ABSTRACT

The active skeletal muscle and the maintenance of muscle mass are essential for good health, wellness and disease prevention and treatment. It has recently been documented that the muscle, as an endocrine organ, is capable of synthesizing myokines. These peptides are secreted in response to muscular contractions induced by exercise, and can develop molecular communication with other tissues, improving cardiovascular, metabolic, and mental health.
The endocrine function of a muscle continues to be in a constant investigation; however, knowledge up to date urges us to continue promoting physical activity. Additionally, the extended knowledge of myokines is useful to prescribe individualized physical exercise programs to each patient.

Keywords: Adaptive plasticity, muscles, cytokines, physical exercise, motor activity, chronic disease (Source : MeSH - NLM).

RESUMEN

El músculo esquelético activo y el mantenimiento de la masa muscular son esenciales para la salud, el bienestar, la prevención y el tratamiento de enfermedades. Recientemente se ha documentado que el músculo, como órgano endocrino, es capaz de sintetizar mioquinas. Estos péptidos son secretados en respuesta a las contracciones musculares inducidas por el ejercicio, y son capaces de crear comunicación molecular con otros tejidos, beneficiando así la salud cardiovascular, metabólica y mental.
La función endocrina del músculo continúa en investigación constante, sin embargo, lo conocido hasta ahora nos insta a seguir promoviendo la actividad física. Adicionalmente a esto, extender el conocimiento sobre las mioquinas, es útil para poder prescribir el ejercicio físico de manera individualizada y a la medida de cada paciente.

Palabras Clave: Plasticidad adaptativa, músculos, citocinas, ejercicio físico, actividad motora, enfermedad crónica (Fuente: DeCS BIREME).

INTRODUCTION

The muscle is a Dynamic tissue implied in movement, posture, respiration ⁽¹⁾, and corporal thermoregulation ⁽²⁾. It is considered the most abundant organ in the human body ⁽²⁾, since it represents 30 to 50% of total corporal weight ⁽³⁾.

Since 450 B.C., we have evidenced the positive effects of physical activity in health and the prevention of chronic diseases. As was cited by “the father of medicine, Hippocrates of Kos: “Walking is man’s best medicine” and “sports is a preserver of health”. ⁽⁴⁾ in this sense, exercise could also be prescribed as treatment for lifestyle related diseases: cardiovascular diseases, type 2 diabetes, neurodegenerative diseases and cancer ⁽⁵⁾.

The benefits of exercise for health and wellness of humans have been attributed to innumerable physiological mechanisms, however, the transcendental role that the muscle possesses in these processes has been documented in recent years ⁽⁶⁾.

In recent years, the skeletal muscle has been identified as a endocrine organ, since it is capable of synthesizing cytokines called myokines, which possess autocrine, paracrine and endocrine function ^(7,8). Thanks to the exercise stimulus, these protein molecules are released to the blood stream, allowing the communication of the muscle not just with itself but also with other organs such as the brain, bone, pancreas, intestine, liver, adipose tissue, cardiovascular system, and skin ⁽⁵⁾, therefore creating a physiological and unique connection between exercise and metabolism regulation ⁽²⁾.

Taking into account the progressive deterioration of muscle physiology with age, the active skeletal muscle and the maintenance of muscle mass are essential for the health care, prevention and treatment of diseases ⁽⁹⁾. For this reason, this article seeks to carry out a current literature review about the importance of physical exercise in the preservation of muscle mass during a lifetime, for prevention as well as for treatment of non-transmissible chronic diseases.

METHODOLOGY

A review of scientific articles in Spanish and English related to the research topic was carried out, which were collected from PubMed, Elselvier and SciELO. On the other hand, we took into account certain criteria for the adequate article selections: that the article title be chosen with the research topic and that it has a maximum of 6 years old, meaning dated from 2015 onward. We excluded the letter to the editors related with the topic.

RESULTS

Out of the 37 articles found, 35 were chosen. One was excluded because it was published before 2015 and the other because it was a letter to the editor. Tables 1 and 2 detail the most relevant results and conclusions of the chosen articles according to the objective of the present study.

