for muscle contraction. They are made of contractile units (called sarcomeres) composed of key contractile proteins: actin and myosin. Increased production or “synthesis” of these contractile proteins adds additional myofibrils and makes them become larger.
As myofibrils become larger and more numerous, they are capable of generating greater force while contracting. As such, myofibrillar hypertrophy contributes to the strength gains following resistance training.
2) Sarcoplasmic hypertrophy - an increase in the volume of fluid, non-contractile proteins and other molecules in the sarcoplasm.
Increased production of non-contractile proteins causes sarcoplasm to expand and muscle fibers to grow in diameter.As the sarcoplasm is not actively involved in muscle contraction, sarcoplasmic hypertrophy itself is not thought to contribute to strength gains.
- Hypertrophy occurs due to increases in the size and number of myofibrils and volume of sarcoplasm.
- Greater numbers of myofibrils results from increased production of contractile proteins. This leads to strength gains.
- Enlargement of sarcoplasm results from increased production of non-contractile proteins. This doesn’t lead to strength gains.
What causes hypertrophy?
If you’ve regularly hit the gym at some stage in life, chances are that you gained muscle mass and increased your strength. But, have you ever gone for a period of time without exercising a set of muscles? Perhaps you’ve been ill or injured or forced to rest in bed? In this scenario, you would have most likely lost muscle mass and dropped strength. So, why does this happen?
Rather than being static, passive organs, your muscles are continually adapting to the environmental stresses and demands placed upon them. To do this, your muscles are constantly balancing two concurrent processes:
- Muscle protein synthesis (MPS) – the building up of amino acids (the building blocks of proteins) into new proteins.
- Muscle protein breakdown (MPB) – the breakdown or degradation of muscle proteins into amino acid blocks.
Whether or not you gain muscle depends on the overall or net balance of these two processes. We term this “net muscle protein balance” or “net muscle protein turnover” and it’s calculated simply as follows:
Net muscle protein balance = rate of muscle protein synthesis (MPS – rate muscle protein breakdown (MPB)
- Your muscles are continually building up and breaking down proteins.
- The balance of these processes influences muscle gains and hypertrophy.
Hypertrophy requires a positive net muscle protein balance
Rate of muscle protein synthesis (MPS) > rate of muscle protein breakdown (MPB) --> Hypertrophy
When the rate at which you build new proteins (i.e. muscle protein synthesis) is greater than the rate at which you break down protein (i.e. muscle protein breakdown), then you will have a positive net muscle protein balance. This corresponds to the "fed gains" areas of the graph above. We can also say that your muscles are in an anabolic state.
Being in this state means your muscle fibers will, on balance, produce more proteins and subsequently increase in size. This leads to hypertrophy of your muscles.
If this enhanced protein production includes contractile proteins in myofibrils (a process known as myofibrillar protein synthesis), then you will also gain strength.
Rate of muscle protein synthesis (MPS) < rate of muscle protein breakdown (MPB) --> atrophy
If your muscle cells break down proteins at a greater rate than they synthesize new proteins, you will have negative net total protein balance. This corresponds to the "fasted losses" areas of the graph above. This state can also be described as being catabolic.
In this scenario, you will lose muscle mass, with individual muscle fibers becoming smaller in size. This is known as muscle atrophy.
If there is net breakdown of contractile proteins within myofibrils, then you will also lose strength.
- Hypertrophy occurs when muscles produce new proteins at a higher rate than they break down protein.
Why is muscle protein synthesis important?
Studies suggest that, in healthy individuals, changes in muscle protein synthesis (MPS) are much more pronounced than changes in muscle protein breakdown (MPB).
We can see this pattern in the previous graph.
Muscle protein synthesis therefore has a considerably more significant effect on muscle gains, compared to muscle protein breakdown.
- Changes in the production of new proteins have a greater effect on muscle gains than changes in protein breakdown.
How does mTOR increase muscle protein synthesis?
mTOR is a key molecule that regulates protein synthesis in muscle fibers and other cells.
It acts as a sensor of both the internal and external environments of a cell and “decides” whether conditions are right to switch on production of proteins.
By integrating various cell signals, mTOR monitors several conditions such as: availability of amino acids, mechanical load, glucose levels, overall energy status, inflammation, growth factors, and circulating levels of hormones. When these conditions are correct (e.g. there is an abundance of available amino acids), mTOR activates various biochemical pathways that lead to protein production.
For example, mTOR stimulates cell structures (or ‘organelles’) called ribosomes. Ribosomes work by linking individual amino acids together to build large protein chains. mTOR also promotes the growth of new ribosomes, allowing cells to produce more proteins.
mTOR doesn’t work in isolation. Rather, it joins up with other molecules to form “multi-protein complexes.” The other molecules in these complexes help to regulate the activity of mTOR and also respond to various cell signals.
There are two distinct complexes of which mTOR is a key component:
- mTORC1 (mTOR complex 1)
- mTORC2(mTOR complex 2)
Of both of these, mTORC1 is the most widely studied and understood. When mTOR is activated, the larger mTORC1 complex acts on various signalling pathways to boost protein production.
mTORC1 also stimulates the production of fats and cholesterol, as well as new mitochondrial components (see the Mitochondrial Biogenesis blog for more detail).
