Journal of Exercise & Organ Cross Talk

Abstract Type 3 diabetes (T3D), defined by the concurrence of type 2 diabetes and age-related cognitive impairment, is linked to progressive deterioration in both cognitive and physical function. Emerging evidence suggests that functional exercise training prescribed in relation to individualized lactate thresholds may enhance neurocognitive and physical adaptations by matching exercise intensity to individual metabolic capacity and systemic organ cross-talk. Randomized controlled trial will examine the effects of long-term, lactate-threshold–based functional training on cognitive and physical function in older adults with T3D, highlighting the role of exercise intensity in optimizing outcomes. Sixty-six adults aged 60–80 years with Type 3 diabetes and cognitive impairment, assessed by the Mini-Mental State Examination, will be recruited from the Chaharmahal and Bakhtiari Diabetes Association and randomly assigned to three groups. The intervention group will undertake a six-month, individualized high-intensity functional training program combining supervised and home-based sessions. Primary outcomes include changes in cognitive performance and physical function assessed using validated and standardized measures. It is hypothesized that lactate-threshold–guided functional exercise at tailored intensities will lead to significant improvements in both cognitive and physical function, emphasizing the critical role of exercise intensity in modulating neurocognitive and functional adaptations in elderly individuals with type 3 diabetes. This study aims to provide robust evidence for intensity-specific, lactate-threshold–based exercise prescriptions in this population.

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 Dear Editor-in-Chief
While the systemic benefits of exercise are undeniable, the precise language of inter-organ communication remains a "black box." Recent advances suggest we are poised to decode this language, transitioning from a model of diffuse hormonal signaling to one of targeted vesicular trafficking and epigenetic reprogramming. This letter posits that the next frontier for the Journal of Exercise & Organ Cross Talk lies in elucidating the rules of cargo loading, addressing, and delivery within exercise-induced extracellular vesicles‒a process likely fundamental to the remarkable specificity of organ crosstalk.
This topic moves beyond cataloguing exerkines to interrogate the mechanisms of their targeted delivery and organ-specific effects. The most compelling frontier is understanding how exercise governs the packaging, release, and uptake of extracellular vesicles, including exosomes, which function as discrete signaling packets between organs. This intersects powerfully with metabolomics and epigenetics, bearing profound implications for metabolic disease, cancer, and neurodegeneration.
First, the paradigm is shifting from humoral to vesicular signaling. The field is moving beyond viewing exerkines as freely circulating factors to recognizing their active encapsulation into extracellular vesicles (EVs). These vesicles protect their cargo, enable tissue tropism (e.g., liver-derived EVs homing to adipose tissue or brain), and deliver diverse cargo‒proteins, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and metabolites. This mechanism explains specificity in organ crosstalk previously attributed to stochastic distribution (Vechetti Jr et al., 2021).
Second, regarding the "exercise metabolome" and organ reprogramming, focus has turned to exercise-induced metabolites (e.g, lactate, succinate) which serve as potent signaling molecules. A cutting-edge perspective is how these metabolites act as histone modifiers (e.g., via lactylation) in remote organs, directly altering gene expression in the liver, brain, and immune system to mediate long-term adaptive crosstalk (Xiao et al., 2025).
Third, the gut-muscle-brain axis represents a critical microbiome-mediated highway. Exercise modulates gut microbiota composition, which subsequently produces metabolites (e.g., short-chain fatty acids (SCFAs), bile acids) that signal to both muscle, enhancing anabolic processes, and brain, modulating neurogenesis and brain-derived neurotrophic factor (BDNF) expression. This tripartite axis is a major, yet underexplored, vector in systemic communication (Frampton et al., 2020; Liu et al., 2025).
Looking forward, the concept of personalized exerkine signatures presents a translational goal. Given individual variability in exerkine response, can we define an individual's "exerkine signature" to predict their metabolic or neuroprotective gains from exercise? This links the mechanistic basis of crosstalk directly to precision medicine.
We therefore urge the research community to prioritize the following key questions:
1. What are the exercise-intensity- and modality-dependent "sorting signals" that dictate cargo loading into EVs from distinct tissues?
2. How do tissue-specific EV uptake mechanisms confer selectivity to the remote effects of exercise?
3. To what extent do chronic exercise patterns establish organ-specific epigenetic "memories" via persistent metabolite signaling?
By leveraging single-vesicle analyses, spatially resolved metabolomics, and cell-type-specific models, we can advance from observing crosstalk to understanding its precise syntax. Decoding this language will not only illuminate fundamental physiology but also pave the way for rationally designed, organ-specific "exercise mimetic" therapies.