DISCUSSION

MUSCLE AND PLASTICITY

The muscle is a tissue structurally organized and functional, acting as the main reservoir of amino acids, hosting approximately 75% of body protein ^(3,8,10).

Muscle tissue is highly malleable, plastic ^(3,8), and with a great capacity of adaptation and regeneration in the face of diverse stimuli such as nutrient ingestion, restriction or increase of calories, physical activity, diseases, hormones, physical stress and cytokines ⁽¹¹⁾.

It should be emphasized that nutrition and exercise are key for increasing and preserving muscle mass ^(3,8,12,13). Muscle maintenance through life is necessary for health and wellbeing and recover from diseases ⁽³⁾. Furthermore, it guarantees physical independence, improves quality of life ⁽¹³⁾ and prevents comorbidities, such as insulin resistance ⁽¹²⁾. Likewise, muscle strength has been seen as a predictor of mortality, disability, and weakness in older adults ^(13,14).

The normal physiological aging behavior causes a decrease in muscle mass ^(13,14,15). During the aging process type II muscle fiber atrophy occurs. Furthermore, there is a change from type II to type I fibers, meaning, from fast to slow ⁽³⁾.

Under optimal conditions, the musculoskeletal system remains stable during the lifetime until approximately 50 years, afterwards muscle loss descends progressively around 1% per year. After 70 years of age, it increases to 1.3% - 2.4% and after 80 years of age it could reach 5% per year ^(13,14,15).

The aforementioned conceptualizes what is known as sarcopenia. The word sarcopenia is derived from the Greek: sarx which means flesh, and penia: loss. It is defined as a chronic, degenerative muscular disorder ⁽⁸⁾, generalized, progressive, associated with age, that is characterized by decrease in musculoskeletal mass, muscle strength, and its functionality ⁽¹³⁾.

The mechanisms behind sarcopenia are multifactorial involving intrinsic factors such as imbalance between protein synthesis and protein catabolism, hormone alterations, chronic inflammation, neurodegenerative conditions, genetic factors, ectopic fat deposits and mitochondrial dysfunction ^(12,15,16). As well as exogenous factors, for example, nutritional deficiencies and physical inactivity. While it is true that sarcopenia is a process parallel to age, a poor lifestyle could eventually accelerate this process ^(8,12,14).

A cross-sectional study carried out in Portugal with a total of 3493 older adults (1166 men, 2327 women) evidenced that a decrease in muscle mass and strength generates 1.65 to 2.2 greater risk of becoming physically dependent ^(17,18)

On the other hand, a reduction in muscle mass and strength leads to effects in the locomotor function of the musculoskeletal system, predisposing to alterations in glycemia and blood lipid levels, particularly in state of obesity ⁽¹⁹⁾.

Scientific evidence exists where only 2 weeks of physical inactivity (650- 1000 steps per day), as occurs in complete bedrest or hospitalizations, could cause important changes in the muscular level. This leads to the introduction of insulin resistance and an increased risk of developing type 2 diabetes mellitus, in young people as well as older adults ⁽²⁰⁾.

Consequently, sarcopenia negatively impacts the economic level as well, since it increases health care costs due to comorbidity worsening or complications, in addition to major risk of hospitalizations ⁽¹³⁾, considered a public health problem ⁽⁸⁾.

THE MUSCLE AS AN ENDOCRINE ORGAN

The muscle is highly vascularized and possesses abilities to secrete myokines ⁽²²⁾. During physical activity and exercise, repetitive contractions take place which generate an adaptation to muscle cells, strengthening its contractile and metabolic properties. This contractile activity is key for the production and release of myokines ⁽¹¹⁾. These peptides not only participate in the regulation of energy demands, but also benefit cardiovascular, metabolic and mental health ⁽²³⁾.

Myokines regulate the muscular function and adaptation in oxidation, hypertrophy, and angiogenesis ⁽⁷⁾. Furthermore, they are channels of communication between muscle and different organs ⁽²³⁾. By the way, two of the main positive consequences of this molecular link between tissues are: a) decrease of systemic inflammation and with this reduction of sarcopenia and accumulation of visceral fat, and b) greater sensitivity to insulin ⁽²³⁾.

