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A complete guide on MTOR and AMPK

It is a pleasure to offer you today’s entrance as it is a topic that I am passionate about  the balance between AMPK and MTOR routes . When we talk about metabolism there are many doubts, the type of hormones, biochemical complexes or enzymes that act in the anabolic or catabolic episodes create controversy. I will try to help you understand these processes better.

The actions of many processes derived from insulin, testosterone, cortisol, types of training (aerobic, anaerobic), nutrients, supplements etc, which can interfere in the correct functioning of the metabolism, are increasingly well known. The muscular hypertrophy, the increase of the strength, the thinning or the metabolic acceleration, the mitochondrial biogenesis, among others, are linked to the metabolism. When we talk about it, we do not only refer to the construction or catabolism of tissues, but to the impact that metabolism has on many diseases (carcinogenic processes, autoimmune diseases, degenerative diseases, etc.). That is why we are going to develop this post talking about the most specific enzymatic pathways that originate in the organism at the metabolic level.This is the MTOR route (mammalian target of rapamycin) and the AMPK route.

 

MTOR ROUTE

It is a metabolic route formed by a set of proteins , its name obeys the definition of biological objective to which rapamycin binds. When we talk about MTOR we refer to the   metabolic pathways designed to control certain anabolic and physiological functions in mammals, within which we have very important functions at the liver, muscle, adipose tissue, brain, etc. There is a great variety of pathologies associated with imbalances of the MTOR route (diabetes, obesity, certain types of cancer, etc).

The MTOR route functions as a complex sensor of nutrients, energy or bioelectric activity in the body, and controls protein synthesis and cell hyperplasia. The activity of the MTOR route is regulated by rapamycin, insulin, by growth factors derived from insulin, phosphatidic acid, certain amino acids (especially leucine) and some mechanical / muscular or oxidative stimuli.

 

MTOR AND AGING

It has been observed how the inhibition of the activity of the MTOR route, as well as the restriction of methionine or leucine, can increase the life of certain animals, in this way it was discovered that rapamycin inhibited the entire protein complex of the MTOR metabolic pathway. and prolonged the life expectancy of the mice. It should be noted that the genes linked to the expression of Mtor complex proteins give rise to a process called pleiotropic antagonism. This means that the activation of genes linked to this route throughout young age in living beings, is linked to hypertrophy and muscle growth, or to certain states of energy activity in the body. These genes are linked to the growth and repair of tissues, with what the activation of these genes in the juvenile age is beneficial and nevertheless, the activation of the same genes from the second vital stage of the animals shortens the life expectancy.

That is why the caloric restriction or methionine and leucine cause a decrease in the MTOR route, which increases the life expectancy in certain animal species as has been demonstrated. On the other hand, we know that over the years mitochondria stop working properly and it has been observed how the inhibition of the MTOR route favors biogenesis and mitochondrial respiration at the same time as autophagy.

 

CANCER AND MTOR

The excessive activation of the MTOR route is linked to the processes of initiation and development of certain tumors. The most linked are carcinomas of the breast, prostate, lung, melanoma, bladder, brain or kidney. Because the MTOR route is closely linked to activation by insulin, by growth factors derived from insulin, or by leucine, diets with a high amount of these components may be associated with carcinogenesis.

We know that diets with high glycemic load that have an impact on insulin end up producing insulin and IGF-1 in plasma, which generates an activation of the receptors and protein complexes associated with MTOR, which in turn cause the activation of oncogenes that can lead to the first beginnings of formation of cancer cells.

One of the processes that oncology has observed is the malfunctioning of mitochondria at the level of tumor cells, so that the cell has an inhibition of oxidative respiration and starts to ferment glucose. When this occurs, as a consequence of the inactivation of mitochondrial function, the processes of tumor apoptosis (cell suicide) are inhibited.