Abstract The purpose of this research is to determine the effect of different methods of resistance training on diabetes in men with type 2 diabetes. This is a semi-experimental and practical study. Forty-four subjects with type 2 diabetes, randomly divided to 4 groups. The three experimental groups of 11, 11, and 12 people and a control group of 10 people, were performed the pre-test and post-test of after 12 weeks of training intervention under high intensity, moderate intensity and low intensity programs. The research variables were glucose, insulin, adiponectin, insulin resistance and glycated hemoglobin. ELISA kit was used to test adiponectin. For analyzing the data, one-way ANOVA statistical test of gain scores and LSD post hoc test was used. All tree Exercise protocols had a positive effect and caused a significant decrease in glucose (P>0.001), insulin (P>0.001), insulin resistance (P>0.001), adiponectin (P>0.001) and serum HbA1C (P>0.001), which had a significant difference with the control group (P>0.05). But there was no difference between the three training groups. Calculating the effect size on the serum factors of diabetes showed that the low intensity had the greatest effect on insulin (ES = 1.11), insulin resistance (ES = 1.39) and HbA1C (ES = 2.05), while glucose (ES = 1.09) and adiponectin (ES = 0.38) were affected more by high intensity. According to the effect sizes, it is recommended to clinician to prescribe high intensity programs to reduce glucose and low intensity programs to improve insulin, insulin resistance and serum HbA1C in type 2 diabetic male patients.

Abstract Programmed cell death is a critical element of the body’s defense system. Exercise represents a physiological stressor that triggers an adaptive response within the body. It has been suggested that various forms of programmed cell death are essential for the adaptation process associated with exercise. During physical activity, mechanisms such as apoptosis and autophagy are activated to mitigate tissue damage, restore cellular integrity, resolve inflammatory responses, and facilitate direct signals that promote adaptation. The induction of programmed cell death is mediated by specific factors, including reactive oxygen species, cytokines, and hormones. These cell death pathways are initiated by the presence of altered proteins and organelles, with the objective of conserving and recycling cellular resources. In scenarios where cells accumulate damaged molecules and repair mechanisms become overwhelmed, programmed cell death is triggered. In this review article, we have examined the types of programmed death and the effect of aerobic training on these deaths.

Abstract Dear Editor-in-Chief
We are writing to highlight the significant benefits of organ crosstalk during exercise, a phenomenon that refers to the biochemical interactions among various tissues stimulated by different factors, with exercise being a prominent trigger (Sabaratnam et al., 2022). This phenomenon is increasingly acknowledged for its crucial role in sustaining metabolic health and staving off chronic diseases (Sabaratnam et al., 2022).
Typically, mechanisms of organ crosstalk encompass myokines, exerkines and extracellular vesicles (EVs). Acting as an endocrine organ, skeletal muscle releases myokines (both cytokines and peptides) into the circulation during exercise. These myokines enhance interactions between muscles and other vital organs like the liver, adipose tissue and brain, thus modulating metabolism and promoting overall health (Sabaratnam et al., 2022; Severinsen & Pedersen, 2020). The term "exerkines" collectively refers to exercise-induced signaling molecules released from various organs, including myokines from muscles, hepatokines from the liver and adipokines from fat tissue. These molecules are pivotal in mediating the beneficial effects of exercise on systemic health (Jaworska et al., 2024). Additionally, exercise prompts the release of extracellular vesicles that carry bioactive molecules, boosting organ communication. These vesicles transport proteins, lipids and nucleic acids, which play significant roles in intercellular communication and influence metabolic functions across different tissues (Severinsen & Pedersen, 2020; Verboven & Vechetti, 2023).
Current research highlights several key benefits of organ crosstalk during exercise, such as metabolic regulation, neuroprotective effects and adaptation to exercise. The interactions between myokines and other organ-derived factors are essential for regulating glucose and lipid metabolism as well as reducing inflammation, thus lowering the risk of metabolic disorders like type 2 diabetes and obesity (Sabaratnam et al., 2022; Severinsen & Pedersen, 2020). Some myokines are known to cross the blood-brain barrier, fostering neurogenesis and enhancing cognitive functions. For instance, myokines like irisin can affect levels of brain-derived neurotrophic factor (BDNF), which is vital for maintaining brain health (Severinsen & Pedersen, 2020; Verboven & Vechetti, 2023). Moreover, regular exercise modifies the concentration of circulating exerkines associated with various health conditions, a necessary adaptation for enhancing cardiovascular health and promoting muscle regeneration (Jaworska et al., 2024).
In summary, understanding the mechanisms behind organ crosstalk during exercise is fundamental for developing targeted interventions aimed at preventing chronic diseases. The dynamic interaction between skeletal muscle and other organs highlights the critical role of physical activity in fostering holistic health through complex biochemical signaling pathways. Continued research in this area may lead to novel therapeutic strategies that leverage these interactions for improved health outcomes.

