22 May 2017

Muscles of internal secretion

Natalia Reznik, Candidate of Biological Sciences, "Chemistry and Life" No. 9-2016
Published on the website "Elements"

In motion – life

Remember, as in Zhvanetsky: "Maybe big sport is bad. But basic physical training ..." Yes, it is necessary, and not only in order to easily catch up with a departing bus or look cool on the beach. Physical activity is the key to active longevity, and this is not a slogan, but an experimentally established fact. They began to prove it, as usual, on rodents. For example, in rats that could run in a wheel for their own pleasure, the survival rate, that is, the number of individuals who have reached a certain age, is significantly higher than in animals deprived of the opportunity to train. In mice, exercise improves the functioning of the nervous system, including neuromuscular synapses, reduces the level of hyperglycemia and normalizes cholesterol. Physical activity has a beneficial effect on the heart, kidneys, brain and liver of various animals. Epidemiological studies confirm that it prolongs people's health and life. Conversely, with a sedentary lifestyle, type 2 diabetes mellitus, cardiovascular diseases, obesity, breast cancer (postmenopausal) and other malignant tumors often develop, as well as dementia, depression and neurodegenerative diseases such as Alzheimer's disease.

There are several hypotheses explaining the connection between health and movement. It has been observed, for example, that physical education stimulates the release of adrenaline, cortisol, growth hormone, prolactin and other molecules that regulate the immune system. Long-term systematic training reduces the level of stress hormones. In addition, and this is noted by many researchers, physical activity allows you to get rid of the cause of many diseases – chronic systemic sterile inflammation. It is so named because it develops in the absence of infection – as a result of autoimmune processes or other events. Chronic sterile inflammation is a frequent companion of a sedentary lifestyle. This is a very dangerous phenomenon, fraught with the development of insulin resistance, atherosclerosis, neurodegenerative diseases and malignant tumors. Cytokines of inflammation are secreted by overgrown adipose tissue, as well as liver and inactive skeletal muscles. Physical exercises can change the situation, they perfectly help even people who have already started practicing at an advanced age in order to prevent or stop the development of any ailments. But it is important not to overdo it, because excessive physical activity also provokes inflammation, weakens the immune system and increases the risk of developing infectious diseases. Muscle work and inflammation are related to each other in a complex way, and exercise can both help and harm, depending on the amplitude, frequency and other variables. Serious sports without an instructor is akin to self-medication.

Muscles and PGC-1a

The movement of the human body is provided by about 600 skeletal muscles, which make up about 40-50% of the body weight. They consist of myofibrils formed by fused myoblast cells, and myofibrils consist of actin and myosin filaments organized into repeating blocks-sarcomeres. The movement of these threads relative to each other causes muscle contraction. Unlike smooth and cardiac muscles, skeletal muscles contract arbitrarily at the signal of the neurotransmitter acetylcholine.

Work requires energy. During dynamic contractions, which require endurance (long running, swimming), and when maintaining a pose, energy is provided by ATP, obtained due to oxidative phosphorylation occurring in the mitochondria. Glucose and glycogen are primarily oxidized. With movements requiring great strength and speed (sprinting, lifting weights), muscle fibers break down glycogen anaerobically during glycolysis. At the same time, ATP is formed two to three times faster, and the mechanical energy produced by the muscle is two to three times greater than during oxidative phosphorylation. But fatigue in this case comes much faster.

Depending on the type of work performed, muscle fibers synthesize different transcription regulators, growth factors and other molecules that allow them to adapt to a particular type of load. Strength training leads to the predominant development of so-called fast fibers, which use glycolysis to synthesize ATP. With appropriate loads, their number and cross-sectional area increase. Fibers that perform dynamic work are called slow. They need a lot of mitochondria, a developed capillary network to supply oxygen, counteract protein degradation, apoptosis and inflammation. A significant role in meeting these needs is played by the transcription regulator PGC-1a (coactivator of the peroxisome proliferation receptor), which is synthesized during the reduction of slow fibers. Let's remember this squirrel, it is one of the main characters of our story. Perhaps its role in myofibrils is no less than that of actin with myosin. In mice, it regulates the expression of more than one and a half thousand genes: the activity of some suppresses, others stimulates, how many in humans – have not yet been counted. PGC-1 has many functions, including stimulating mitochondrial formation, fatty acid oxidation, and resistance to muscle atrophy. Transgenic mice with an excess of PGC-1a are pumped up and muscular, and animals with an inactive gene have very weak endurance. During exercise, cellular factors are released that modify the PGC-1a protein, making it more stable, and therefore active. At the end of the workout, the PGC-1a level returns to normal within an hour.