The activation of the MTOR route gives rise to the progression of the oncological cell cycle thanks to its direct action on the synthesis of proteins, in such a way that the cycle of construction of these is accelerated associated with the oncological processes. On the other hand, autophagy (which is the process by which the body activates the immune system enough to detect cancer cells and eliminate them) is inhibited as a consequence of the MTOR route. Among the functions associated with the activation of this route (especially when insulin is very high) we find the increase in the production of HIF1A, which leads to angiogenesis and a greater contribution of nutrients to the oncological territory.

A point very studied since the thirties is the Warburg effect . This episode is observed in all tumor cells and refers to the process by which the healthy cell (which has oxidative respiration and uses glucose to obtain 36 molecules of ATP) goes on to perform a glycolysis anaerobically, obtaining only two molecules of ATP through glucose. It has been observed that the activation of the MTOR route favors the upward expression of enzymes linked to glycolysis, such as PKM2 or AKT2.

 

MTOR AND NEURODEGENERATIVE PATHOLOGIES

In recent years, evidence has emerged between the link between the hyperactivity of the MTOR protein complex and neurodegenerative pathologies such as Alzheimer’s, Parkinson’s, epilepsy or even rare diseases such as tuberous sclerosis or Huntington’s disease. The fact that the overactivity of the MTOR route generates a hyperexpression of the proteins, has made it possible to know that when this complex is highly activated there is a greater deposition of beta-amyloid plaques or neurofibrillary tangles in Alzheimer’s disease. Several studies have shown that the inhibition of the MTOR route allows the autophagic route to be activated to eliminate Beta-amyloid deposits and the improvement of the symptoms associated with this neurodegenerative pathology.

When the MTOR complexes are highly activated, there is a greater probability of suffering diseases due to the deposit of proteins, which can seriously affect neuroplasticity and have very negative consequences in learning and in memory. Hence, over time, the excess of food (especially high glycemic load carbohydrates or even diets with a high amount of protein that generates an impact on circulating insulin) affects the hyperactivity of the MTOR route and the glycation of proteins, which gives rise to Beta-amyloid. This is why alzheimer is increasingly referred to as type 3 diabetes, due to its link with chronic hyperinsulinemia.

 

MTOR AND SPORT

The link between the activation of the MTOR complex, the necessary synthesis of muscle protein and the skeletal muscle hypertrophy in human beings before the response of exercise and the intake of certain amino acids is known. It is important to know that before any type of injury or the need to regenerate muscle mass (for example after a surgery or a traumatological accident) it is necessary to have active the MTOR route to rapidly generate proteins and muscle tissue. Therefore, to avoid the cachexia produced by physical activity, aging, long convalescence in bed etc, it is essential to stimulate the MTOR route in an appropriate way for the manufacture of muscle mass.

At sport level we can stimulate this route and achieve the activation of muscle mass through the entry of glucose via insulin , through growth factors similar to insulin, through amino acids (especially leucine) and through inhibition of autophagy.

 

ROUTE AMPK

It is the route composed of the enzymatic complex designed to act as a physiological energy sensor in the body. It is in charge of detecting ATP and energy deficiency and putting in place the necessary mechanisms to obtain it. The activation of AMPK has long-term effects in terms of gene expression, protein synthesis and the rest of metabolic functions of the organism. These may be the synthesis and secretion of insulin by the pancreas or certain functions in the hypothalamus and pituitary gland. In the same way, AMPK is linked to processes of obesity, diabetes, inflammation or cancer.

 

ACTIVATORS OF THE AMPK

  • CELL STRESS

 Any process involving a decrease in ATP concentrations and an increase in AMP, as well as those that generate cellular stress (due to metabolic toxins or inflammations), can produce an increase in the AMPK route. Likewise, stressful processes for the cell, such as hypoxia, ischemia, or the excessive increase of free radicals through oxidative stress or glucose deprivation, may also imply an acceleration of activity in the AMPK pathway. 

