Journal of Exercise & Organ Cross Talk

Abstract Crosstalk between muscle and adipose tissue via myokines and adipokines has critical implications for the metabolic regulation of type 2 diabetes. Irisin and adipolin are key secretory proteins involved in glucose homeostasis and anti-inflammatory pathways, yet the combined impact of pharmacological and physical interventions on their metabolism remains insufficiently characterized. This experimental study investigated the effects of metformin therapy and structured exercise on serum levels of irisin and adipolin, as well as related metabolic parameters, in male diabetic rats. Type 2 diabetes was induced in male Wistar rats (fasting glucose >250 mg/dl), while the healthy control group maintained normal glucose levels (~95 mg/dl). Animals were randomly assigned to control, metformin, or exercise (combined aerobic and resistance training) groups. Over eight weeks, interventions were administered and serum irisin, adipolin, and fasting blood glucose were measured pre- and post-intervention. Data were analyzed using the Shapiro–Wilk test, ANOVA, and Tukey post hoc tests. Results showed that both metformin and exercise significantly increased adipolin levels (p<0.01). As expected, irisin levels were higher in the non-diabetic control group compared to diabetic groups (p<0.05), consistent with the known reduction of irisin in diabetes. Fasting glucose improved most notably in the exercise group. These findings indicate that metformin and exercise exert distinct yet complementary effects on key metabolic regulators—adipolin and irisin—highlighting the benefits of integrating pharmacological and lifestyle approaches in type 2 diabetes management. Future research should explore underlying molecular mechanisms and translational potential in human populations.

Abstract Irisin, a myokine cleaved from the membrane protein Fibronectin type III domain-containing protein 5 (FNDC5), has emerged as a critical exercise-induced hormone. It is implicated in the browning of white adipose tissue, enhanced metabolic rate, and potential anabolic processes. In bodybuilding, where precise manipulation of training variables—specifically repetitions (reps) and sets—is paramount, understanding how these variables influence irisin secretion could optimize both physique and health outcomes. This narrative review aims to synthesize current evidence on the effects of resistance training protocols, with a focus on reps and sets, on irisin secretion. Furthermore, it explores the potential subsequent benefits of elevated irisin levels for bodybuilders, including its putative roles in fat metabolism, muscle remodeling, and overall metabolic health. Evidence suggests that high-volume resistance training protocols, characterized by multiple sets (≥3) and moderate repetitions (8-12 reps), may be potent stimulators of irisin release. This secretion is hypothesized to be mediated by muscle contraction-induced PGC-1α expression. Elevated irisin levels are often correlated with improved lipid oxidation, which could aid in cutting phases by promoting a leaner physique. Additionally, preclinical and some human studies suggest irisin may support muscle hypertrophy through enhanced nutrient partitioning and autocrine/paracrine signaling, though this mechanism requires further elucidation. Strategic manipulation of resistance training volume and intensity may represent a viable method for modulating irisin secretion. Incorporating protocols that could elevate this myokine might provide bodybuilders with a dual advantage: enhancing metabolic efficiency to reduce adipose tissue and potentially supporting muscle growth and recovery. However, the current evidence is not yet definitive, and more research is needed to confirm these links.

Abstract Skeletal muscle functions as an endocrine organ by releasing myokines—cytokines and peptides that mediate systemic physiological adaptations. This review synthesizes evidence establishing mechanical stretching (active/passive) as a potent mechanotransductive stimulus for myokine secretion. Key pathways include integrin-mediated signaling, stretch-activated ion channels (Piezo/TRP), and mechanosensitive transcriptional regulators (YAP/TAZ), which activate MAPK, calcium-dependent kinases, and other cascades to modulate myokine gene expression. We highlight stretch-responsive myokines (IL-6, irisin, myostatin, BDNF, SPARC) and their roles in metabolism, tissue repair, and inflammation. Clinical implications for aging, metabolic disease, and rehabilitation are discussed, emphasizing how targeted stretching protocols may harness myokine-mediated benefits in mobility-limited populations. Future research directions include optimizing stretch "dosing" and elucidating tissue-specific myokine actions.