With prolonged, systematic endurance training, the proportion of slow fibers increases at the expense of fast ones, and PGC-1a again plays an essential role in these transformations (Fig. 1). In trained muscles, the level of PGC-1a is higher than in untrained muscles, even at rest, and since it regulates metabolism and the work of many genes in myofibrils, then physical activity can be useful in some diseases associated with impaired muscle activity. Studies in mice have confirmed that PGC-1a really mitigates the effects of Duchenne myopathy and mitochondrial myopathy (muscle depletion with mitochondrial dysfunction).

Fig. 1. The role of PGC-1a in endurance-trained muscle fibers

PGC-1a also suppresses the activity of factor NFkB, the main regulator of the expression of pro-inflammatory genes. Consequently, a sedentary lifestyle provokes the synthesis of pro-inflammatory cytokines and the development of local and systemic inflammation, the deplorable consequences of which we have already discussed.

We have all heard that a healthy body has a healthy mind. And this is true, because PGC-1a protects from depression as well. This disease poisons the lives of millions of people around the world. Depression is associated with the formation of kynurenine – a product of tryptophan degradation – under the influence of stress and inflammation. Synthesis of kynurenine occurs mainly in the kidneys, liver and cells of the immune system, but from there the substance enters the blood and brain. Kynurenin causes the death of neurons and inflammation of the nervous tissue, leading to depression. Specialists of the Karolinska University (Sweden), experimenting with mice, found that PGC-1α enhances the synthesis of the enzyme kynurenine aminotransferase in skeletal muscles (Skeletal Muscle PGC-1a1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression // Cell, 2014, 159, 33-45). This enzyme also enters the bloodstream and converts kynurenine into kynurenic acid, which cannot overcome the blood-brain barrier. The content of kynurenine in plasma is reduced, which protects the brain from damage and stress-induced depression. Researchers do not rule out that PGC-1a can be used for therapeutic purposes, but isn't it more useful to do physical education?

So, physical activity, mainly endurance training, increases the level and activity of PGC-1a, which has a beneficial effect on many vital processes or protects us from health problems. In addition, muscle contractions and PGC-1a activate the synthesis of proteins that affect the processes occurring both in muscle tissue and in other organs, so skeletal muscles can rightfully be considered an organ of internal secretion (Fig. 2). These regulatory proteins are called myokines. The list of myokines is constantly growing, and it often includes compounds already known to us in another capacity, for example, interleukins – a product of leukocyte synthesis and indispensable participants in the immune response.

Fig. 2. Muscle tissue – an organ of internal secretion


There are three interleukins in the list of myokines so far: IL-6, IL-8 and IL-15. IL-6 and IL-15 are known as inflammatory factors, in addition, IL-6 causes insulin resistance, and also, under certain conditions, increases the level of anti-inflammatory cytokines. IL-8 is responsible for attracting neutrophils and angiogenesis. In muscle cells, they have other tasks. All three proteins are typical myokines, their synthesis in skeletal muscles and concentration in blood plasma increase after physical exertion, and IL-8 is mainly affected by exercises in which the loaded muscle lengthens.

IL-6 acts on different tissues. It triggers cascades of biochemical reactions, as a result of which muscle cells consume more glucose and actively oxidize fatty acids, lipolysis increases in adipose tissue, glycogen cleavage and glucose formation in the liver, and insulin secretion in the pancreas. The formation of glucose in the liver and the release of fatty acids from adipose tissue provide energy to working muscles.

