Journal of Exercise & Organ Cross Talk

Abstract Dear Editor-in-Chief
The brain weighs about 1.36 kg and is mainly composed of blood. Although the brain includes only 2% of the body's weight, it receives 25% of the whole body oxygen consumption, 15% of the cardiac output volume and 2000 L of blood flow per day (Hartmann et al., 1994; Ohta et al., 1992; Xing et al., 2017). The brain has largest and most complex structure of the central nervous system. This organ regulates the functions of human body and stands for the basis of higher neural activities such as consciousness, alertness, learning, memory, intelligence, spirit and language learning. Cognitive function in a person means the brain ability to process, store, and extract information. In addition, this ability is a kind of advanced psychological function such as thinking, memory, and attention. Cognitive function plays an irreplaceable role in our daily life and study. Based on Cognitive psychology, the brain can modify its structure and function according to environmental changes and the experience of different types of exercising, especially exercise training, plays a crucial role in the evolution of the brain (Barnes. 2015; Raichlen et al., 2017). For example, exercise can positively affect synaptic plasticity and synaptic function to promote cerebral cortex, neural network and hippocampus function (an important structure in the memory information processing) (Ding et al., 2006; Li et al., 2019; Loprinzi et al., 2017). Exercise also has a significant effect on brain metabolism. Exercise not only promotes physical health of people, but also prevents mental illness and delays cognitive aging (Robinson et al., 2018).
Brain function depends on nerve fibers, number of neurons and synapses.  The cognitive performance is also closely related to the number of nerve fibers and synaptic connections, which can be reduced by diseases and aging process. The neurotrophics factors, such as neurotrophic factor (NGF) and brain-derived neurotrophic factor (BDNF) are required to provide nutrients to maintain the structure and function of nerve fibers and synaptic connections (Ivanov, 2014). However, with aging, sharp decrease of dendritic branches, degeneration of glial cells, the reduction of neuron number and contraction of nerves may impede the transmission of electrical signals in the nervous system, leading to the shrinkage of gray matter in the brain and cognitive impairment (Reisberg et al., 2008; Thorin-Trescases et al., 2018).
Several studies have shown that an active lifestyle could delay the aging of cognitive-control areas in the brain, and exercise can significantly improve brain health in patients with Alzheimer's disease and schizophrenia (Falkai et al., 2017; Frederiksen et al., 2018). Colcombe et al. (2003; 2006) used high-resolution magnetic resonance imaging (MRI) to scan the brain of 55 healthy people aged from 55 to 79 years old and observed a decrease in tissue density in the frontal and temporal lobes with age. The important point is that brain structure atrophy was related to aerobic fitness. In another study, 59 healthy people aged from 60-79 years old were divided into exercise training groups and control group. In the exercise training group, aerobic exercise intervention was conducted for 6 months. The results showed that the volume of gray matter and white matter was significantly increased in the exercise training group, and the researchers concluded that aerobic training could effectively delay brain aging process and lead to promote brain health (Colcombe et al., 2003; Colcombe et al., 2006; Colcombe & Kramer, 2003).
In terms of the mechanism based on which exercise training may enhance cognitive ability and  delay brain aging, it has been proved that exercise training can induce fibronectin type III domain-containing protein 5 (FNDC5) expression in skeletal muscle which will be released into the circulation with Irisin variant (Wrann et al., 2013). Spiegelman found that exercise training for 30 days in mice increased the activity of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which is a metabolic regulatory molecule in skeletal muscle. PGC-1α could stimulate the upregulation of FNDC5 expression, and when FNDC5 enters the hippocampus through the blood-brain barrier, it enhanced the expression of BDNF in the dentate nucleus of the hippocampus (responsible for learning and memory). Interestingly, the study on sedentary mice injected with FNDC5 produced by exercise showed it activated gene for the brain health and improved the growth of new neurons involved in learning and memory. This new discovery links FNDC5, PGC-1α and BDNF in the cross talk between the brain and skeletal muscle upon exercise (Wrann et al., 2013). In addition to PGC-1 α/FNDC5 signaling on other molecules have also been found to affect BDNF expression in cognitive impairment.
In a cell model simulating the effect of exercise by adding AMPK agonist to L6 myoblasts rat, proteomics and mass spectrometry were performed to screen the factors secreted by myoblasts. Data showed that Cathepsin B (CTSB) increased after treatment while other cytokines did not changed. Meanwhile, CTSB levels also increased in gastrocnemius muscle and plasma of rats after voluntary wheel running exercise, anti-fatigue ability; spatial memory ability and coordinated movement improved in the exercised rats compared to the sedentary control group. However, these beneficial effects were absent in CTSB knockout rat. In addition, intravenous injected CSTB is able to enter the brain through blood-brain barrier and upregulate DCX and BDNF expression and thus enhancing hippocampal nerve growth (Moon et al., 2016).
Aerobic Training not only promotes physical health of people, but also prevents mental illness and effectively delays brain aging process, prevents brain structure atrophy, promotes volume gray and white matter and  promotes cognitive ability in patients with Age-induced cognitive impairment. Therefore, it is very important to conduct original and cross-sectional research in order to discover relevant and new mechanisms.
 

