Journal of Exercise & Organ Cross Talk

Abstract Dear Editor-in-Chief
As our field continues to map the intricate networks of exercise-induced organ crosstalk, the concept of "intelligent substrate utilization" remains a compelling yet incompletely understood frontier. While much focus has been placed on the acute actions of individual myokines and exerkines, a more integrated, systems-level perspective is emerging‒one that positions chronic exercise adaptation as the remodeling of an endocrine matrix. This matrix, I propose, governs a form of metabolic intelligence characterized by the dynamic, context-dependent allocation and utilization of energetic substrates across organs. Recent breakthroughs are beginning to decode the spatiotemporal logic of this system, moving beyond simple linear pathways to reveal complex networks that enable the body to adapt fuel metabolism with remarkable precision. Three key advances, in particular, illuminate new variables and pathways that underpin this intelligent substrate utilization.
First, the "Myokine-mediated Multi-organ Metabolic Network" theory provides a comprehensive framework for understanding how myokines act not in isolation but as a coordinated signaling hub. This work meticulously maps interactions from skeletal muscle to over a dozen organs, orchestrating programs across six biological axes, including energy substrate flux. Crucially, the framework highlights how myokines function as pleiotropic modulators within an integrated system, a property that fundamentally reshapes our view of substrate allocation. It suggests that the "intelligence" of the system lies not in any single molecule but in the emergent properties of this multi-target network (Chen et al., 2025). Second, a landmark systems genetics study, leveraging multi-tissue data from the MoTrPAC consortium, reveals that endurance training fundamentally remodels the entire
inter-organ endocrine network. This work demonstrates that the strength and specificity of endocrine signals between tissues are significantly altered with training. Notably, subcutaneous white adipose tissue (scWAT) emerged as a major endocrine hub, and extracellular matrix factors, along with secretory WNT signaling molecules, were identified as central mediators of training adaptations. These discoveries offer a crucial new variable‒the network-wide remodeling of endocrine crosstalk‒demonstrating that "intelligent" substrate use is a learned property of the whole system, not a pre-programmed one. The bidirectional and training-dependent plasticity of tissue-pair signaling adds a new layer of complexity to how we model metabolic control during exercise (Ahn et al., 2025).
Finally, the identification of novel metabolic signaling molecules, termed "metabokines" and "lipokines," expands the classic myokine paradigm to include bioactive metabolites and lipids as direct mediators of inter-organ signaling. These molecules are not mere energy sources but are sophisticated signals that coordinate systemic adaptations. This reframes substrate utilization itself as a mode of communication: the very act of metabolizing a substrate can generate a signal that informs and directs systemic metabolic priorities (Gad et al., 2024). These three insights‒the multi-organ myokine network, the training-induced remodeling of the endocrine matrix, and the signaling roles of metabolites‒converge to describe a system with genuine adaptive intelligence. Chronic exercise, through this lens, is not simply a stressor but an educational process for the body's metabolic network, teaching it to anticipate demands and allocate resources with greater efficiency and precision.
I write this letter to the Journal of Exercise and Organ Crosstalk because it stands at the ideal intersection to champion such a systems-level, integrative approach. Pursuing these ideas will require not only advanced multi-omics but also sophisticated computational modeling to predict network-level adaptive strategies. This is the central challenge for our field: to decode the syntax of exercise-induced communication.

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 This article explores the impact of exercise training on brain health in older adults, focusing on the concept of muscle-brain crosstalk. As the global population ages, understanding how lifestyle interventions like exercise can support cognitive function is increasingly important. The article reviews evidence suggesting that physical activity, particularly aerobic and resistance training, plays a crucial role in maintaining and enhancing brain health. It discusses the mechanisms underlying the beneficial effects of exercise, including improved blood flow, neurogenesis, and the release of myokines proteins produced by muscle contractions that influence brain function. Additionally, the article highlights how these myokines facilitate communication between muscles and the brain, contributing to neuroplasticity, reduced inflammation, and enhanced cognitive abilities. The concept of muscle-brain crosstalk is emphasized as a key factor in understanding how exercise promotes brain health, with potential implications for designing targeted interventions to preserve cognitive function in older adults. The article concludes by suggesting that regular exercise should be a cornerstone of public health strategies aimed at improving the quality of life and cognitive health in aging populations. Further research is encouraged to deepen our understanding of the molecular pathways involved and to develop personalized exercise programs that maximize brain health benefits for older adults.