  • PHYSICAL EXERCISE

Physical exercise (usually of high intensity) causes an increase in the activity of the AMPK route in an attempt to obtain ATP. In this way, when the exercise gives rise to the activation of AMPK, it in turn triggers the activation of the metabolic pathways destined for catabolism to replenish the levels of ATP in the organism. Therefore, if AMPK is activated thanks to exercise, an increase in the oxidation of fatty acids and insulin sensitivity is obtained. 

  • MEDICATIONS AND ACTIVE SUBSTANCES

There is high evidence of how the AMPK route can be activated through Metforfina or Thiazolidinedione, which are drugs used in the treatment of type 2 diabetes and to improve insulin sensitivity. We know that these drugs activate the AMPK pathway and all positive processes derived such as autophagy, modulation of the immune system or weight loss. It should be noted that we also find another type of active ingredients such as epigallocatechin (EGCG), caffeine, curcumin, resveratrol or alpha-lipoic acid; all of them have turned out to be products that activate the AMPK route.

 

FUNCTIONS OF AMPK IN THE BODY

  •  AMPK AND LIVER FUNCTION

The activation of the AMPK pathway at the liver level acts as a sensor of the energy state , so that the homeostasis of glucose and lipid concentrations can be regulated through the activation or inhibition of certain genes. At the liver level, AMPK is activated by different physiological stimuli such as high intensity exercise, fasting (both elongated and intermittent), or lack of ATP, energy or glucose in the muscles.

Regarding fasting, after 10-12 hours of implementation, there is a decrease in the levels of ATP, resulting in a hepatic activation of the enzyme AMPK to try to compensate the energy demand in the body. At that time appears an inhibition in the synthesis of fatty acids, hence an activation of AMPK can be a good tool to improve the so-called fatty liver. As a consequence of this activation, an inhibition occurs in terms of lipogenesis and hepatic glycogenosynthesis. Once the person returned to eat, that excess food (especially carbohydrate) would inactivate the AMPK route and allow the anabolic routes destined for the synthesis of fatty acids, proteins and glycogen to be reestablished. 

  • INSULIN RESISTANCE AND AMPK

Insulin resistance is closely linked to the resistance of peripheral receptors at the muscular level. The muscle at rest is responsible for the metabolism of 20% glucose, something that shoots up to 80% in conditions of physical exercise. This means that the metabolism of glucose and insulin is directly related to muscle activity and peripheral insulin receptors of the musculature.

It should be noted that when we are facing an insulin resistance, there is a decrease in glucose metabolism of between 35-40% less in relation to individuals without this type of syndromes. 90% of the decrease in glucose uptake is mainly due to less use at the muscle level.

Insulin resistance at the muscle level is closely linked to the decrease in the AMPK pathway. Therefore, this is one of the mechanisms by which the person can develop insulin resistance and type 2 diabetes. It is important in patients who suffer all the metabolic syndromes derived from this process, that they try to perform an activation of the AMPK route. We can achieve this with alpha-lipoic acid, berberine, chromium, insulin-sensitizing drugs and activators of AMPK (such as metformin or pioglitazone), or with intermittent fasting and high-intensity exercise. 

  • AMPK AND OBESITY

The AMPK route is one of the main enzymatic complexes that regulate the energy balance. Its activity plays a very important role in the regulation of lipogenesis, lipolysis and the oxidation of fatty acids in adipocytes.Any process that produces an activation of AMPK (such as a decrease in ATP or plasma glucose, intermittent fasting or high intensity exercise) causes a decrease in lipogenesis (new formation of triglycerides in adipocytes) and promotes a induction in the ability to oxidize fatty acids at the mitochondrial level. Currently, adipose tissue is considered as an endocrine organ totally involved in the energy homeostasis processes of the organism, which is why leptin (which is a hormone released by adipocytes) is a crucial hormone linked to metabolic balance. 