Abstract Dear Editor-in-Chief
Diabesity is a modern epidemic challenge associated with metabolic disorder and chronic inflammation (Ng et al., 2021). Diabesity is reported to cause several complications in the musculoskeletal system such as sarcopenia and osteoporosis (Collins et al., 2018). Evidence suggests that obesity and diabetes negatively affect musculoskeletal system which is in favor of increasing sarcopenia and osteoporosis (Barazzoni et al., 2018; Trierweiler et al., 2018). Sarcopenic obesity (SO) is a multifactorial condition ultimately leading to body composition changes (muscle mass decrease and fat mass increase) (Wang et al., 2020) while osteoporosis is a condition in which bone density gradually decreases, increasing bone fracture risk. Diabetes has been strongly associated with an increased risk of osteoporosis-associated fractures (Romero-Díaz et al.,  2021).
Hormonal changes are suggested as one of the contributing factors involved in the pathogenesis of diabesity (Wang et al., 2020). Both muscles and bones are recognized as endocrine organs secreting hormones involved in regulating metabolic and inflammatory pathways. There are numerous indications that muscle secretome contains osteoinducer and osteoinhibitor myokines; it also seems likely that bone cells secrete myoinducer and myoinhibitor osteokines (Trajanoska et al.,  2019). 
Meanwhile, irisin and meteorin-like hormone (Metrnl) are signaling proteins that have opened a new window at the diabetes research. Scientists from the Dasman diabetes institute in Kuwait in collaboration with scientists from other departments of surgery, pharmacology and toxicology at Kuwait university have been investigating Irisin and Metrnl involvements in obesity and type 2 diabetes (T2D) (Jamal et al., 2020).  As Irisin and Metrnl are discovered in the last decade, they are relatively new to scientific research. These proteins are signaling molecules produced by muscle and fat tissues in response to exercise and exposure to cold temperatures. These proteins signal mitochondria to generate energy which elevates energy expenditure and ultimately promotes weight loss (Jamal et al., 2020). This makes Irisin and Metrnl promising targets for obesity and T2D. Interestingly, researchers from Dasman diabetes institute recently discovered that these molecules are already elevated in people with obesity and T2D (AlKhairi et al., 2019). High levels of Irisin and Metrnl can be a sign that the body is attempting to restore its normal functioning. In rats undergoing a weight loss surgery (sleeve gastrectomy), the research team found increases in Irisin and Metrnl levels correlated with improvement in metabolic health (Jamal et al., 2020). This increase was also beneficial in boosting heat production as reflected by higher expression of the thermal protein UCP-1 in mitochondria. Separate experiments revealed how Irisin and Metrnl interact with muscle and the bone (Cherian et al., 2021). Results show a strong association between Irisin and Metrnl and the bone markers osteoactivin and osteoprotegerin which are involved in bone formation (Cherian et al., 2021). This molecular crosstalk might play a role in bone and muscle complications associated with T2D and obesity. More research is needed to understand the interaction between these various markers. Mapping these relationships could lead to new treatments counteracting the effects of T2D and obesity. 

Abstract Regular physical activity is the best defense against many diseases, illnesses, and abnormalities. Aerobic exercise and the consumption of herbal supplements strengthen the body's immune and defense systems. This study aimed to investigate the effect of a period of swimming endurance training with trachyspermum copticum (Ajwain) consumption on serum levels of some inflammatory factors in young men in a randomized clinical trial. The statistical population included all male students less than 25 years of age at the Islamic Azad University of Varamin Phishva, Iran. Among them, sample sizes of 60 people were selected by simple random sampling and were divided into four groups of 15 people each: trachyspermum copticum + training, trachyspermum copticum, training, and control. The training program included endurance swimming for 10 weeks either with or without the addition of trachyspermum copticum. Serum concentrations of tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and heat shock protein 70 (HSP70) were measured in two-time stages before and after the study period. The level of CRP inflammatory index, TNF-α cytokine, and HSP70 were lower among the training + trachyspermum copticum than in the control group and other experimental groups. Endurance swimming training and trachyspermum copticum with anti-inflammatory properties strengthened the immune system, increased antioxidant defense, and decreased inflammatory markers. Also, the level of physical activity has improved this condition by improving endothelial function.