The role of IL-8 in skeletal musculature is still unknown, but there is reason to believe that this factor stimulates the growth of new vessels.

IL-15 is initially known as a muscle anabolic, it also causes the synthesis of contractile proteins, promotes the absorption of glucose and the oxidation of fatty acids, in rats it counteracts cancer cachexia (exhaustion). The higher the concentration of this myokine in plasma in humans, the less white fat they have, and in rats it enhances thermogenesis.

Neurotrophic factors

These proteins, as the name implies, are synthesized in nerve cells and regulate their development and activity. For example, the brain's neurotrophic factor BDNF affects learning and memory, and its deficiency is associated with obesity and type 2 diabetes. However, after exercise, the level of BDNF in the blood increases significantly, with 70-80% of this amount consumed by the brain. In skeletal muscles, BDNF enhances fat oxidation and regulates cell regeneration.

Another protein, ciliary neurotrophic factor CNTF, is responsible for the work of osteoblasts – cells that build bone tissue. Mice deficient in this gene have massive and poorly mineralized bones. Citizens who lead a sedentary lifestyle, with a lack of CNTF, often develop osteoporosis (a violation of bone metabolism, resulting in their fragility). In case of calcification of muscles and overgrowth of the periosteum, physical activity, on the contrary, is harmful, because increased synthesis of CNTF will only aggravate these signs.

Growth factors

Vascular Endothelial Growth Factor VEGF really regulates endothelial growth and stimulates angiogenesis. Its synthesis in muscle fibers is controlled by PGC-1a and coordinated with the synthesis of another myokine, SPP1. This protein stimulates the activity of macrophages, endothelial cells and smooth muscles, which also contributes to the formation of capillaries.

Fibroblast growth factors regulate cell division, growth and differentiation, and cellular metabolism. One of them, FGF21, is synthesized mainly in the liver, as well as in adipose tissue, pancreas and skeletal muscles. Depending on the place of synthesis, FGF21 performs different functions. Hepatic stimulates the expression of PGC-1a, which, in turn, activates the oxidation of fatty acids and glucose synthesis in the liver. In adipose tissue, FGF21 increases glucose intake, and in transgenic mice, an excess of FGF21 protects against the development of obesity. This protein reduces the level of sugar and triglycerides in the blood of diabetic rodents, that is, theoretically it can be a medicine.

The synthesis of FGF21 in skeletal muscles does not depend on muscle load, but on an excess of insulin or low temperature. In the first case, FGF21 regulates insulin levels, in the second it stimulates thermogenesis in brown fat cells.

Three myokines and thermogenesis

Recently, three new members have appeared in the list of myokines: irisin, meteorin-like protein Metrnl and β-aminoisobutyric acid (BAIBA). All three myokines stimulate thermogenesis in brown fat cells.

Irisin is formed by contraction and trembling of skeletal muscles, it participates in the transformation of white fat into brown and enhances thermogenesis, preventing adipose tissue from growing. Under the influence of physical activity and PGC-1a, irisin is also synthesized in the hippocampus, stimulating the synthesis of BDNF and neurogenesis in this area of the brain. In mice, irisin accelerates the metabolism of skeletal muscles and increases energy consumption in muscle cells, but how it is in humans remains to be seen.

Metrnl is a hormone whose synthesis is enhanced in skeletal muscle cells during exercise and in white adipose tissue in the cold. Unlike irisin, Metrnl synthesis does not depend on PGC-1a, but on its spliced form PGC-1a4, which is formed during strength training and regulates the work of another set of genes. Metrnl increases energy consumption, increases glucose tolerance in obesity and diabetes, and promotes browning of white fat.

BAIBA, although not a protein, behaves like a classic myokine: it is synthesized in active muscles by the PGC-1a signal, activates thermogenesis and browning of white fat and enhances the oxidation of fatty acids in liver cells. The content of BAIBA in the blood is inversely proportional to the risk factors for cardiovascular and metabolic disorders, and scientists suggest that it protects against metabolic syndrome.