Abstract The aim of this study was the effect of endurance exercise and probiotic supplement enriched with amino acid leucine and vitamin D on the gut-muscle axis in aged male rats. For this purpose, 25 male Wistar rats (5 rats in each group) in two age groups of 8 to 12 weeks (young) and 18 to 24 months (elderly) were randomly divided into 5 equal groups of old control (OC), young control (YC), endurance exercise (OE), supplement group (OS) and endurance exercise plus supplement (OES) were divided. The results showed that 8 weeks of endurance training (three times a week) and supplemental oral gavage (5 times a week) caused a significant change in postbiotics (decrease of indoxyl sulfate (IXS) and increase of Short-chain fatty acids (SCFAs)). The role of OS in reducing IXS was more prominent than OE and OES variables; of course, the synergistic effect of OES (P=0.000), caused a greater improvement in the amount of SCFA. Also, Administering the supplement alone and at rest (without exercise) could not cause a significant increase in VO_2max (P=0.449). But, the effect of exercise on increasing VO_2max index was more effective than OS and even OES. Eventually, the independent variables made a significant difference on the Villus height (VH) (except for the OS group) and number of goblet cells (GC) compared to the OC group (P<0.05).

Abstract Dear Editor-in-Chief
Meteorin-like protein (METRNL) has drawn a lot of interest in the field of exercise because of its potential contribution to muscle health (Das et al., 2020). When exercising, skeletal muscle, designed for movement, goes through a variety of adaptations (Hamilton & Booth, 2000). This letter sheds light on the complex interplay between METRNL and muscle health by providing an outline of METRNL interaction with muscle tissue and the impact of exercise on this relationship.
A newly discovered adipokine called METRNL has a variety of effects on the physiology of muscles. It seems to be involved in myogenesis, muscle growth, and muscular function. According to animal research, METRNL may promote myoblast differentiation and proliferation, promoting muscle growth and repair (Lee et al., 2022). The anti-inflammatory qualities of METRNL may also lessen muscle inflammation and injury brought on by exercise.
A strong trigger for METRNL secretion is exercise. Exercise sessions, whether short-term or long-term, have been demonstrated to boost METRNL expression in circulation and muscle tissue. Numerous signaling pathways, such as those involved in metabolic adaption, muscular contraction, and inflammation, are thought to mediate this response (Alizadeh, 2021). Research is currently being done to determine the precise processes by which exercise causes the production of METRNL.
Exercise-induced METRNL release highlights its possible importance in maintaining muscular health. Exercise-related advantages like increased muscle regeneration, less inflammation, and improved energy metabolism may be aided by METRNL (Alizadeh, 2022). Exercise-induced muscular contractions and metabolic demands may trigger METRNL release, which in turn may promote additional muscle adaptation. This suggests that there may be a bidirectional relationship between exercise and METRNL.
There could be numerous clinical implications regarding fully grasping the effect of exercise on METRNL's effect on muscle health. To improve muscle regeneration, reduce muscle-related diseases, and reverse age-related muscle degeneration, strategies focused at modifying METRNL levels through exercise treatments could be investigated. To guide focused therapeutic methods, future research should concentrate on illuminating the precise connections between exercise, METRNL, and muscle health.
The connection between METRNL and muscle health is a fascinating topic of research, especially in response to exercise. Its potential as a modulator of exercise-induced muscle adaptations becomes more intriguing as our knowledge of METRNL's impact on muscle physiology expands. Exploring how exercise affects METRNL secretion and how METRNL affects muscle growth, regeneration, and function could offer fresh perspectives on how to construct exercise regimens that are most effective for different people and circumstances.