Abstract Dear Editor-in-Chief
The world has recently experienced one of the hardest pandemics, COVID-19. Clinical signs of this disease include fever, dry cough, and diarrhea, or different symptoms that lead to acute respiratory distress syndrome with a further increase in the severity of the disease. Although the first observations of this disease are the involvement of symptoms and respiratory and heart injuries, various studies have also shown the nerve damage caused by this disease. Common neurological symptoms include headache, dizziness, anosmia, seizures, or paralysis. The elderly and critically ill are in the high-risk group and have shown severe neurological symptoms after COVID-19. Apart from COVID-19-induced cellular and neurological damage, this disease has a profound effect on the mental health of people around the world. Increasing the duration of this disease and staying at home causes social and economic problems and as a result mental health problems (Verma et al., 2020). Neurological and mental illnesses are very common all over the world.
Psychological resilience was an important issue during COVID-19 epidemic. In other words, during an epidemic, mental health of people should be consider and cheeked, and entertainment programs should be prevented from causing psychological damage. Research during the COVID-19 epidemic found that because of the psychological pressures to increase psychological resilience, people tended to be more exposed to the outdoors, exercise more, receive more social support from family, friends and important people, sleep better, and pray more, that these factors were effective in mitigating psychological trauma. In most studies, spiritual health affects mental health, because repeated prayers and worships have been more independently associated with psychological resilience (Killgore et al., 2020). In other words, those who actively participate in these spiritual activities and strengthen their relationship with God are found to have the most psychological resilience to the mental health challenges imposed by COVID-19. In addition, the effects of exercise at the cellular level can help improve memory and psyche and be effective in improving psychological resilience. To date, no studies have been performed on secretions due to muscle contraction and its effect on the brain and psychological function, and psychological resilience especially to control the psychological damage caused by an epidemic.
Exercise has many beneficial effects on brain health and helps reduce the risks of dementia, depression, and stress, and is involved in restoring and maintaining cognitive function and metabolic control. The fact that exercise is sensed by the brain suggests that environmental factors induced by the muscle allow a direct link between muscle function and the brain. Muscles secrete myokines that help regulate hippocampal function. Evidence is accumulating that myokine cathepsin B crosses the blood-brain barrier to increase brain-derived neurotrophic factor production, resulting in neurogenesis, memory, and learning. In addition, the muscle tissue itself can affect the central nervous system, memory, and psyche in form of endocrine by increasing BDNF expression. Exercise also increases the expression of the neurogenic gene FNDC5 (which encodes myogenic FNDC5-dependent PGC1α), which in turn can help increase levels of brain-derived neurotrophic factor (Pedersen, 2019).
Serum levels of myokine, IL-6, increase with exercise and may have beneficial effects on the central nervous system. Exercise also increases PGC1α-dependent muscle expression and the enzymes kynurenine aminotransferase, which beneficially alters the balance between the neurotoxic kynurenine and the neuroprotective Kynurenic acid, thereby reducing depressive symptoms. Signaling myokine and other muscle factors and exercise-induced hepatokines and adipokines play a role in the beneficial effects of exercise on neurogenesis, cognitive function, appetite, and metabolism, thus supporting the existence of a muscle-brain endocrine axis. Also, it can affect psychological resilience which needs more studies.

Abstract Disorders of glucose metabolism in various tissues, including skeletal muscle tissue and adipose tissue are features of diabetes. The aim of the present study was to evaluate the long-term effect of moderate-intensity continuous exercise on the expression of irisin and sirtuin-1 genes in the skeletal muscle of streptozotocin-nicotinamide-diabetic rats. Thirty-six 8-week-old males were randomly divided into three groups: healthy control (n = 12), diabetic (n = 12), and moderate-persistent diabetes (n = 12). Diabetic groups developed diabetes by intraperitoneal injection of nicotinamide and STZ solution at a doses of 95 and 55 mg/kg. The diabetic-moderate-intensity continuous exercise group performed their training protocol by running on a treadmill for 12 weeks, 5 sessions per week. Forty-eight hours after the last training session, the subjects were anesthetized and their horseshoe muscle tissue was removed and the expression of the genes Irisin and Sirtuin-1 was measured. 12 weeks of moderate-intensity continuous exercise in diabetic mice resulted in a significant increase in the expression of the genes Irisin and Sirtuin-1 (p <0.05). Performing 12 weeks of continuous exercise with moderate intensity in diabetic rats increased the expression of Irisin and sirtuin-1. Thus, changes in the expression of irisin and serotonin-1 may improve the symptoms of metabolic syndrome and can be a compensatory mechanism for reducing oxidative stress in diabetics.

