La vía mTOR en la hipertrofia muscular

The mTOR pathway in muscle hypertrophy

When discussing a controversial topic such as mTOR and hypertrophy, we analyze the theory and conclude with a presentation by Roberto Castellano.

Before discussing the mTOR pathway, let us remember that achieving hypertrophy ultimately comes down to activating satellite cells. There are three mechanisms for doing this: training, diet, and hormones (the endocrine system).

Roberto Castellano tells us that when training takes place, damage occurs, triggering an immune response.

This is a critical point that is not always recognized, because if the immune system is not functioning properly, growth simply does not occur, and the body is also much more susceptible to disease.

Training produces an immune response, which leads to inflammation and induces an influx of blood into the damaged tissue.

This blood flow helps eliminate waste because when muscles are damaged, macrophages need to reach them to consume the debris from damaged cells, remove lactic acid, and so on.

Only once that inflammatory process has ended can hypertrophy occur; that is precisely why training the same muscle group again immediately is ineffective, since the full recovery process needed for hypertrophy does not take place.

mTOR: What is it?

It is a protein kinase responsible for cellular metabolism at the level of hypertrophy, but it is also involved in tumors.

Therefore, what is fashionable is not always entirely best; in medicine, mTOR is studied precisely because it can cause certain conditions, such as cancer, for example.

However, according to a study published in the journal Frontiers – Physiology in 2017, the maintenance of skeletal muscle mass is regulated by the balance between anabolic and catabolic processes (1)

  • The mammalian target of rapamycin (mTOR) plays vital roles in protein synthesis.
  • Recent findings have continued to refine our understanding of the role of mTOR in maintaining skeletal muscle mass.

In a sense, this protein controls anabolic and catabolic signaling in skeletal muscle mass, resulting in the modulation of muscle hypertrophy and muscle wasting.

mTOR and satellite cells

During myogenesis, satellite stem cells are induced to proliferate and differentiate into myogenic precursors. Myogenesis is the process that forms muscle tissue cells, and it is crucial for hypertrophy.

mTOR, a key regulator of protein synthesis, cell proliferation, and energy metabolism; however, for our purposes, we need to determine its function in muscle stem cells (satellite cells) and skeletal muscle regeneration.

In a 2015 study, researchers observed in a laboratory that skeletal muscle regeneration after an injury (such as one caused by training) was severely impaired in the absence of mTOR (2).

  • The scientific method showed that a greater number of necrotic myofibers infiltrated by Evans blue dye appeared, along with a reduced number and size of regenerated myofibers in these rodents.
  • To dissect the cellular mechanism, primary myoblasts derived from satellite cells that grew on individual myofibers or adhered to culture plates were analyzed.

In this method, the myoblasts from the modified rodents exhibited defective proliferation and differentiation kinetics compared with myoblasts derived from their littermates.

These results suggest that mTOR is essential for satellite cell function and skeletal muscle regeneration through the control of myogenic gene expression.

mTOR: Amino Acids and Carbohydrates

Protein turnover in the muscle cell is a complex process that encompasses both protein synthesis and protein breakdown.

Increasing muscle mass requires a greater amount of muscle protein synthesis together with a reduction in muscle protein breakdown, and nutritionally, this requires the proper intake of macronutrients.

More specifically, certain macronutrients achieve greater muscle protein synthesis by activating mTOR, which promotes muscle growth.

Recently, several scientific studies have drawn attention to the activation of mTOR by essential amino acids, especially leucine.

  • In the first study, Walker et al.2 demonstrated that consuming essential amino acids, specifically leucine, increased mTOR activity.
  • Interestingly, this study also confirmed that consuming greater amounts of essential amino acids increased the cell’s amino acid pool.
  • More essential amino acids inside the muscle cell stimulate the insulin signaling pathway, thereby activating mTOR.

However, other studies, such as those conducted by Wilson et al., show that carbohydrates should be added and that, as the preferred energy source of muscle cells, they will improve the anabolic environment.

Interestingly, the preferential use of carbohydrates by muscle cells generates cellular energy (ATP).

  • In this scenario, AMPK, the cell’s energy sensor, will be turned off by ATP production.
  • Since AMPK activates mTOR by inhibiting it, turning off AMPK will also stimulate mTOR activity.

mTOR: What About Fats?

Long-chain omega-3 fatty acids stimulate muscle protein synthesis through the activation of mTOR.

Gingras et al.'s5 latest research presents long-chain omega-3 fatty acids as specific activators of this protein kinase and muscle protein synthesis through the insulin-signaling pathway.

Thus, it was established that long-chain omega-3 fatty acids improve the protein synthesis–mTOR–insulin signaling pathway.

It does this by reducing inflammation throughout the body, which has been shown to cause insulin insensitivity.

They also showed that consuming long-chain omega-3 fatty acids increased the incorporation of amino acids into muscle protein synthesis by 108%, provided they were consumed several hours after training, but not immediately after a training session.

Just as certain macronutrients stimulate mTOR activity and muscle protein synthesis, other macronutrients inhibit their signaling and muscle protein synthesis.

A study by Rivas et al.7 confirmed that consuming a high-fat diet triggers insulin insensitivity, resulting in decreased signaling through this pathway and reduced muscle protein synthesis.

mTOR inhibition results from negative feedback within the insulin-signaling pathway. Chronic consumption of a high-fat diet overactivates it, which in turn strongly activates the S6K molecule.

A hyperactive S6K molecule produces inactivating signals within the insulin-signaling cascade, thereby decreasing insulin sensitivity along with mTOR activation and protein synthesis.

mTOR: restricted diet

mTOR integrates various internal and external signals to regulate many cellular activities, including mRNA translation, protein synthesis, cell proliferation and growth, autophagy, lipogenesis, and thermogenesis

In this regard, it carries out its biological activities in mammalian cells by forming two distinct complexes:

  • The mTOR1 complex (mTORC1)
  • The mTOR2 complex (mTORC2).

In all scenarios, the two differ in their components, regulation, function, and sensitivity to rapamycin.

Specifically, mTORC1 activity is stimulated by growth factors, hormones, and other factors.

It is also regulated by nutrients such as glucose and amino acids; consequently, diet must be taken into account.

Thus, just as branched-chain amino acids (BCAAs) such as leucine and arginine are potent activators of mTORC1, energy limitation, such as glucose deprivation and hunger, strongly inhibits mTORC1 activation by stimulating AMPK in response to energy deprivation.

AMPK is another critical cellular energy sensor that suppresses mTORC1 activity.

Conclusions

As we can see in this illustration, mTOR is connected to protein synthesis and cell growth through different pathways.

This means that it indirectly influences hypertrophy. It is somewhat like the way a car's engine is necessary for it to move, but it still needs other «pathways» such as the steering wheel, cooling mechanisms, the clutch, etc., and this must be clear.

Resistance exercise (with weights or accessories) activates mTOR, and since training stimulates muscle gains, there is a link to hypertrophy.

mTOR is associated not only with protein synthesis but also with protein degradation (a catabolic effect).

The Goodman study conducted in 2014 shows that it is inversely connected to this process, which prevents catabolism (3).

Finally, Roberto Castellano explains in a video how the mTOR pathway is activated and its relationship with hypertrophy.

References

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