There have been over 650 myokines identified ⁽⁵⁾. Below, we will mention some of the more relevant and their implications in chronic diseases.

Interleukin-6 (IL-6):

Originally this interleukin was considered as a proinflammatory cytokine, however, in recent years, studies have demonstrated its anti-inflammatory properties ^(11,24). Muscular contraction induced by physical activity generates and increase in genetic expression and release of IL-6 by the myocyte ^(6,23), contributing with the homeostasis of glucose ⁽⁸⁾. The plasmatic levels of IL-6 can increase up to 100 times, depending on the volume, intensity and density of physical exercise ^(6,23).

Some of the target organs for circulating IL-6 are the liver, pancreas and adipose tissue. IL-6 optimizes the viability of pancreatic β cells, improves insulin sensitivity and favors lipolysis in adipose tissue ^(7,22). Furthermore, it has been seen to stimulate hepatic gluconeogenesis, glucogenesis and glucose release ^(7,11).

On the other hand, this myokine, through alternative pathways, promotes the activation of macrophages, which are involved in the protection against inflammation and insulin resistance secondary to obesity ⁽⁷⁾.

Immediately after performing physical exercise, released IL-6 significantly increases the levels of IL-10 and the interleukin 1 receptor antagonist receptor (IL-1Ra). These changes are characterized by having an anti-inflammatory effect ^(6,11).

A very interesting data is that this anti-inflammatory effect is more evident in certain pathological conditions, especially in those which inflammatory cytokines and CRP are found 2 to 3 times above the basal levels, such as atherosclerosis, type II diabetes, obesity and cardiac insufficiency ⁽⁶⁾.

Overall, IL-6 improves glycemic control, favors fat loss, suppresses tumoral growth and collaborates in the maintenance of muscle mass ⁽⁷⁾.

Interleukin 15 (IL-15):

In humans, this interleukin is able to be expressed in various cells and tissues, including the musculoskeletal system, epithelial cells, monocytes, and dendritic cells ⁽⁹⁾. It is released at the muscular level mainly after strength and resistance physical exercise ^(2,9).

IL-15 has been characterized by its anabolic properties in the skeletal muscle ^(6,11), its ability to induce hypertrophy has been demonstrated though the reduction of protein degradation in sarcopenia and cachexia, emphasizing this therapeutic power ^(6,11). Another interesting data that reaffirms this concept is that the plasma levels of IL-15 decrease with age, studies report that older adults with sarcopenia have significantly lower levels of this myokine ⁽⁹⁾.

Parallel to this, IL-15 has been found to inhibit tumor necrosis factor α (TNF-α) in the muscle during the states of cachexia. In addition, a decrease of this cytokine has been associated with autoimmune disease such as rheumatoid arthritis and leukemia ⁽⁶⁾.

Myostatin:

It was the first identified myokine, despite not being called a myokine during its discovery era ⁽⁷⁾. The main function of myostatin is to negatively regulate muscle mass ^(7,11). It is said that this cytokine is “inverse” compared to other muscular cytokines, in aerobic as well as strength and/or resistance exercise, decreases its expression in myocytes considerably ^(9,11). Its ablation generates muscular hypertrophy, increases muscle strength and improves bone architecture ⁽²⁴⁾.

Patients with cardiac insufficiency and cancer possess high levels of this protein, which could eventually result in cachexia. However, during physical activity these levels decrease, which illustrates the anti-catabolic benefit in these types of patients ^(6,9). The same result is observed in patients with chronic renal disease ⁽⁹⁾.

Myostatin has received new attention due to its potential for treatment of metabolic syndrome, since the levels of this substance are found elevated in patients with type 2 diabetes and women with obesity ⁽⁷⁾.