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 Physical fitness and psychosocial health might improve through resistance training programs. However, there has been controversy regarding the efficacy of different exercise programs. Therefore, this study attempted to compare the effect of 8-week resistance training with linear and undulating programming on physical fitness and mental health. Twenty-nine healthy and untrained students (age: 16.06±0.83) were randomly divided into three groups: (1) control (n= 6), (2) linear programmed resistance training (LPRT) (n= 12), and (3) undulating programmed resistance training (UPRT) (n= 11). After two weeks of familiarization, 1RM (one-maximum repetition) values were obtained. Thereafter, experimental groups attended a resistance training program of 3 sessions/week (lasted 60 min each) for 8 weeks. Both groups had a similar plan until the fourth week. Then, intensity increased up to 70% of 1RM on a weekly basis for the LPRT group, and varied on a daily basis for the UPRT group. Upper- and lower-extremities strength and endurance, balance, speed, explosive-power, lean body mass, general mental health (GSQ) and physical self-concept (PSCQ) were measured. Experimental groups produced significant improvements in physical outcomes, in comparison with the control group. There were no improvements in GSQ and PSCQ. There were no statistically significant differences between the two programs. Both linear and undulating programs improved physical fitness of previously sedentary adolescent males to a similar extent. For practical purposes, as long as loads are individually adjusted, the type of program may not be relevant in beginner practitioners. Furthermore, both models were ineffective in producing changes in the psychosocial variables.

Abstract Steatosis is a common disease worldwide. High intensity interval training (HIIT) may ameliorate steatosis, possibly through interactions between skeletal muscle and liver; however, mechanistic pathways are poorly understood. We aimed to determine potential mechanisms involved in skeletal muscle-liver crosstalk by measuring the gene expression of skeletal muscle interlukin-18 (IL-18) and fibronectin type III domain-containing protein 5 (FNDC5) and hepatic matrix metalloproteinase 2 (MMP-2) and 9 (MMP-9). Thirty-two adult male Wistar rats were randomly divided into four group including normal control (C), high intensity interval training (HIIT), hepatic steatosis+ HIIT (HS+HIIT) and sedentary hepatic steatosis (SHS). HIIT was performed 5 days per week for 5 weeks. Tetracycline (140 mg/kg) was administered by gavage for 7 days to induce NAFLD. We found that HIIT and HS+HIIT increased skeletal muscle expression of FNDC5 relative to SHS group but the increase was attenuated in HS+HIIT. SHS increased muscle IL-18 expression relative to HIIT, HS+HIIT, and C. Expression of hepatic MMP-2 and MMP-9 increased significantly in SHS in comparison with C. There was a significant increase in MMP-9 in HIIT compared with C. Moreover, hepatic MMP-9 expression decreased in both HIIT and SHS+HIIT relative to SHS. MMP-2 decreased significantly in HIIT compared with SHS. Furthermore, muscle IL-18 gene expression was significantly associated with gene expression of hepatic MMP-2 and MMP-9. We conclude that HIIT-induced alteration of skeletal muscle-derived myokines may alter the gene expression of hepatic matrix metalloproteinases, collagenases involved in pathogenesis of liver diseases. Furthermore, steatosis may possibly influence myokine profiles in skeletal muscle. Accordingly, skeletal muscle-liver crosstalk is possibly targeted by HIIT and steatosis in terms of therapeutic approach.

Abstract One of the harmful factors that affect athletic performance is exercise-induced fatigue, which results from excessive stress and leads to reduced physical and mental function. Physical fatigue resulting from physical activities, especially sports activities, affect the human immune system. Because the immune system responds to physiological and psychological stress, and like other physiological systems in our body, it causes temporary disorders in response to a session of exercise. The immune system is also affected by the intensity, duration, and type of exercise. As a result of exercise that leads to extreme fatigue, It also may affect immune function by causing stress responses, including inflammation, and cause immune system defects. Leukocyte blood flow and functional capacity may decrease over a long time with repeated strenuous exercise, possibly due to increased levels of stress hormones during exercise. Decreased blood glutamine levels have also been suggested as a possible cause of deficiency in one or more of the immune systems associated with strenuous exercise, although the evidence is less convincing. Also, during exercise, the production of reactive oxygen species increases and some functions of immune cells can be disrupted by excess free radicals. During exercise, exposure to airborne pathogens is higher due to the speed and depth of respiration. Therefore, the increased prevalence of infection in athletes is probably due to several factors: a variety of stressors (physical, psychological, or environmental, nutritional) can suppress immune function, and these effect, along with increased exposure to pathogens.