All three myokines actively cause browning of white adipose tissue, thus stimulating the release of energy. It is possible that skeletal muscles regulate and coordinate both types of thermogenesis: tremulous, which occurs when skeletal muscles contract, and non-tremulous, which occurs in brown adipose tissue. Indeed, irisin, like FGF2, is synthesized in response to cold, and its secretion is closely related to the intensity of shivering.

Two against Cancer

An active lifestyle not only reduces the risk of developing metabolic disorders, but may also protect against certain types of malignant tumors. Thus, according to the World Cancer Research Foundation, physical exercise reduces the likelihood of developing breast and colon cancer by 25-30%. Scientists explain this influence in different ways. In particular, two recently discovered myokines, SPARC and OSM, inhibit the division of cancer cells in the colon and mammary gland and cause their apoptosis. What role these proteins play in a healthy body is still unclear. Perhaps they regulate cell division and apoptosis in contracting muscle fibers, but it is possible that the effect of SPARC and OSM on non-cancerous cells is not related to their division and death at all.

The list of myokines turned out to be long and may have tired the reader. However, it would be incomplete without myostatin, which can be called an antimyokine: muscle contractions do not stimulate, but suppress its synthesis.

The Hercules Mutation

Myostatin (MSTN) belongs to the group of growth factors. It is synthesized in inactive muscles and prevents the formation of muscle tissue: mountains of muscles, if not used, only absorb energy in vain. Regular physical training, both strength and aerobic endurance, inhibits the synthesis of myostatin, which contributes to the formation of relief muscles. The MSTN gene is very conservative, its sequence is almost the same in all vertebrates. In laboratory mice lacking the MSTN gene, the mass of muscle tissue is two to three times greater than in wild-type rodents. MSTN mutations that disrupt protein synthesis lead to the appearance of extremely fleshy cows and sheep with hypertrophied muscles. All myostatin mutants have a reduced adipose tissue content. Apparently, the fat mass decreased mainly due to an increase in muscle mass, and not due to the absence of myostatin.

Recently, American and British researchers discovered a small deletion of MSTN in the genome of Whippet hounds (PLoS Genetics 2007, A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs). The mutation was named mh. According to the breed standard, a whippet should be a powerful, strong animal with a harmonious, elegant structure. Mutant dogs retained their power and harmony, but lost their elegance, especially homozygotes (Fig. 3). They run faster than ordinary whippets. Interestingly, the mh mutation has not yet been detected in other breeds.

Fig. 3. Wild-type whippets (+/+), as well as heterozygous
and homozygous for the mh mutation inactivating the MSTN gene

The researchers planned to look for a similar mutation in other species. And doctors from Germany and A few years earlier, an extremely muscular boy was observed in the Berlin Charite Clinic (The New England Journal of Medicine, 2004, Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child). The newborn impressed specialists with the developed musculature of the arms and legs, by the age of four and a half, the boy continued to build muscle mass and could hold a three-kilogram dumbbell at arm's length (Fig. 4). The boy is still healthy.

Fig. 4. A boy with an inactive myostatin gene. 
On the right – a newborn, on the left – at the age of seven months.
Pay attention to the relief muscles of the calves and thighs.

A mutation was found in the myostatin gene in the baby, but not the same as in dogs; this is a single nucleotide replacement that disrupts RNA splicing and leads to the formation of an inactive protein. The boy obviously inherited this mutation. Although the researchers could not analyze the DNA of his relatives, it is known that his brother, father and grandfather of the mother were distinguished by extraordinary strength. How can I not remember Hercules, who strangled two snakes with his bare hands at the same time on the first day of his life, maybe he was a mutant?

Spending life in a chair, we deprive ourselves of a lot of useful proteins that could synthesize our muscles. The time is not lost – it's never too late to do physical education. We can't even fully imagine how useful this is, because research on myokines continues.

Based on the article Schnyder S., Handschin Ch. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise // Bone, 2015, 80, 115–125.

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