Abstract Intense exercise training is associated with Lung inflammation. Fasl protein on the cell surface is responsible for the initiation of the inflammatory response that finally leads to cell death at the site of inflammation, and can be interpreted as Fasl induced apoptosis. Therefore, the aim of this study was to investigate the effects of increasing and intense interval exercise training on Fasl levels of mature rat lungs. 30 rats within three weeks of birth with mean weight 68±9 g were randomly divided into three basic, control, and exercise groups. Increasing interval training for 6 sessions per week, each session 30 minutes at a speed of 15 to 70 meters per min was employed and Fasl levels were measured using the kitby Elisa method. The data were analyzed with two-way ANOVA and LSD test was done at p≤0.05 significant level. The results showed that Fasl protein levels in the interval training group compared to baseline group increased by 23.75 % and was significant (p≤0/05). However, although the amount of this protein in the interval training group compared to the control group was high, this value was not significant. In addition, Fasl protein levels in the control group compared to the baseline group increased by13.58 % and was significant (p≤0.05). The findings indicated that intense and prolonged exercise training causes damage of the respiratory tract, and in turn, leads to the increased levels of Fasl.

Abstract Brain-derived neurotrophic factor (BDNF) plays a vital role in the brain. On the other hand, researchers showed that exercise may cause more release of BDNF and thus have a positive effect on the brain. Studies have reported controversial findings in multiple sclerosis, and there are no broad conclusions on this topic. This study aims to systematically investigate the effect of exercise training on BDNF concentration in multiple sclerosis animal models. Searches were conducted in the electronic databases of PubMed, Scopus, Medline, Cochrane Library and Google Scholar search engine to obtain the related articles about the role of exercise training on BDNF levels just in animal models of multiple sclerosis. All of the database searches were limited to the period from inception to February 2021. Two reviewers extracted study details and data. The methodological quality of the studies that used animal models was assessed using the PEDro Scale. Fourteen articles were included in this review with scores from 7/10 to 8/10 according to the PEDro scale. Five articles reported elevation, one article reported a reduction; and eight articles reported no changes in BDNF level following or preconditioning exercise training in model of multiple sclerosis. The findings of this study showed that aerobic exercise increases changes in central BDNF concentration in multiple sclerosis in animal model.