Abstract It has been proven that strenuous endurance training increases oxidative stress in body. This study investigated the effects of curcumin supplementation and light resistance training during 8 weeks of endurance training on muscle and serum antioxidant capacity and lipid peroxidation of male wistar rats. 44 male Wistar rats (weight: 254.31±17.72 g and age: 8 weeks) were randomly divided to 6 groups; Control (n=6, sham), Curcumin (n=6), Endurance (n=8), Endurance-curcumin (n=8), Endurance-Resistance (n=8), and Endurance-curcumin-resistance (n=8). Endurance training performed on rodent treadmill for 8 weeks and 5 sessions a week. The speed and duration of running were 10 m/min and 30 min at first week. The intensity and duration reached to the 35 m/min and 70 min up to the last week. Resistance training (8 weeks, 2 sessions / week) performed on vertical ladder (with 30-70% BW). The animals received curcumin supplement by sub peritoneal injection (8 weeks, 3 sessions / week, 30 mg/kg.Bw). Superoxide dismutase (SOD) enzyme activity was measured by Elisa kit and Malondialdehyde (MDA) was measured by the thiobarbituric acid reactive substances (TBARS).  The results of this study showed that strenuous endurance training (p<0.05) reduces the serum levels of SOD significantly, and caused a significant increase in the lipid peroxidation (MDA in muscle and serum). Curcumin supplementation and light resistance training could increase antioxidant enzymes activity (SOD) and decrease the MDA levels. The prolonged strenuous endurance training can induce oxidative stress and curcumin supplementation along with light resistance training could restore antioxidant enzymes activity and decrease the MDA levels.

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
New approaches to endocrinology have confirmed that every cell secretes hormones. These secreted substances are called cytokines. However, they are also named based on their origin. For example, the secretions of adipose and muscle tissue cells are called adipokines and myokines, respectively (Chait & den Hartigh, 2020).
The endocrine function of adipose tissue has been determined in some studies. It secretes substances called adipokines. Released adipokines (such as leptin, adiponectin, visfatin, resistin, omentin) act as autocrine/paracrine and endocrine (Landecho et al., 2019).
 Adipokines play an essential role in regulating glucose and lipid metabolism, energy homeostasis, nutritional behavior, insulin sensitivity, inflammation, the immune system, adipose tissue production, vascular function, coagulation, and other bodily functions (Chait & den Hartigh, 2020). Leptin, for example, regulates body fat mass and obesity (when it increases in the bloodstream) through appetite and satiety receptors (in the hypothalamus). Unlike leptin, adiponectin reduces body fat mass and regulates glucose and lipid homeostasis. The resistin can be thought of as a link between obesity, diabetes, and insulin resistance. The visfatin plays an essential role in inflammatory and infectious diseases through pro-inflammatory and anti-apoptotic ability. Omentin significantly reduces the acute phase protein in endothelial cells and can be considered an anti-inflammatory adipokine (Landecho et al., 2019). In general, adipokines act as a mediator in regulating the function of tissues and other organs such as the liver, skeletal muscle, pancreas, and cardiovascular system. Adipose tissue dysfunction plays a significant role in insulin resistance, type 2 diabetes, cardiovascular disease, and metabolic disease (Balistreri, Caruso, & Candore, 2010).
Exercise promotes adaptation to skeletal muscle, adipose tissue and consequently prevents metabolic disorders. Physical activity causes these beneficial effects by altering myokines (skeletal muscle secretions) and adipokines. Adipokines and myokines play a role in facilitating tissue-to-tissue communication (tissue crosstalk) and work together to improve health. Studies show that skeletal muscle releasing myokines during a contraction may influence adipokines (Leal, Lopes, & Batista, 2018). Moreover, Shirvani et al. showed a significant positive correlation between plasma levels of irisin with the nesfatin-1 and a significant negative correlation with resistin. Therefore, physical activity could create metabolic crosstalk between skeletal muscle and adipose tissue (Shirvani & Rahmati-Ahmadabad, 2019). Doing crosstalk research by researchers is crucial to better understand the health-related molecular mechanisms (created by exercise).

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.