The Leptin regulates appetite and satiety in people, so that when there is proper nutrition and balanced leptin is released by the adipocyte and activates receptors in the hypothalamus that make us to notice satiety and stop eating. Likewise, it has been observed that when a sensitivity to leptin is correct, said hormone is able to directly activate the AMPK pathway in the muscle to promote the oxidation of fatty acids. 

  • AMPK AND HEART

When the demand of ATP is high in the heart, it is important to know that the correct activity of the AMPK is fundamental for the good development and well-being of this muscle. The activation of this route at the cardiac level will promote a better mitochondrial oxidative metabolism, said activation will also facilitate the transport of glucose to the interior of the cardiac cells through nitric oxide, which allows the energy to be increased and the processes of apoptosis to be inhibited and necrosis that can occur in states of ischemia or lack of cardiac oxygen. 

  • AMPK and hypothalamic axis functionality

The activity of the AMPK pathway is crucial for the proper development of neuronal cells. On the other hand, this route is linked to energy intake, body weight and regulation of orexigenic and anorexigenic signals in the hypothalamus. When a person is fasting or have spent more than 12 hours from the start of it, AMPK route starts producing a higher level of hypothalamic regions activity, resulting in an orexigenic signal to stimulate the search and intake calorie .

This means that when an individual performs a fast of about 12 hours, the orexigenic signals give rise to neoglucogenic activities such as the release of growth hormone, catecholamines (adrenaline, noradrenaline), glucagon, T3 or cortisol that allow accelerated fat burning in the search for a new formation of glucose molecules. Obviously, this process will have a positive effect on the control of glucose and insulin concentrations in plasma, hence it may be beneficial for metabolic control in type 2 diabetics or patients with insulin resistance. 

  • AMPK AND CANCER

The genetics of cancer has been investigated for many decades and there are tests in which the expression of oncogenes is associated with cellular metabolism and bioenergetic regulation of the cell. For a long time it was tried to search for certain oncogenes that were responsible for the start and evolution of tumors, however, it is increasingly visible that the theory of oncogenes is lame and we found more evidence that the tumor development of the tissues are linked to a metabolic disequilibrium thereof.

In 2003 it was discovered that the tumor suppressor LKB1 was mediated by the AMPK route. Since then, epidemiological studies have shown that the activation of AMPK (for example, metformin) reduces the incidence of cancer.

This gave rise to the enthusiasm of many scientists who rely on new therapies to fight against this disease. It has been observed that the activation of AMPK leads to a suppression of tumor metabolism regulating the metabolism of glucose, lipids and proteins, and acting on the inhibition of MTOR, P53, COX-2, ACC or FASN.

Other studies indicate that the suppression or inhibition of the AMPK pathway in patients with cancer, results in a much worse evolution, especially in cancers of the lung, colon or liver. We know that the activation of AMPK is closely linked to autophagy and the improved functioning of the immune system, especially CD8 T lymphocytes, which results in a much higher tumor suppression. That is why more and more research is being done on the metabolic balance, to facilitate the development of the activity of the AMPK route in order to favor autophagy and that the patient’s immune system be able to fight against the tumor cells.

One of the aspects that has been observed in tumor metabolism is the suppression of mitochondrial activity, so that cells go from having an oxidative metabolism at the mitochondrial level to having a fermentative process. Thus, in the tumor cells there is no mitochondrial activity. There are more and more studies showing that by activating the AMPK route, mitochondria can be reactivated and induced to tumor apoptosis (cell suicide). 

  • AMPK AND POLYCYSTIC OVARIAN SYNDROME

It has been observed that the polycystic ovary, whose symptoms derive from a hyperandrogenism (greater release of testosterone by the ovaries), is linked to peripheral insulin resistance in women from adolescence.