Abstract Dear Editor-in-Chief
Originally, macrophages are known for the critical role of phagocytosis in innate immunity (Yan & Hansson, 2007). They have also been shown to play crucial roles in the homeostasis of white adipose tissue (WAT) and skeletal muscle (SKM) tissue (Baht et al., 2020; Rao et al., 2014). Macrophage plasticity is an important hallmark enabling them to respond to altered settings (Shapouri‐Moghaddam et al., 2018). In response to those changing environments, macrophages demonstrate different polarizations of the classic/proinflammatory M1 phenotype and an alternative/anti-inflammatory M2 phenotype (Shapouri‐Moghaddam et al., 2018). Obesity, as an adipose tissue’s milieu-altering stimulant, shifts the macrophage phenotype to the pro-inflammatory M1 phenotype, with the resultant consequences of inflamed adipose tissue and insulin resistance, showing that adipose tissue macrophages (ATMs) are central players in adipose tissue homeostasis (Goh, Goh, & Abbasi, 2016). On the other hand, exercise has been well documented to reduce obesity-induced adipose tissue (AT) inflammation. Exercise-induced mechanisms through which AT inflammation is attenuated, include a combination of: i) a decrease in inflammatory adipokines production, ii) a reduction of toll-like receptors (TLR2 and TLR4) expression in immune cells, and iii) an increase in the production of muscle-secreted factors called myokines (Abbasi et al., 2014; Pedersen & Febbraio, 2008). The latter mechanism, muscle-fat crosstalk, is mediated by myokines to deliver exercise-induced health benefits (Pedersen & Febbraio, 2008). Basically, exercise, in a tissue-specific manner, upregulates lipid oxidation-related genes and proteins which in turn decrease oxidative stress and pro-inflammatory cytokine production in the inflamed AT (Ruschke et al., 2010). In parallel, exercise-induced muscle contraction triggers the production of genes and proteins in SKM that are responsible for the secretion of molecules called myokines to mediate the beneficial effects of exercise (Pedersen & Febbraio, 2008). Meterorin-like protein (Metrnl) is a newly-identified adipomyokine with immune-regulatory hallmarks (Rao et al., 2014). Metrnl was originally identified as a myokine with immune regulatory functions in AT (Rao et al., 2014). Exercise-induced increases in blood Metrnl levels act as a signaling molecule to recruit eosinophils into AT, driving the M2-phenotype of ATMs, and finally resulting in the browning of white adipose tissue (BWT) (Rao et al., 2014). Metrnl has been shown to upregulate the production of type 2 immunity anti-inflammatory cytokines, IL-4 and IL-13 which in turn activate ATM’s M2 phenotype in a STAT6-dependent pathway in macrophages in animal models (Rao et al., 2014). Exercise-induced Metrnl is correlated with its increased blood levels which is associated with elevated whole-body energy expenditure via stimulating the thermogenesis process in AT (Rao et al., 2014). Based on this evidence, Metrnl-mediated ATMs phenotype shift is related to improved metabolic health in obesity, suggesting Metrnl as a possible therapeutic agent in metabolic challenges.
In the study of Rao et al., given the ability of Metrnl in recruiting type 2 immunity, and that type II immunity has characteristics in repairing processes like those in damaged SKM, it was hypothesized that Metrnl might also play roles in regenerating damaged SKM. In this regard, in a recently published study by Baht et al., Metrnl was described as a necessary regulator for SKM regeneration process (Baht et al., 2020). Baht et al’s study’s finding was that Metrnl is induced upon SKM-damaging exercise. In that study, SKM-derived Metrnl was delineated as dispensable for the regeneration of damaged SKM, whereas macrophage-derived Metrnl was shown as a critical coordinator for SKM regeneration (Baht et al., 2020). Macrophage-derived Metrnl, in an auto-/paracrine manner, activates STAT3 which in turn promotes an anti-inflammatory function and induction of insulin-like growth factor 1 (IGF-1), which activates muscle progenitors to help myogenesis (Baht et al., 2020). Similar to its actions in AT, Metrnl exerts its physiological functions through macrophage accretion and phenotypical shift in SKM. Of note, in the study of Rao et al. Metrnl was established as a molecule that is selectively expressed in different tissues based on physiologic stimuli with being expressed in AT upon cold exposure and in SKM upon exercise (Rao et al., 2014). With regard to this, in the study of Baht et al. it was shown that there was no Metrnl expression in myogenic cells after injury and that mice with Metrnl silenced in myofibers exhibited a normal phenotype in terms of muscle regeneration while macrophages were the main Metrnl-secreting cells in SKM injury (Baht et al., 2020). There are a handful of studies reporting Metrnl responsiveness to SKM-damaging exercise protocols like unaccustomed resistance exercise (Baht et al., 2020; Rao et al., 2014), downhill running exercise (Alizadeh & Alizadeh, 2021; Rao et al., 2014) in both animal and human subjects. These observations prompt questions regarding the molecular mechanisms that control the selective expression of Metrnl molecule by different cell types according to tissue homeostasis: myofibers after exercise versus macrophages after damage.
In summary, this letter addressed two outstanding studies of Rao et al., and Baht et al., describing Metrnl mechanisms of action in both AT and SKM physiology. Metrnl actions are mediated via macrophage phenotype switch (MPS) in AT and SKM. In AT, Metrnl -mediated MPS leads to BWT, while, in SKM, Metrnl-mediated MPS results in muscle regeneration, representing Metrnl as a new therapeutic target for inflammatory diseases. What remains unknown, in addition, is that these findings (BWT and SKM regeneration) observed in transgenic animal models still need to be verified in humans. In relation to SKM regeneration, the good news is that Metrnl is induced in damaged human SKM, suggesting that Metrnl is responsive to exercise-induced SKM damage. However, the critical question is which stimuli trigger Metrnl expression in macrophages and whether also other exercise-induced challenges like hypoxia, oxidative stress and so on could induce Metrnl. These new findings raise the question of whether Metrnl could be employed to reprogram pro-inflammatory into anti-inflammatory macrophages and, as such, serves as a new therapeutic target for inflammatory diseases not directly related to muscle repair. What would be useful to speculate, is the type, duration and intensity of exercise that can modulate the release and uptake of Metrnl, possibly also affecting the macrophage polarization state further downstream.

Abstract Sarcopenia, an age-associated phenomenon, is characterized by the reduced skeletal muscle mass and function. Research studies indicate that a wide range of factors can play a key role in the onset of muscle atrophy and its progression, especially during old age. However, the pathophysiology of this event is not well understood and there are many unresolved issues yet. Performing different training methods (aerobic, resistance, and concurrent) is among the strategies that may be beneficial for the prevention and improvement of sarcopenia by affecting the signaling pathways of muscle cells. On the other hand, the way in which this type of training affects the signaling pathways involved in sarcopenia has not been well understood. Even the previous research has been incapable of well introducing an effective training method for the elderly at risk for sarcopenia. Generally, in this review article, we investigate and summarize the important and key mechanisms that may contribute to sarcopenia. In the following, we have examined the effect of regular physical activity on cellular signaling pathways involved in sarcopenia, as well as the usefulness of aerobic, resistance, and concurrent activities in adaptation and prevention of the pathology of sarcopenia in the elderly.