Muscle – adipose tissue and irisin:

A tissue that maintains a tight “communication” with the muscle is adipose tissue. Adipose tissue is constituted by 2 types of fat: white fat and brown fat. White stores the excess energy and secretes innumerable proinflammatory substances, meaning, in general terms it could be said that it is metabolically unfavorable. However, brown fat is beneficial ⁽²²⁾, since it has the capacity of regulating thermogenesis due to its high concentration of mitochondria ⁽⁶⁾, which means it consumes accumulated energy and therefore the levels of triglycerides decrease ⁽²²⁾.

The muscle – adipose tissue communication during muscle contractions provoke decrease in adiposity, increase in thermogenesis due to the increments in adrenergic activity, browning of white fat tissue, and increase in lipolysis ^(6,22). This browning process occurs mainly by the myokine called irisin, which joins a receptor in the adipocytes, favoring the phenotypic modification of fat and with that the increase in energy waste. This thermogenic effect is

mediated by the expression of an uncoupling protein present in mitochondria, also known as thermogenin or UCP1 (uncoupling protein 1) ⁽⁶⁾ Figure 1 summarizes this process clearly.

Additionally, it has been reported that it protects pancreatic function through the stimulation of pancreatic β cell proliferation and protection in face of apoptosis ⁽²⁴⁾. Irisin production is greater in cardiac muscle than in skeletal muscle. However, aerobic exercise favors its genetic expression generating an increase in plasma level ⁽⁹⁾.

On the other hand, several studies have been documented trying to demonstrate if irisin levels increase more significantly with aerobic training versus anaerobic. However, there are discrepancies between this evidence, which explains through the technique used to measure serum levels of irisin. Still, there is overwhelming scientific evidence that both types of exercise could increase circulating irisin ⁽²⁵⁾.

Muscle-brain:

Physical activity represents one of the most effective strategies to reduce prevalence and incidence of depression, cognitive impairment, neurodegenerative disorders ⁽¹⁾. Parallel to this it has a positive impact on stress and anxiety ⁽⁵⁾.

Exercise influences the hippocampus more than any other anatomical brain structure ⁽⁵⁾ through numerous myokines including cathepsin B, irisin, brain derived neurotrophic factor (BDNF), fibroblastic growth 21 (FGF-21), which play an important role in the muscle-brain interaction ^(22,26). The same, could measure neurological functions such as: cognitive development, memory, neuroplasticity, motor coordination, sleep, mood ⁽²⁶⁾, learning ability and memory ⁽²⁴⁾. At the same time, offer neuroprotection and decrease in brain inflammation ⁽²⁶⁾.

One of the noted benefits of physical exercise is central and peripheral induction of BDNF ⁽²⁶⁾, which plays a dominant role in this muscle-brain interaction ⁽⁵⁾. BDNF is a growth factor that belongs to the neurotrophin family, which look out for the neuronal survival and synaptic plasticity ^(11,26).

It is important to mention that patients carrier of Alzheimer’s disease, with depression, obesity, and type 2 diabetes, possess reduced serum levels of BDNF ⁽¹¹⁾.

The type 1 insulin growth factor (IGF-1), mainly produced by the liver, is able of crossing the hematoencephalic barrier and acts as mediator of attributable changes in physical activity in neurogenesis of the hippocampus and expression of BDNF. The formation and maintenance of dendritic spines at the hippocampus neuronal level in basal conditions, depend on BDNF induced by PGC-1α (coactivator of 1α of the gamma activated receptor of the peroxisome proliferator) after exercise. In the neuronal tissue, PGC-1α is a potent suppressor of the reactive oxygen species (ROS), which explains its neuroprotective effect ⁽²⁶⁾.

Muscle-cancer:

Epidemiological studies suggest that physical activity carried out in times of leisure reduce the risk of 13 different types of cancer ⁽⁵⁾. People that are physically active after their diagnosis of prostate, colon, and breast cancer have a greater survival rate than those that are sedentary with the same type of neoplasia ⁽⁵⁾.

Exercise stimulates NK cells (natural killer), which play a central role in reducing tumoral growth. Furthermore, IL-6 and IL-5 regulate the maturity and redistribution of NK cells ⁽⁷⁾.