Every time there are more treatments in this type of pathologies that are made with insulin sensitizers, especially with metformin or pioglitazone, since these drugs increase the AMPK route and we know that through them many of the symptoms of polycystic ovarian syndrome remit 

 

HOW TO BALANCE THE MTOR AND AMPK ROUTES

The human being tends to praise or demonize certain aspects, behaviors or physiological processes of the organism. In the case of MTOR and AMPK metabolic pathways, we discovered high benefits in the activity of both, but the suppression or inhibition of any of these two routes can have disastrous consequences for health.

A goal to achieve in every person to achieve good health and especially to maintain it in the long term is homeostasis, which is the balance of all the constants in the extracellular internal environment that favor the cell is stable. Therefore, to achieve metabolic and physiological health in the body we must achieve a balance between AMPK and MTOR routes.

The MTOR route will allow the construction of tissues, the expression of proteins, building muscle mass, regenerating tissues after accidents, etc. However, in excess it will facilitate the formation of aberrant structures, protein deposits in tissues in which it is not adequate, even the new formation of both benign and malignant tumors. On the other hand, the activated AMPK pathway allows a better functionality of the mitochondria, to have greater sensitivity to insulin and will facilitate greater oxidation of both fats and carbohydrates.

In the same way, the activity of the AMPK route will favor a better autophagy and functioning of the immune system, but its excessive activity can cause cachexia or loss of muscle proteins, osteoporosis and general frailty of the organism. Therefore we must be aware that the important thing is that the body is balanced and active at certain times one route or another. 

 

RECOMMENDATIONS

  • INTERMITTENT FASTING

It is a technique that will allow us to activate the AMPK route. For this we must establish a fast of at least 12 hours, normally reaching up to 14-16 hours. With this we will favor the activation of the enzymatic route AMPK, which will help us to use liver glycogen, to decrease the levels of glucose and plasma insulin, in addition to releasing neoglucogenic hormones such as cortisol, adrenaline, noradrenaline, growth hormone or glucagon. With this we will allow to burn and oxidize the fat deposits.

On the other hand, after 12 hours of fasting, the activation of the AMPK pathway allows a greater activity and mitochondrial biogenesis, as well as a greater formation of the neurotrophic-cerebral factor, which is closely linked to improving neurodegenerative processes. 

  • FOOD

Except for the environment close to muscular or anaerobic training, it is preferable that the meals be with low glycemic index proteins, fats and hydrates. However, meals around weight training where mechanical stress is already going to induce the body to activate the MTOR route, should be accompanied by high glycemic index hydrates and especially high glycemic load (white rice, pasta, potato etc), which will allow at that moment activate the MTOR route and favor the expression of proteins. 

  • SPORT

We recommend aerobic exercise (especially during intermittent fasting hours) to promote the activity of the AMPK pathway, favor neoglycogenic activity, and decrease plasma glucose and insulin. However, I also recommend training with weights several times a week to promote MTOR route activity and muscle building.

This will allow to increase the basal metabolic rate because building more muscle mass we will have more peripheral receptors to insulin.

  • SUPPLEMENTS

 

 

We find supplements that may favor the activity of the AMPK route such as Alpha-Lipoic acid , chromium, epigallocatechin, resveratrol or berberine. Taken early in the morning or intermittently fasting will help an expression of the AMPK route. Also, there are supplements that taken around the hours of weight training can promote further development of the MTOR route and easier to build muscle mass, including leucine, Whey protein or hydrolysed carbohydrates that generate a peak of insulin and help increase expression of the MTOR route.

 

TO END…

I have tried to tell you about metabolism in its most intimate form, the AMPK and MTOR routes. I am in love with the physiological understanding of the organism and the way in which it always seeks to balance and balance any process in order to favor homeostatic episodes.

If you want to stay healthy in your day to day, promote a proper longevity and prevent aging and associated pathologies, you must understand that we have to favor both anabolic processes in the body (MTOR) and catabolic processes (AMPK). With small tools of which we have spoken, in addition to nutrition and adapted sports, there are many problems that we will have the possibility of preventing. In exchange for small efforts we will gain in health and well-being.

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