Journal of Exercise & Organ Cross Talk

Abstract Dear Editor-in-Chief
The global epidemic of childhood obesity continues to challenge healthcare systems, with recent epidemiological data confirming a tenfold increase in prevalence over four decades. While the complications of pediatric obesity are well documented, the field of predictive medicine urgently requires reliable biomarkers that identify at-risk children before irreversible metabolic dysfunction develops. The Journal of Exercise & Organ Cross Talk has consistently highlighted the importance of inter-organ communication in metabolic health. Herein, we propose that the brain-muscle-adipose tissue triad represents a pivotal axis for developing predictive strategies in childhood obesity.
Recent evidence has substantially advanced our understanding of adipose tissue signaling in pediatric populations. A study of 104 children aged 7-18 years demonstrated that circulating spexin and adiponectin are significantly associated with insulin resistance in pediatric obesity. Notably, spexin exhibited a biphasic pattern characterized by an initial compensatory increase followed by a decompensated decrease, suggesting its potential as an early warning signal for metabolic deterioration. Adiponectin emerged as an independent determinant of HOMA-IR (β = −0.577, p = 0.005), reinforcing the central role of adipose-derived signals in systemic insulin sensitivity (Lian et al., 2026). These findings position adipokines as accessible biomarkers for stratifying risk in children with obesity.
Expanding beyond adipose tissue, large-scale proteomic analyses have revealed multi-organ signatures of cardiometabolic risk. In a cross-sectional study of 4,024 children and adolescents, Stinson and colleagues identified protein signatures linking obesity to dyslipidemia, insulin resistance, and hypertension. Using machine learning approaches, a three-protein panel (CDCP1, FGF21, HAOX1) combined with liver enzymes improved prediction of steatotic liver disease compared to enzymes alone (ROC-AUC = 0.83 vs. 0.77, p < 0.05). Importantly, reductions in adiposity during a one-year intervention were associated with decreased inflammatory cytokines, demonstrating the modifiable nature of these biomarkers (Stinson et al., 2026). This work underscores that circulating proteomic signatures reflect integrated signals from multiple organs, including liver, adipose tissue, and potentially skeletal muscle.
The central nervous system's role in this crosstalk cannot be overlooked. A comprehensive Mendelian randomization study investigating the fat-brain axis revealed bidirectional causal relationships between body fat measures and brain phenotypes. Body fat composition showed negative genetic correlations with intelligence and cognitive performance, while positive correlations emerged with attention-deficit/hyperactivity disorder, stroke, and depression. These genetic insights suggest that the brain is not merely a passive recipient of peripheral metabolic signals but actively participates in a bidirectional dialogue with adipose tissue. For predictive medicine, this implies that neurobehavioral assessments could complement biochemical markers in identifying children at greatest metabolic risk (Baranova et al., 2025).
The convergence of these findings carries translational implications. First, the identification of early biomarkers such as spexin and adiponectin enables risk stratification before frank insulin resistance develops. Second, proteomic signatures incorporating multiple organ-derived proteins offer enhanced predictive accuracy for specific outcomes like steatotic liver disease. Third, genetic evidence linking brain phenotypes to body fat measures suggests that predictive models should incorporate both biochemical and neurobehavioral parameters.
For JEOCT readers, these advances highlight opportunities for exercise-based interventions targeting inter-organ communication Physical activity potently modulates the secretome of skeletal muscle, adipose tissue, and potentially the brain. Understanding how exercise-induced signals influence the brain-muscle-adipose triad could inform personalized exercise prescriptions for children with obesity. Future research should prioritize longitudinal studies mapping the temporal dynamics of these biomarkers during childhood development and in response to lifestyle interventions.
In conclusion, the brain-muscle-adipose tissue triad represents a conceptual framework for predictive medicine in childhood obesity. By integrating adipose-derived signals, multi-organ proteomic signatures, and brain-body genetic links, we can move toward early identification of at-risk children and targeted preventive strategies. The Journal of Exercise & Organ Cross Talk is ideally positioned to advance this research agenda.
 