- mTOR acts as a sensor of various cell conditions and switches on protein production when conditions are right (e.g. there is a good supply of nutrients).
- mTOR functions as part of two larger clusters or complexes of molecules: mTORC1 and mTORC2
- mTORC1 stimulates synthesis of protein, fat and mitochondrial components.
What activates mTOR / mTORC1?
As explained earlier, mTOR (or the mTORC1 complex) acts as a sensor of the internal and external environments of a cell. It can switch on production of proteins and cell growth in response to various stimuli.
Exposing your muscles to a mechanical load (e.g. lifting weights) triggers several different biochemical signalling cascades in your muscle cells that lead to muscle protein synthesis. In one of these pathways, studies show that mechanical stretch of skeletal muscle leads to the generation of a molecule called phosphatidic acid (PA). PA then activates the mTORC1 complex, leading to increased protein synthesis.
Amino acids are the building blocks of proteins. When a cell has a good supply of amino acids, it can increase its production of proteins.
The mTORC1 complex is sensitive to levels of amino acids inside cells, particularly the essential amino acid leucine. When levels rise, mTORC1 switches on protein production.
If you’re looking to build muscle, it is therefore important to consume enough protein, particularly post-exercise. This will provide your muscle cells with a good supply of amino acids for muscle protein synthesis.
Growth factors and hormones
Growth factors are special signalling proteins that stimulate the growth of cells. Some growth factors, such as insulin, can also be classified as hormones – chemical messages transported in the bloodstream.
Both insulin and a closely related molecule, called Insulin-like growth factor 1 (IGF-1), can activate mTORC1 and promote protein synthesis. This mechanism allows cells to produce protein and grow following meals, when insulin levels increase in response to rising blood sugar levels.
When insulin and IGF-1 bind to their respective receptors, they trigger a signalling cascade known as the PI3K/AKT/mTOR pathway. This pathway ultimately activates mTORC1 and switches on protein production.
Another hormone, testosterone, may also interact with this pathway to promote protein synthesis. For this reason, it’s important to maintain healthy testosterone levels to optimize muscle protein synthesis and ensure your muscles develop.
- Mechanical loading of muscles, high levels of amino acids, and growth factors such as insulin all activate mTOR and stimulate protein synthesis.
What is autophagy?
In addition to stimulating protein synthesis, mTOR also inhibits the breakdown of proteins. More specifically, mTOR inhibits a process called autophagy – the breakdown of old and damaged cell components and proteins.
During autophagy, damaged cell components and proteins are rounded up and isolated into specialized chambers called autophagosomes. These chambers then fuse with other chambers, called lysosomes. Lysosomes contain enzymes that break down and degrade cell components into smaller molecules such as amino and fatty acids. These molecules can then be recycled and used to build new cell components and proteins.
Autophagy is a beneficial process for two main reasons.
Firstly, during times when there is limited availability of nutrients (for instance, during fasting), the breakdown of old cell components provides a fresh supply of nutrients (e.g. amino acids). These can then be used to produce new cell materials and fuel processes key to survival.
Secondly, the removal of old, damaged cell components and proteins allows cells to recycle and rebuild new components, allowing them to function more efficiently.
- Autophagy is process by which old and damaged cell components are broken down and recycled.
- Autophagy increases the supply of nutrients during times of scarcity (e.g. fasting) and rejuvenates cell components.
- mTOR inhibits the process of autophagy.
How does mTOR affect ageing?
Autophagy helps to rejuvenate cells by getting rid of old and damaged cell components and proteins. Disruption to the autophagy process, however, allows damaged proteins to accumulate. The accumulation of these damaged molecules gradually impairs cell function, shortening their lifespan, and leads to ageing.
By inhibiting autophagy, mTOR may allow damaged cell components to accumulate and contribute to the ageing process. High activity of mTOR may therefore be linked to increased ageing.
On this note, laboratory experiments show that artificially inhibiting mTOR activity can increase the lifespan of various non-human animals, including fruitflies, nematode worms and mice.
- mTOR inhibits autophagy which leads to the accumulation of damaged proteins and other molecules.
- The accumulation of damaged proteins impairs cell function and is linked to ageing.
- Excessively high mTOR activity may promote ageing.
Genetics and lifestyle
Your latest trait analyzes variants of genes that affect activity in the various mTOR/ mTORC1 signalling pathways.
In this respect, one main gene we consider is your MTOR gene, which encodes the mTOR protein.
Variants of this gene can influence the amount and activity of mTOR protein you produce, and therefore affect how well your cells synthesize new proteins. This, in turn, can affect how effectively you gain muscle.
As mTOR also stimulates fat deposition and ageing, these processes will also be influenced by your MTOR gene variants.
As we explored earlier, several environmental or lifestyle factors (e.g. consuming protein, lifting weights) can alter the activity of mTOR.
While increasing mTOR activity may be beneficial for muscle gains, these benefits must be weighed up against the increased risk of fat accumulation and ageing.
Be sure to check out the Actions in your Protein synthesis and hypertrophy trait for diet, exercise and supplement recommendations personalized to you.
- FitnessGenes analyze variants of your MTOR gene.
- Variants of your MTOR gene affect the activity and quantity of mTOR protein.
- MTOR gene variants can affect muscle gains, fat deposition and ageing.