Cachexia is an extremely serious syndrome which occurs in most patients with different cancers, and it is characterized by systemic inflammation, a negative protein and energy balance, and involuntary loss of body mass. This syndrome has a dramatic impact on the patient’s quality of life, and it is also associated with a low response to chemotherapy leading to a decrease in survival. Despite this, cachexia is still underestimated and often untreated. New research is needed in this area to understand this complex phenomenon and ultimately find treatment methods and therapeutic targets. The skeletal muscle can act as an endocrine organ. Signaling between muscles and other systems is done through myokines, cytokines, and proteins produced and released by myocytes. In this review, we would like to draw attention to some of the most important myokines that could have potential as biomarkers and therapeutic targets: myostatin, irisin, myonectin, decorin, fibroblast growth factor 21, interleukin-6, interleukin-8, and interleukin-15.
Cachexia is an extremely serious syndrome manifested by anorexia, weight loss through loss of muscle mass and fatty tissue, inflammation, and increased energy consumption that occurs in many chronic diseases, of which cancer occupies a special place (80% of patients with cancers develop cachexia) [
Cachexia is still underestimated and often untreated [
The current strategy focuses on treating cancer, with the hope that it will completely reverse cachexia syndrome. But this is not valid in advanced cancers. Another option is to increase nutritional intake, but the anorexia of cachectic patients is only part of the problem, nutrition as unimodal therapy not yielding the expected results. In addition, radiochemistry may exacerbate the progression of cachexia in a number of patients [
Until ten years ago, cachexia was seen as an untreatable syndrome. In recent years, however, the management of cancer cachexia has greatly improved, as studies on the involved mechanisms have developed. Current treatment of cachexia in malignant neoplasm is a palliative one. Many anticancer products may have beneficial effects in treating cancer but worsen cachexia [
There are papers showing that the skeletal muscle can act as an endocrine organ [
In this review, we will refer to myokines, one of the components of this complex mechanism that leads to the appearance of muscle weakness and muscle mass loss in cancer, that have an important potential to become therapeutic targets.
Myokines have been defined as cytokines and proteins produced and released by myocytes [
For the reasons above, myokines are essential therapeutic targets in cachexia and the modulation of their expression could improve the maintenance of skeletal muscles at parameters as close as normal in cancer patients (Figure
Effects of myokines in muscle cachexia. The schematic representation of myokine activity in the skeletal muscle shows the following: except for myostatin, which decreases after exercise, all others have a higher level after effort; between myostatin and decorin, there is an antagonistic relationship of mutual inhibition; the arrows show an activation or stimulation relationship between myokines and various metabolic processes that occur in the skeletal muscle.
Without going into the details about the signaling pathways in myocytes, already described in other publications, we would like to draw attention to some of the most important myokines that would have potential as biomarkers and therapeutic targets.
The main myokines studied to date are myostatin, decorin, irisin, myonectin, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), follistatin, fibroblast growth factor 21 (FGF21), bone morphogenetic protein (BMP), and brain-derived neurotrophic factor (BDNF) [
Between these myokines, we would like to draw attention on some of the most studied so far (Table
The most studied myokines and their action mode in skeletal muscular tissue.
Myokine | Action | Level after muscle exercise |
---|---|---|
Myostatin | Stops myoblast proliferation |
Lower level |
Irisin | Activates genes related to oxidative metabolism |
High level |
Myonectin | Induces nutrient uptake |
High level especially in muscle, less in circulation |
Decorin | Acts antagonistically with myostatin |
High level |
FGF21 | Induces glucose uptake |
High level |
IL-6 | Increases glucose uptake, oxidation of fatty acids |
High level |
IL-8 | Elevated in cancer cachexia, especially like cytokine |
High level in muscle, not in plasma |
IL-15 | Anabolic effect |
High level |
Also called growth differentiation factor 8 (GDF-8), it is a member of the transforming growth factor-
Its main function is the negative regulation of the muscle mass [
Myostatin influences the physiology of adipocytes, but it seems in an indirect manner. Pharmacological administration of myostatin
It seems that in myostatin null mice, reduced body fat is caused especially by muscle mass growth. Myostatin null mice develop a massive muscular hypertrophy resulting from an accelerated myogenesis [
Interestingly for our subject, cachexia, is that the circulating leptin level, the “satiety hormone,” secreted by adipocytes, is reduced in mice with myostatin deficiency, although food intakes compared to control mice (WT) were not different [
Although there are relatively few studies on the expression of myostatin in muscle cachexia, especially as a biomarker and therapeutic target, we consider it to be a good research approach in cachexia treatment, especially in conjunction with decorin and leptin.