Abstract This study aimed to investigate the interactive effect of aloe vera intake and eight weeks’ aerobic exercise on serum BDNF, glucose, and insulin levels in women with type 2 diabetes. In this experimental study, 32 women with type 2 diabetes were selected and randomly divided into four groups of control, supplement, exercise, exercise + supplement. The exercise program was performed 3 sessions per week for 8 weeks (40 min of exercise with 50-60% of heart rate reserve in the first four weeks and 60 min of exercise with 60-80% of heart rate reserve in the second four weeks). The supplement taking groups received 400 mg/kg of oral aloe Vera 3 days per week for 8 weeks. The data were analyzed using analysis of covariance (ANCOVA). A significant increase was observed in BDNF levels, insulin sensitivity of patients in the supplement, exercise, and exercise + supplement groups (p=0.001). The glucose and insulin levels, insulin resistance, BMI, and body fat percentage significantly decreased in the supplement, exercise, and exercise + supplement groups (p=0.001). It seems aloe Vera intake and aerobic exercise to have protective effects against development of type 2 diabetes complications in women.

Abstract The current study aimed to compare the effect of hypertrophy-, strength-, and power-type resistance exercise in resistance-trained women with considering cortisol and androgen cross talk. After one-repetition maximum (1-RM) estimation, ten resistance-trained women (age: 26.30 ± 4.95 years; body mass index: 22.07 ± 2.02 kg/m2; body fat: 24.64 ± 4.98%) conducted hypertrophy- (70% of 1-RM), strength- (90% of 1-RM), and power-type (45% of 1-RM) resistance exercise for three consecutive weeks. The movements included lever leg extension, reverse-grip lat pull-down, horizontal leg press, standing biceps cable curl, lying leg curl, machines bench press, standing cable triceps extension, and seated calf raises. Fasting blood was taken before and immediately after each trial. Statistical analyses were performed at a significance level of P

Abstract Dear Editor-in-Chief
Physical exercises decrement a network of diseases risk, and exercise may be suggested as medicine for lifestyle-related risk factors like insulin resistance, obesity, type 2 diabetes mellitus, dementia, cardiovascular diseases, and cancer. Recently, it has increasingly been approved that bone cooperates with several tissues and impacts several metabolic pathways in both animal and human models. The manner in which bone and muscle cross communicate and how they influence glucose homeostasis depends on osteocalcin (OCN)—an osteoblast-specific protein. OCN is a principally bone-derived hormone that exists in the circulation in carboxylated, undercarboxylated, and uncarboxylated forms. Because it was demonstrated that the un- or undercarboxylated forms (ucOCN) enhanced insulin sensitivity and secretion through direct impacts on the pancreatic beta-cell, it has been the center of most study (Kirk, Feehan, Lombardi, & Duque, 2020; Mohammad Rahimi, Bijeh, & Rashidlamir, 2020; Mohammad Rahimi, Niyazi, & Alaee, 2020).
Several clinical research has displayed that ucOCN rises following exercise training, and this has been connected to some metabolic effects with the overall effect of enhancing insulin secretion and sensitivity, and in glucose uptake (Kirk et al., 2020; Mohammad Rahimi, Niyazi, et al., 2020). Direct binding has never been seen; nevertheless, it has been suggested the G protein-coupled receptor family C group 6 member A (GPRC6A) as the putative receptor for ucOCN in both models and computational modelling. UcOCN, in muscle, results in an insulin-dependent enhance in glucose uptake after muscle contraction in animal models, with an alongside rising in GPRC6A. Moreover, from a more practical view, ucOCN has been involved in muscle hypertrophy and strength. In this regard, OCN-deficient mice have been shown to have lower muscle mass; inversely, improved muscle mass was found in older mice with ucOCN administrations. Recent data has figured out a novel mechanism of bone-muscle crosstalk in relation to OCN and IL6 signaling (Kirk et al., 2020).
After observing meaningful increments in both muscle-derived IL-6 and ucOCN following endurance training, it was observed that these alterations are dependent on one another. Mice with IL-6 deletions did not display the typical rise in OCN after exercise, showing that chemokine was needed for this crosstalk (Kirk et al., 2020). This influence was adjusted via the application of injected IL6, presenting strong evidence for the underlying mechanisms. As addressed above, it was demonstrated that the bone impacts of IL-6 happen through osteoblast signaling, with a resultant increment in receptor activator of nuclear factor kappa-Β ligand (RANKL) expression and osteoclastogenesis, and it seems that muscle performance advantages of IL-6 are mediated through the skeleton. While IL-6-deficient mice have been frequently demonstrated to have endangered muscle response to exercise training, mice lacking the IL-6R in myofibers did not suffer from the deficit. Alternatively, mice lacking IL-6R in osteoblasts mimicked the impact of total IL-6 deficiency, revealing that OCN was a mediator of the muscle response to the chemokine. Eventually, this mechanism was demonstrated to underpin the influences of OCN on muscle by enhancing glucose uptake and metabolism (Kirk et al., 2020).
Cross-sectional human investigations have suggested that resistance training leads to an increment in ucOCN, alongside a reduction in HbA1c, insulin resistance, and circulating glucose level as well as quadriceps strength (Levinger et al., 2014; Mohammad Rahimi, Niyazi, et al., 2020). This exercise-induced elevation in OCN has also been revealed to rely on IL6 secretion from muscle. The utilize of the IL6 antibody-drug tocilizumab resulted in an almost complete deletion of the exercise-mediated raise in OCN following an endurance training program, demonstrating that the associations found in rodent research also translate to human (Kirk et al., 2020). Notwithstanding these relationships, no interventional trials have presented causative evidence in vivo for the impacts of ucOCN on muscle metabolism or function.
It is acknowledged that when OCN is released to the circulation it becomes a mediator that stimulates pancreatic beta-cell proliferation and insulin secretion; on the other hand, it also increments the expression of peroxisome proliferator-activated receptor 𝛾 (PPAR-𝛾) and adiponectin in fat cells. The signaling cascade responsible for the influence on ucOCN is explained by crosstalk among cAMP–protein kinase A and extracellular signal-regulated kinase pathways through activation of Ras-proximate-1 (Rap1). The signaling of ucOCN in adipocytes in vivo leads to a reduction in the size of the adipocyte, which probably contributes to insulin sensitivity enhancement and glucose tolerance improvement via the up-regulation of the expression of adiponectin (Mohammad Rahimi, Niyazi, et al., 2020). Besides, ucOCN might has a direct role in enhancing skeletal muscle translocation of glucose transporters (GLUT-4) and has the capability to consume more glucose. Nevertheless, in order to examine these mechanisms, additional research is required. The metabolic impact of insulin may be bone-mediated via the release and decarboxylation of OCN. Taken together, these actions demonstrate a positive feedback mechanism between pancreatic beta-cells/adipose tissue/bone and the insulin increase of ucOCN production, which, in turn, increases insulin production and sensitivity (Ferron, Hinoi, Karsenty, & Ducy, 2008).