PHYSICAL EXERCISE: PREVENTION AND TREATMENT

Given the anti-inflammatory effects of myokines as a response to physical exercise, it is clear that physical inactivity leads to inflammation and increase in adipose tissue deposits ⁽²⁶⁾.

In fact, the association between physical inactivity and visceral fat has been clearly established, which is more inflammatory than subcutaneous, leads to systemic chronic inflammation that predisposes to atherosclerosis, dyslipidemia, insulin resistance, neurodegeneration, anemia, and muscle degeneration. These pathologies are factors that provoke inactivity. The lack of movement generates more inflammation, and this continues to open the path to more chronic diseases, establishing a chronic vicious cycle ⁽⁵⁾.

Given the above, it is clearer that physical exercise helps improve the body composition in individuals with overweight and obesity ⁽⁶⁾. Furthermore, it decreases visceral fat, which includes pericardial fat ⁽⁵⁾. It is evident that the therapeutic strategy for sarcopenia is still physical exercise. And with these additional benefits are obtained such as increasing strength, increasing basal metabolic rate, decreasing blood pressure, and optimizing blood lipid levels ⁽¹²⁾.

It’s important to note that during decades the importance of aerobic exercise has been mentioned. However, recently it has been demonstrated that physical activity that involves strength and resistance could be just as effective for reducing morbidity and optimizing health ⁽¹⁸⁾.

Given the above, different exercise modalities have been demonstrated for blood pressure decrease. Studies support that all type of training, whether it is aerobic, or anaerobic (resistance or strength), or a combination of both, are equally effective for reducing pressure in persons with arterial hypertension ⁽²⁷⁾.

Delving into this more than what was described in the prior paragraph, and despite that cardiovascular exercise is the most prescribed for this type of patients, the benefits of strength training exercise such as weight lifting, or a combination of aerobic exercise and resistance exercise, are similar and even superior in the decrease of arterial pressure, The following reductions have been registered: 8.7 mmHg in cardiovascular exercises, 7.2 mmHg in resistance and 13.5 mmHg in the combination of both ⁽²⁷⁾.

There is evidence supporting that regular exercise, even without important weight loss, the levels of leptin decrease. Similarly, intense acute exercise reduces the circulating levels of proinflammatory adipokines tightly linked with insulin resistance and obesity. For this, physical exercise offers benefits to individuals with arterial hypertension, as well as other chronic diseases, secondary to positive effects generated by the increase of myokines and reduction of adipokines during and after training ⁽²⁷⁾.

On the other hand, the systemic response to myokines is greater after physical exercise with a greater level of fiber breakdown, for example in resistance training, taken in downhill slopes and eccentric exercises. In the same manner, we have observed an important increase in levels of myokines after training of long duration and vigorous intensity and much less pronounced in physical activity of moderate intensity ⁽⁷⁾.

Physical activity impacts glucose and lipid homeostasis, altering the composition of muscle fibers. Specifically, strength and resistance training favor the growth of muscle tissue, and at the same time increase oxidative and glycolytic capacity of fast fibers. It is scientifically documented that diabetics with a resistance exercise regimen have improved their insulin sensitivity. Likewise, in obese patients when gaining muscle mass, increase their basal metabolic rate ⁽²⁸⁾.

Lastly, the best road to maintain a healthy musculoskeletal system is increasing and maintaining a good muscle mass through physical exercise, and with that not just guarantee longevity but also quality of life ⁽⁹⁾. Furthermore, science continues to reaffirm that physical exercise is effective not just as prevention but also as medical treatment for different chronic diseases ⁽²³⁾.

CONCLUSION

Muscular activity is crucial for health and physical-mental wellbeing. Recently, with the discovery of myokines, the muscle has been involved in the maintenance of metabolic and cognitive homeostasis. If the muscle’s endocrine function is not sufficiently stimulated with physical exercise, the production of myokines necessary for the optimal functioning of organs would not be adequate, generating as a consequence the development of diseases. The knowledge on cytokines released by the muscle in response to physical exercise, is of key help for the prescription of exercise in an individualized manner and at the measure of each patient for the treatment of diseases associated with inactivity.

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