Discovered in 2012 as a transmembrane protein [
It has been studied especially in relation to obesity but also with myopathies such as muscular dystrophy. In these latter studies, injection of irisin induced muscle hypertrophy, improving muscle strength and reducing necrosis and development of connective tissue in a murine model [
Myonectin is a protein belonging to the C1q/TNF-related protein (CTRP) family, and it is found mainly in muscle, less in circulation, being especially related to nutritional metabolism. Thus, the expression of myonectin is stimulated by exercise and nutrients and is supposed to induce nutrient uptake and storage in other tissues, such as adipose tissue, causing a flux of glucose or fatty acids [
It is less studied in connection with cachexia. We suppose that it could be a therapeutic target, just like other myokines, being linked to nutrient uptake.
Decorin is a small leucine-rich proteoglycan released by myotubes, and as other myokines, its circulating level is increased after acute exercise. Decorin is overexpressed in the skeletal muscle in humans and mice after chronic training [
Considering all of this, we can say that this myokine could be taking into account as the therapeutic target along with myostatin, being able to modulate the maintenance of muscle mass in cachexia.
Fibroblast growth factors are present in many tissues as signaling proteins and are implied in development and metabolism [
FGF21, as a myokine, is induced by stress [
There is a close link between FGF21 and adiponectin that acts as downstream effector of FGF21, controlling in an endocrine mode the lipid homeostasis and glucose in the skeletal muscle and other organs, such as the liver. In turn, adiponectin regulates the influence of FGF21 on energetic metabolism and insulin sensitivity [
FGF21 is a very poorly addressed myokine in the study of cachexia, although its involvement in the energy metabolism of the myocyte is demonstrated. Future research would be wanted to highlight its potential in therapeutic strategies as long as the energy metabolism of the muscle is very important in maintaining a normal state of this tissue.
IL-6 is the first myokine that has been discovered in the bloodstream, secreted by muscle cells after contraction [
It was originally described as a prototypic proinflammatory cytokine, then having anti-inflammatory properties also [
But how does IL-6 bind to cachexia and what therapeutic role can it have? A review on this subject was made by Narsale and Carson [
It is clear that diminishing this myokine can alleviate the progression of cachexia in cancer patients [
Numerous
Unlike
IL-8 is a chemokine produced by muscle cells and also by other cells like macrophages, epithelial cells, and endothelial cells. It is a member of the CXC cytokine family and was originally described as a chemoattractant for lymphocytes and neutrophils [
In recent years, some researchers have shown that IL-8 is involved in cachexia, finding an elevated level in the serum of patients with this syndrome [
An additional argument that IL-8 plays a role in cachexia is brought by a publication that has shown that the genetic polymorphism of this myokine can contribute to the pathogenesis of cachexia in gastric cancer [
A team of researchers found IL-8 in the muscle, not the plasma, following exercise, indicating its local role in angiogenesis for example [
It has been shown in healthy subjects that after muscle exercise, the level of myokines in the blood has increased. These include IL-8 and IL-15. Interestingly, a continuous muscle contraction with a moderate intensity induces a higher concentration of myokines than a shorter muscular contraction but with a high intensity [
Attention should also be paid to the fact that IL-8 is also produced in adipose tissue, especially the visceral one, and has a high level in obese patients [
IL-15 is present in the skeletal muscle, having an anabolic effect on the metabolism of muscle proteins, and is also modulated by exercise [
This myokine is connected with the alteration of mitochondrial function, overexpression of muscle IL-15 increasing mitochondrial activity and adipose tissue mass [
The role of IL-15 in cachexia is not fully understood. An earlier study on a rat model with cancer cachexia showed that IL-15 decreases the rate of protein degradation without affecting protein synthesis [
Despite these controversial results, the potential of this interleukin is not excluded, and other studies are needed to show this.
An important idea that should be considered is that there are cytokines that can be released by both the immune system and the muscles. Inflammation occurs in cancer and may even induce cancer [
We cannot draw conclusions about the place and role of myokines in
One of these important
Consideration should be given to the possibility of cancer
The authors declare that there is no conflict of interest regarding the publication of this paper.
This study was partially supported from Project IDs PN-III-P1-1.2-PCCDI-2017-0341 (PATHDERM) and PN-III-P1-1.2-PCCDI-2017-0782 (REGMED), PN 18.21.02.02/2018.