Abstract Dear Editor-in-Chief
Coronaviruses are a very large family of viruses that are phenotypically and genetically diverse and are common in humans and animals. The Prevalence of Coronavirus disease 2019 (COVID-19) began in Wuhan, China. As of 17 March 2020, extensive human-to-human transmission mainly occurs via the respiratory particles of the infected person.  Among COVID-19 cases, it seems that new pandemic complications are already well-defined in obese and overweight people with body mass indexes (BMI) over 25 kg/m2 or even higher that contribute to increased risk of SARS-CoV-2 infection. The higher BMI in COVID-19 patients, the higher risk of medical complications, hospitalization in the intensive care unit (ICU), and invasive mechanical ventilation (IMV) (Földi et al., 2020). However, BMI does not show the distribution of body fat, and therefore research results cannot show the effect of excess fat in different parts of the body on the severity of COVID-19. In confirmation of this finding, it can be said that although the ratio of total body fat in women is higher than men on average, the incidence of COVID-19 is higher in men (Simonnet et al., 2020).
The possible critical mechanism by which adipose tissue accumulation increases the risk of COVID-19 in patients is unknown. However, fatty tissue may serve as a reservoir for viral production that might contribute to the increased risk from COVID-19 for patients with obesity. It is suggested that fatty tissue is targeted by SARS-CoV-2. The mechanism by which SARS-CoV-2 enters cells is not fully elucidated. But apart from a direct fusion of the virus with the plasma membrane, it appears that various types of endocytosis might be involved in this process. These lipid membrane trafficking events include clathrin-mediated endocytosis, caveolin- mediated involved in muscle hypertrophy and strength. In this regard, OCN-deficient mice have been shown to have lower muscle mass; inversely, improved muscle mass was found in older mice with ucOCN administrations. Recent data has figured out a novel mechanism of bone-muscle crosstalk in relation to OCN and IL6 signaling (Kirk et al., 2020).
Endocytosis, macropinocytosis, and phagocytosis. Caveolin-mediated endocytosis is especially interesting to study as caveolae are abundant in fat cells, caveolins participate in fatty tissue function because caveolin was shown to interact with various viral proteins. In addition, the increased number of fat cells would increase the pool of infection susceptible cells. Fatty tissue contains not only fat cells but cells of stromal vascular fraction among which adipocyte precursors and macrophages. These cells also express ACE2 and display a potential target of SARS-Cov-2 infection and thus may contribute to increased inflammatory status (Dugail, Amri, & Vitale, 2020). Another possibility is that fatty tissue droplets could provide a platform for virus replication and production. Concerning the hypothesis that fatty tissue is an infection place for the SARS-CoV-2 virus, it has not yet been established if viral loads are proportional to fatty tissue mass in patients. The ACE2 activity leading to increased levels of angiotensin II and so increased inflammation and lung damage. It seems that fat cells play a substantial role in viral infection and the viral life cycle. Adipose tissue is directly involved in contact with the viral membrane of the host cell. For example, fats are critical to the formation and function of the viral replication complex and can provide some of the energy required for viral replication. In addition, specific fats are needed for the formation of double-membrane vesicles for viral genome amplification and the production of viral particles. Viral internalization can occur with endocytosis and viral release from cells. It is possible that fat availability and fats metabolism modifications occurring in an obese patient also contribute to improving several stages of the virus's life cycle and severity of the disease (Dugail et al., 2020).
In this regard, any approach should consider reducing the costs of intensive care units to reduce the mortality of patients. Especially with concerning increase their number and people at higher risk in obese people. Moderate-intensity exercise can directly boost the immune system, antioxidant defenses, and anti-inflammatory responses Adipose tissue molecular adaptation always was considered as one of the mechanisms for the anti-inflammatory effects of physical exercise. Aerobic exercise is a physical activity that is moderate-intensity and does not put much pressure on the body. Regular exercise has been shown to improve infection, antibacterial and antiviral immunity, reduce inflammation, and delay immune aging (Campbell & Turner, 2018). Following the moderate-intensity physical activity, an increase in the number of neutrophils and natural killer (NK) cells is detected, and salivary IgA concentrations increase (Brolinson & Elliott, 2007). During physical exercise, rapid and general mobilization of NK cells into the bloodstream is induced by adrenergic B signaling and catecholamines. It is suggested that mobilized NK cells are affected by muscle-derived myokines, exercise-related hyperthermia, and coronary arteries, which are affected by regulation, redistribution, and activation of mobilized NK cells (Brolinson & Elliott, 2007). Moreover, adipocytes play a critical role in NK cell activations. Adipose tissue may respond to the activation of NK cells during exercise in a cross-talk with the immune system.
Moderate exercise was exercise is one of the mechanisms in NK cell activation following physical exercise.  The results show a 20 to 30 percent reduction in upper respiratory tract infections in people who do moderate-intensity of physical activity in their daily lives (Brolinson & Elliott, 2007). Therefore, it can be said that moderate-intensity training can be an effective way to boosting the immune system. Possible cross-talk between fat and immune tissues was approved in some other studies. It is suggested that some exercise factors such as IL-6 and Hsp70 can be effective in the possible cross-talk between the immune system and fat tissue. Molecular and structural changes in adipose tissue following physical exercise can be effective in improving immune responses.
Fatty tissue is probably targeted by the SARS-CoV-2 virus, which causes adipose tissue dysfunction. Accumulation of fat tissue also serves as a platform for replication and production of virus. Based on the evidence, it seems that exercise activities, especially combined exercise training, reduce fat mass in obese or overweight people, reduce the risk of COVID-19, as well as the risk of severity and side effects in patients. Possible cross-talks between the immune system and adipose tissue could be one of the possible mechanisms in boosting immune responses against the virus.
 