Abstract The aim of this study was to considering the correlation between the muscle fibronectin type III domain-containing protein 5 (FNDC5), blood and heart level of Irisin in exercise-trained rats with Nano selenium supplementation after intraperitoneal injection of cigarette smoke extract induced chronic obstructive pulmonary disease (COPD). To this end, 49 male Wistar rats (8 weeks old) were divided into seven groups: control, SeNPs (2.5 mg/kg b.w by oral gavage, 3 days/week, 6 weeks), AIT (49 min/day, 5 days/week for 6 weeks, interval), SeNPs+AIT, CSE (150 µL by IP injection, 1 day/week for 6 weeks), CSE+AIT, and CSE+SeNPs+AIT. The results of the present study showed that CSE injection caused inflammation and damage to lung tissue, especially alveoli, compared to the healthy group. In other words, based on the histological examination of cigarette smoke extract, it was able to cause lung tissue damage similar to COPD, and doing exercise and taking nanoselenium antioxidant supplement could control these lung tissue damage. Pearson's correlation method was used to investigate the relationship between muscle FNDC5, serum and heart Irisin, and the results of this correlation were not significant in different groups (p>0.05). It seems that exercising and taking nanoselenium supplements can increase Irisin levels in serum and heart tissue by expanding muscle contraction and increasing muscle FNDC5. However, the relationship of this factor in muscle and heart crosstalk should be investigated more closely.

Abstract Dear Editor-in-Chief
 
Based on recent studies, it is now clear that there is a muscle–brain endocrine loop that can be partly mediated by myokine signaling. There are also other metabolites as mediators which can affect circulating compounds (Rai & Demontis, 2016) and these include noncoding RNAs (Makarova et al., 2014), hormone-associated responses, as well as, muscular enzymes (Pedersen, 2019). Brain-Derived Neurotrophic Factor (BDNF) is considered to be a key role in helping to mediate the impacts of exercise on the hippocampus (Loprinzi & Frith, 2019). Studies conducted on laboratory rats showed an increase in BDNF mRNA and BDNF protein in the hippocampus of these animals when wheel running exercise was performed for 1 to 8 weeks (Adlard, Perreau, & Cotman, 2005; Farmer et al., 2004; Liu & Nusslock, 2018; Neeper, Góauctemez-Pinilla, Choi, & Cotman, 1995; Oliff, Berchtold, Isackson, & Cotman, 1998; Van Hoomissen, Chambliss, Holmes, & Dishman, 2003). In terms of cognitive functions, i.e. memory and learning, BDNF has also been demonstrated to be effective in the improvement of such functions (Vaynman, Ying, & Gomez‐Pinilla, 2004; Vaynman, Ying, & Gómez‐Pinilla, 2004).
Research on humans indicates that their brains can release BDNF while cycling (Rasmussen et al., 2009; Seifert et al., 2010), also in another study in healthy people as well as people with schizophrenia who had been training in aerobic exercise for three months, the level of BDNF increased in their hippocampus by 12% and 16%, respectively (Pajonk et al., 2010). As a growth factor for the hippocampus, BDNF plays a significant role in learning and improving cell survival (Wrann et al., 2013). Interestingly enough, research findings show that BDNF can also be expressed in skeletal muscle tissues during exercise in humans; nonetheless, it is not clear whether muscle-derived BDNF can get into the bloodstream from the muscle to create a direct interaction between muscle and brain (Matthews et al., 2009).
Some fascinating studies indicate that irisin and myokines cathepsin-B might cross the (BBB) blood-brain barrier, and consequently, BDNF levels may increase. In recent a study conducted by Moon et al. (Moon et al., 2016) a novel myokine, cathepsin B (CTSB) was identified. Other work also demonstrated that exercise can increase CTSB systemic level, therefore, BDNF expression will be promoted in the hippocampus and lead to the formation of nerve tissue as well. Running on a treadmill for four months increased CTSB plasma levels, as well as CTSB gene expression in humans, mice, and rhesus monkeys. In addition, it was indicated that CTSB could cross BBB in mice. In studies by Moon et al. (2016) on CTSB knockout mice, it was made clear that mice without CTSB refused to do voluntary exercise regarding hippocampal growth and cognitive development. It is not clear whether myokine CTSB can lead to cognitive function development in humans regarding exercise training or not (Moon et al., 2016; Suzuki, 2016).
The PGC-1α-dependent myokine irisin, which is famous for its browning impacts (Boström et al., 2012), can play a role in the intervention of the brain’s physical activity (Wrann et al., 2013). An excessive expression of irisin in the primary cortical neurons can cause a higher BDNF expression, while FNDC5 knockdown mediated by RNAi can cause a lower BDNF expression. Furthermore, irisin delivery to the mice’s liver by adenoviral vectors will raise the systemic irisin level, consequently resulting in a higher level of BDNF in the hippocampus. Whether doing exercise can increase irisin plasma concentration in humans (Albrecht et al., 2015; Wrann, 2015), and whether irisin is affected by a muscle–brain endocrine loop is a disputable issue.

