Journal of Exercise & Organ Cross Talk

Abstract Dear Editor-in-Chief
Osteoarthritis (OA) is a progressive disease and up to now, no effective cure has been found for these diseases. OA was characterized by destruction of articular cartilage (extracellular matrix). As we age, chondrocytes show less response to growth factors, also, there is an increase abnormal accumulation of advanced glycation products (AGEs), mitochondrial dysfunction, and oxidative stress. As a result, cartilage homeostasis is impaired and ECM becomes more vulnerable to injury, leading to the onset of OA (Abramoff & Caldera, 2020). Chondrocytes are the only cell type present in articular cartilage that are solely responsible for circulating and maintaining the matrix. Exercise training with increased mechanical stress can affect the extracellular matrix in the joints. However, exercise apart from mechanical stress can also indirectly affect cartilage metabolism by increasing muscle contraction and the expansion of some myokines, which is a potential therapeutic target for osteoarthritis.
A variety of growth factors and cytokines are actively secreted by muscle tissue. Thus, muscle can act as an endocrine and paracrine organ. Secretoms are secreted not only through muscle tissue but also from other tissues and affect other organs of the body. Adipokines include adiponectin, leptin, resistin, chemerin, IL-6, and TNF-α playing an important role not only during inflammation but also in the metabolic regulation of joint cells including cartilage, osteoblasts, osteoclasts, and mesenchymal stem cells (Xie & Chen, 2019). Muscle tissue also affects cartilage metabolism with its myokines.
    FNDC5 is an important exercise myokine for slowing down age-related diseases, such as sarcopenia, osteoporosis, obesity, and neurodegeneration. Loss of FDNC5 has been shown to be associated with chondrocyte aging in the development of OA in humans and mice. 
Myokine maintains chondrocyte activity by preserving the metabolism and biology of the mitochondrial TCA cycle to protect against inflammation-induced aging. Myokine maintains chondrocyte survival and ECM synthesis by suppressing the cartilaginous inhibitory factor Wnt3a to control autophagy programs and apoptosis (Chen et al., 2020). Recently, it has been discovered that Sox9 was expressed in MTJ, tendon, and bone progenitor cells at E13 and in bone at E16. The expression of Sox9 in muscle precursor cells is also being studied. It is hypothesized that an increase in this factor of muscle tissue after exercise can also affect cartilage metabolism because it is stated that decreased Sox9 expression in connective tissues, tendons and bones is associated with cartilage hypoplasia (Nagakura et al., 2020). These hypotheses elucidated that the role of Sox9 secreted by muscle tissue can also play an important role in the development and healing of joint and cartilage, requiring animal and human studies.

Abstract Dear Editor-in-Chief
During pregnancy, regular physical activity contributes to the health of the mother and fetus, which is due to the effect of exercise on the mother's physiological regulation, growth, and optimal function of the fetal placenta. But the mechanism of this effect is unknown. Recently, studies have shown that exercise can connect multiple tissues through the tissue secretomes. Muscle tissue secreting myokine can affect distant tissues such as the liver, adipose tissue, brain, skin, and even the placenta. However, other tissues can also affect muscle tissue. The human placenta as multifunctional organ releases large amounts of hormones, cytokines, placental proteins, non-coding RNAs, as well as extracellular vesicles into the mother's bloodstream (Adam et al., 2017). Exosomes are nanometer-sized extracellular vesicles produced by the endosomal pathway and packed with tissue-specific molecules. Because these nanoparticles can selectively target specific cells and transmit their contents to receptor cells, they form an integral pathway from cell-to-cell communication (Valadi et al., 2007). For example, exosomes secreted from the placenta reduce insulin sensitivity in muscle tissue and improve glucose metabolism in skeletal muscles during pregnancy (Nair et al., 2018). Since exercise itself is effective in improving insulin sensitivity, especially during pregnancy, it seems that one of the mechanisms involved could be the regulation of placental exosome secretion and its effect on muscle tissue, which has not been studied so far.
Evidence suggests that skeletal muscle during exercise by secreting endocrine factors such as myokines affect liver, adipose tissue, and placenta during pregnancy. Moreover, myokines can improve glucose and fat metabolism in mother’s body (Laurens, Bergouignan, & Moro, 2020).  So far, more than 600 myokines have been identified, the most important of which is irisin. This factor is secreted from muscle tissue and can affect the metabolism of other tissues, including white adipose tissue. It has also been reported that the level of this myokine can increase during pregnancy. The vital involvement of irisin in various key metabolic pathways increases attention to considering the effects of this myokine during pregnancy. Maternal circulating levels of irisin were measured in the range of 5-50 nM (Seven et al., 2019). In pregnant women during normal pregnancy, this factor is significantly higher than irisin levels in non-pregnant women. The potential role of circulation irisin on placenta is currently unknown. Since muscle contraction and exercise cause a significant increase in irisin expression (Sousa, Improta-Caria, & Souza, 2021), it seems that exercise during pregnancy with an increase in irisin also affects the placenta, which needs further investigation.
Recently, it was observed that maternal exercise stimulates the expression of myokine and adipokine apelin in addition to adipose tissue and skeletal muscle in human placenta. The new "exerkine" apelin appears to play a regulatory role in response to exercise during pregnancy in metabolic health (such as energy metabolism, fluid homeostasis, blood pressure, etc.) and fetal muscle development (Son et al., 2020). Furthermore, Bhattacharjee et al. in a current human study showed that regularly physically active women during pregnancy have a significantly increased placental expression of the myokine vascular endothelial growth factor (VEGF) and its VEGF receptor-1 compared to inactive women (Bhattacharjee et al., 2021). Further research is needed to assess the cross-talk between apelin and VEGF and the placenta in more details.
Fibroblast growth factor 21 (FGF21) is also a key regulator of endocrine and paracrine glucose and lipid metabolism, which is secreted from muscle tissue and can affect other tissues, including the placenta. FGF21 appears to affect the placenta through FGFRs and co-receptor β-klotho (Sun, Sherrier, & Li, 2021). Therefore, according to the evidence, it seems that the study of cross-talk subtypes of the endocrine family of FGFs (FGF19, FGF21, FGF23) and especially FGF21 with klotho protein along with the intervention of physical activity is a new topic to identify the mechanism. The effects of exercise on the human placenta need to be examined more closely (Bhattacharjee, Mohammad, & Adamo, 2021).
 