Abstract PH stress can be caused by menopause, poor nutrition, high protein intake, old age, prolonged strenuous and anaerobic exercise, anemia, diabetes, AIDS, and respiratory diseases. High calcium enters the bloodstream from the bones during the proton buffering due to metabolic acidosis, which the renal system excretes a significant amount of this calcium to eliminate the acidosis condition and regulate body pH. At the bone surface, this increase in hydrogen ions due to metabolic acidosis can destroy osteoblastic and strengthen osteoclast activity, which negative bone turnover and increases the amount of excreted calcium, thus accelerating the progress of osteoporosis. Due to the widespread prevalence of osteoporosis in postmenopausal women and the provision of various therapies such as medication, estrogen therapy, and proper diet, in recent studies, special attention has been paid to the role of endurance and resistance exercise to decrease osteoporosis or prevent the development of this disease. Also exercise training increases irisin secretion from muscle tissue, which this myokine has beneficial effects on other tissues especially on bone. Irisin increases osteocytic survival and production of sclerostin in bone tissue, which is associated with bone remodeling. However, exercise training in some intensity through metabolic mechanisms can increase pH stress and acidosis and may contribute to the development of osteoporosis in postmenopausal women.  As a result, the hypothesis of different intensities of exercise and their induced acidosis stimuli in postmenopausal women should be considered.