Journal of Exercise & Organ Cross Talk

Abstract This study investigated the effects of high-intensity interval training (HIIT) and a multi-strain probiotic mixture, on the intestinal expression of FXR and PPAR-γ in a rat model of type 2 diabetes mellitus (T2DM). Forty male Wistar rats were randomly assigned to five groups (n=8): Healthy Control (HC), Diabetic Control (DC), Diabetic+HIIT (DH), Diabetic+Probiotic (DP), and Diabetic+HIIT+Probiotic (DHP). T2DM was induced via a single intraperitoneal injection of nicotinamide (95 mg/kg) followed by streptozotocin (STZ, 55 mg/kg). The HIIT protocol was performed on a rodent treadmill for 8 weeks (5 sessions/week). The probiotic mixture (Lactobacillus rhamnosus GG, Lactobacillus casei, Lactobacillus reuteri; 1×10¹⁰ CFU/mL each) was administered daily via oral gavage. Diabetes induction significantly downregulated the intestinal expression of both FXR and PPAR-γ compared to healthy controls (p<0.001). HIIT and probiotic interventions, individually, significantly increased the expression of both nuclear receptors compared to the diabetic control group (p<0.001). Notably, the combined HIIT and probiotic intervention (DHP) produced the highest expression levels of FXR and PPAR-γ, which were significantly greater than either intervention alone (p<0.01) and restored FXR expression to levels comparable to healthy controls. Both HIIT and multi-strain probiotic supplementation effectively upregulate the intestinal expression of FXR and PPAR-γ in diabetic rats, with the combination exerting a synergistic effect. These findings identify a novel mechanism by which lifestyle interventions may restore intestinal metabolic function and inter-organ communication in T2DM, highlighting the therapeutic potential of targeting the gut through combined exercise and probiotic strategies.

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
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 Dear Editor-in-Chief
Exosomes contain regulatory signals such as growth factors, miRNAs, lipids, proteins, and nucleic acids that can be transported to adjacent or distant cells to affect the target tissue under both physiological and pathological conditions (Isaac et al., 2021). Exosomes are involved in various stages of disease control including apoptosis, immune regulation, angiogenesis, cell migration and cell proliferation. Exosomes are a ubiquitous, evolutionarily conserved mechanism of cellular communication. They play important roles in healthy physiological functions. Proteins, metabolites, and nucleic acids delivered by exosomes to recipient cells effectively modulate their biological response. Such exosome-mediated responses can promote or inhibit disease. The intrinsic properties of exosomes in regulating complex intracellular pathways have increased their potential application in the therapeutic control of many diseases, including neurological conditions and cancer.
Many agents are involved in modulating exosomes and other extracellular vesicles gene expression and release. One of these agents is the mechanical stress caused by exercise training. Exercise with its mechanical and oxidative stress can disrupt cell homeostasis and create adaptations at the molecular and cellular level to improve physiological health, which is effective in prevention of different diseases. Exercise by activation of all organs of the body, especially skeletal muscle, promotes the release of exosomes, through which it can develop organ crosstalk and have beneficial effects at the cellular level. It has been show that exercise promotes the release of exosomes without modification of its vesicle size (Estebanez et al., 2021). Little current data suggests that exosomes are released into the circulation in an intensity-dependent manner in response to acute endurance exercise. Many of the currently reported myokines/exerkines are also produced from exosomes. Finally, exosomes within skeletal muscle are depleted in response to an acute bout of endurance exercise (Safdar & Tarnopolsky, 2018).

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.