Abstract Dear Editor-in-Chief
Different types of exercise training with increasing muscle contraction can stimulate muscle secretome called myokines. Myokines are the main mediators of maintaining muscle structure and function in manner of autocrine and paracrine. These myokines can both affect distant tissues and have positive effects on muscle tissue itself (Chen, Wang, You, & Shan, 2021). In various diseases leading to muscle wasting, it seems that exercise and increased contraction can reduce the rate of muscle wasting and muscle atrophy by regulating myokines. Myostatin is a myokine that negatively regulates skeletal muscle development. In animal models, myostatin degradation has been shown to increase muscle mass and inhibit myostatin signals which can control the loss of muscle mass due to cancer cachexia (X. Zhou et al., 2010). Zhou et al. (2021) showed that exercise training (strength or balance in combination with endurance training) seems to be effective in preventing sarcopenia and maintaining muscle mass in non-dialysis-dependent patients with chronic kidney disease (CKD) with inhibition of myostatin signaling (Y. Zhou, Hellberg, Hellmark, Höglund, & Clyne, 2021).
Apelin is another myokine that decreases in age-dependent manner (Vinel et al., 2018). Apelin signaling in aging helps to increase muscle function by stimulating mitochondrial biogenesis and anti-inflammatory pathways in myofibers and improving regenerative capacity by targeting muscle stem cells (Vinel et al., 2018). It has been shown that exercise can positively regulate the Apelin and improve muscle growth. Apelin, an exerkine, is elevated due to maternal exercise, and maternal apelin administration mirrors the effect of maternal exercise on mitochondrial biogenesis in fetal muscle (Son et al., 2020). In other words, Apelin inhibits skeletal muscle dysfunction.
Leukemia inhibitory factor (LIF) is primarily expressed at low levels in type 1 muscle fibers. LIF has been shown to affect the growth and regeneration of skeletal muscle. For example, the expression of LIF protein in rat plantaris muscle is increased by mechanical load (Sakuma et al., 1998). Furthermore, LIF stimulates the hypertrophic response to increased load in the animal model, and in this respect LIF has been shown to be an important factor in skeletal muscle hypertrophy. In addition, LIF mRNA increases in human skeletal muscle following muscle damage leading to better repair. Therefore, this factor secreted by skeletal muscle can increase in various injuries and diseases with exercise and controls muscle wasting. Irisin is one of the most important muscle myokines that is secreted from muscle tissue through exercise and has auto and paracrine effects. It was shown that the injection of irisin induced muscle hypertrophy, improved muscle strength and reduced necrosis and development of connective tissue in a murine model (Reza et al., 2017). Therefore, increasing this factor with exercise can counteract cachexia and atrophy.
Musclin is an exercise-responsive myokine associated with plasma atrial NP (ANP) and cyclic guanosine monophosphate (cGMP) and the expression of the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α) expression in skeletal muscle after exercise training (Subbotina et al., 2015). Musclin helps increase exercise capacity by increasing mitochondrial biogenesis in mice (Subbotina et al., 2015). In addition to its role in exercise, Musclin reduces muscle tissue damage during the development of cachexia-induced tumors and has beneficial effects on cancer patients at risk for cachexia (Re Cecconi et al., 2019). C - X - C motif chemokine ligand 12 (CXCL12) is another type of myokine that is involved in the growth of skeletal muscle. CXCL12 helps proliferate myogenic and angiogenic somite progenitor cells and controls myotoma formation (Abduelmula et al., 2016). Moreover, it has been shown that the concentration of plasma CXCL12 is enhanced in response to training on a bicycle ergometer (Wang, Lee, Lien, & Weng, 2014). Overall, muscle - muscle crosstalk with several myokines mediates the beneficial effects of exercise training, including regulating muscle growth, preventing muscle loss, and increasing muscle function and regeneration, and these factors can decrease muscle wasting diseases.