Abstract Dear Editor-in-Chief
We are writing to highlight a rapidly advancing frontier at the intersection of exercise physiology, microbiology, and metabolism: the role of the gut microbiome as a critical endocrine organ regulating skeletal muscle function and adaptability
(1) The traditional paradigm of muscle regulation has centered on factors like mechanical load, neuronal input, and systemic hormones. However, cutting-edge research now positions the gut microbiome as a central modulator of muscle physiology. The latest findings move beyond correlation to establish causative mechanisms, primarily through microbial metabolites that serve as inter-organ signaling molecules.
 (2) A key advancement involves microbiota-derived metabolites as ergogenic agents. Butyrate and other short-chain fatty acids (SCFAs) are no longer viewed solely as colonocytes fuels. Recent studies demonstrate that butyrate supplementation enhances oxidative metabolism in muscle, improves mitochondrial function, and reduces exercise-induced fatigue in mouse models (Lahiri et al., 2019). This is mediated through the activation of AMPK and PGC-1α pathways, suggesting that gut bacteria can directly influence the molecular circuitry of muscle energy sensing and biogenesis.
(3) Furthermore, the microbial metabolism of dietary tryptophan into aryl hydrocarbon receptor (AhR) ligands (e.g., indole derivatives) is a breakthrough finding. These ligands are crucial for maintaining intestinal barrier integrity, thereby reducing endotoxemia and systemic inflammation. Furthermore, specific indole derivatives have been shown to directly activate AhR signaling in muscle, potentially influencing protein synthesis and mitigating atrophy pathways, presenting a novel gut-muscle axis.
(4) Perhaps the most direct link comes from microbiome-dependent purine metabolism. A groundbreaking study revealed that gut bacteria, notably Bifidobacterium species, can metabolize dietary purines into inosine. Systemically absorbed, inosine enhances aerobic capacity and exercise performance in mice by enhancing skeletal muscle metabolic activity, directly linking a specific bacterial metabolite to a functional exercise outcome (Besora-Moreno et al., 2025).
(5) Finally, this research is now yielding robust clinical translation, a fact confirmed by the highest level of evidence. A recent systematic review and meta-analysis of randomized controlled trials conclusively demonstrated that probiotic supplementation significantly improves muscle mass, muscle strength, and lean mass in human subjects across various populations (Prokopidis et al., 2023). This comprehensive analysis synthesizes data from multiple studies, including trials like that of Tsuchiya et al. (2023), to provide a definitive summary of the field's progress. The meta-analysis leaves little doubt that modulating the gut microbiome is a novel and viable therapeutic strategy for combating age-related and other forms of muscle loss.
These findings establish the gut microbiome as a potent endocrine organ that communicates with skeletal muscle. We believe this topic is of paramount importance to the readership of exercise and organ cross talk.

Abstract Skeletal muscle functions as an endocrine organ, secreting myokines that mediate crosstalk with organs like the brain, liver, adipose tissue, and vascular system, influencing metabolism, inflammation, and disease progression. Advances in artificial intelligence (AI) are revolutionizing our ability to decode these complex interactions by predicting novel myokines, modeling signaling networks, and identifying therapeutic targets. Exercise training plays a pivotal role in modulating myokine expression, with both aerobic and resistance exercise inducing small to large increases in circulating myokines immediately to 60 minutes post-exercise, though levels typically return to baseline within hours. Different exercise modalities (resistance, aerobic, concurrent, high intensity interval training) stimulate distinct myokine profiles. These exercise-induced myokines contribute to improved metabolic regulation, muscle regeneration, and systemic health benefits, underscoring the therapeutic potential of tailored exercise interventions mediated through myokine signaling networks. This review explores how machine learning and network analysis tools bridge gaps in understanding myokine dynamics, particularly in exercise-induced contexts and pathologies such as obesity, cancer, and neurodegeneration. By integrating multi-omics data, AI-driven approaches offer unprecedented insights into myokine-mediated organ communication and their potential as biomarkers or treatments.

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 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
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).