Abstract The covid-19 disease has spread all over the world since 2019 and many people have been affected by this disease. One of the main characteristics of this disease was lung tissue damage, which subsequently affected the immune system as well. In other words, since there are no registered drugs or vaccines against COVID-19, the immune system is the best defense because it supports the body's natural ability to defend against pathogens and resist infections. As long as the immune system is working normally, infections like COVID-19 cannot cause serious damage to the body. The three types of immunity are: innate immunity (fast response), adaptive immunity (slow response), and passive immunity. Strengthening the immune system can guarantee a better fight against pathogens. Exercising can help strengthen the immune system. In other words, exercise is one of the non-pharmacological factors for controlling diseases related to the immune system. Recently, it has been identified that exercise training with muscle contraction, the secretion of myokines in an endocrine form can affect all body tissues. One of the target tissues of myokines is the immune system. Therefore, this study deals with the strengthening role of the immune system due to exercise and muscle contraction in the conditions of the Covid-19 epidemic.

Abstract Omicron, a new type of SARS-CoV-2 was first reported by South Africa to the World Health Organization (WHO) on November 24, 2021. Two days after Africa was reported to the World Health Organization, the Omicron was identified as a global threat. Omicron has many genetic mutations, the potential effects of which are more dangerous than other SARS-CoV-2 genetic mutations. With the increase in vaccination in the world, the amount of physical activity to improve the functioning of the immune system decreased. Relying on vaccines alone cannot guarantee an improvement in the functioning of the immune system and the people of the world, given the lack of knowledge about the prevalence of omicron and its potential dangers, should look for ways to boost the immune system. In this study, we highlight the importance of increasing physical activity at the time of omicron outbreaks, along with the proposed protocols.

Abstract Dear Editor-in-Chief
Lifestyle-related diseases are usually caused by mistakes in daily life, such as smoking, unhealthy diet, and inactivity. Some of these diseases are including heart diseases, stroke, diabetes, obesity, metabolic syndrome, lung diseases and some types of cancer. These diseases are usually more prevalent in industrialized countries where sedentary lifestyles have spread. At the international level, these diseases are known as non-communicable and chronic diseases or degenerative diseases. Chronic diseases can lead to loss of independence, years of disability, or death, and impose a significant economic burden.
Regular physical activity helps improve your overall health, fitness and quality of life. Also, regular exercise helps reduce the risk of chronic diseases such as type 2 diabetes, heart disease, many types of cancer, depression, anxiety and dementia. Aerobic exercise can help improve your heart health and endurance. Also, these types of exercise help to lose weight. High-intensity interval training is generally safe and effective for most people. In high-intensity interval training, physical activity is performed alternately with high intensity and with low intensity, and these intensity changes have various effects on the health of the body. Strength training can improve muscle strength and endurance, make daily activities easier, reduce disease-related muscle weakness, and provide joint stability. In all these types of exercises, the skeletal muscle tissue has the most activity, and most of the positive effects of exercise are attributed to this tissue. Recently, it has been stated that muscle tissue as a secretome can secrete substances from itself and affect distant tissues. These substances secreted from muscle tissue are known as myokines.
During exercise muscles can produce and release cytokines, signaling peptides or myokines. These molecules can exert paracrine and endocrine actions. Not all of them are produced exclusively by skeletal muscle, as they can also be released by other cells such as adipose tissue (adipomyokines). Nevertheless, skeletal muscle is probably the major source of most myokines, as it constitutes more than 30% of human body mass (Piccirillo, 2019). Myokine irisin produced from muscle tissue can control many damages caused by fatty tissue and reduce the inflammatory damage of this tissue in metabolic diseases such as diabetes, fatty liver or even cardiovascular diseases. β-aminoisobutyric acid (BAIBA) is a myokine involved in browning of fat and it can reduce insulin resistance (Gonzalez-Gil & Elizondo-Montemayor, 2020). Myostatin also controls insulin resistance and prevents fat accumulation in the liver (Mikolasevic et al., 2020). Follistatin is also effective in regulating the growth of muscle tissue and reducing fat tissue (Song et al., 2019). FGF21 also promotes insulin sensitivity. Apelin and METRNL also have anti-inflammatory properties (Gholamrezayi et al., 2020). All these myokines can be effective in reducing lifestyle-related diseases with their role. Therefore, exercise should be included in your daily life.

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 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 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.