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
Many studies have shown that regular physical activity has a significant effect on improving a range of disorders such as metabolic syndrome, cardiovascular disease, and cancer. Regular physical activity improves disease activity in patients by affecting hormones, the reverse cholesterol transport process, factors related to antioxidants and immune defense systems, factors that control cell apoptosis, and more (Myers, Kokkinos, & Nyelin, 2019).
Nowadays, the role of muscle-secreting cytokines (in response to physical activity) in fighting diseases has attracted the attention of scientists. Muscle-secreting cytokines (myokines) provide communication between muscle and other tissues and organs such as the brain, adipose tissue, bone, liver, intestines, pancreas, etc., and physical activity is a way to stimulate the secretion of these myokines from the muscle. Myokines are involved in critical processes of the body such as cognition, lipid, and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure, and tumor growth (Severinsen & Pedersen, 2020); therefore, they can be studied as a mechanism for the effect of physical activity on various diseases.
Irisin is a myokine. It is secreted from skeletal muscle in response to physical activity. Physical activity increases the transcriptional activator of PGC1-α and induces the expression of the FNDC5 gene, and subsequently, irisin is released into the blood. Irisin facilitates glucose uptake by skeletal muscle, improves glucose and liver fat metabolism, has a positive effect on hyperlipidemia and hyperglycemia due to obesity and metabolic syndrome, and acts as an insulin-sensitizing hormone (Severinsen & Pedersen, 2020).
The role of irisin in cancer treatment is unclear, and further studies are needed. The results of a review study show that regular physical activity increases irisin, but the use of irisin in cancer therapeutics requires further researches (Maalouf & El Khoury, 2019). More studies should be performed to determine the mode of administration of irisin for each cancer type and investigate the amount of use. Moreover, studies on the impact of physical activity on irisin in cancer patients are required.

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.

Abstract COPD is an inflammatory disorder caused by prolonged inhalation of harmful substances such as cigarette smoke that leads to an irreversible respiratory disorder. Airway obstruction usually has a progressive period characterized by chronic cough, sputum production, and dyspnea, resulting in decreased physical activity. Two hypotheses have been proposed for the pathogenesis of lung diseases, especially COPD, including the oxidant-antioxidant imbalance hypothesis and the protease-antioxidant imbalance hypothesis. Oxidants can cause irreversible damage to lung cells. Oxidants activate inflammatory gene expression primarily through NFκB signaling. Increase inflammation promotes apoptosis in the epithelial cells, endothelial cells, and airways, that resulting Emphysema. This pathological period causes progress the disease. Recently, has been shown that decreased physical activity is associated with COPD injuries, and the level of physical activity is most associated with COPD mortality. Therefore, the tendency to maintain and improve the physical activity of pulmonary patients, especially COPD was increased. In lung diseases, muscle mass usually decreases and severe atrophy occurs. Most studies suggest increased mobility and exercise to enhance cardiorespiratory endurance and decrease atrophy. However, the exact biological mechanism for the recovery of patients with COPD after a physical activity has not been explained. Exercise can produce Irisin and Semaphorin-3A by stimulating muscle and nerve cell, which have positive effects on other tissues, including the lungs. Limited studies have examined the role of these factors in lung tissue. Therefore, in this mini-review, the lung muscle cross-talk is examined by evaluating the role of Irisin and Semaphorin-3A.

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.