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⁾.

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 1summarizes this process clearly.

Figure 1: Browning process of white adipose tissue. FNDC5 (Fibronectin type III domain containing 5), irisin precursor. Irisin attaches to a WAT (white adipose tissue) receptor and a phenotypic modification (browning) occurs. BAT (Brown adipose tissue) 

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⁾.