Journal of Exercise & Organ Cross Talk

Abstract Dear Editor-in-Chief
What if the therapeutic benefits of exercise could be captured, concentrated, and delivered as a targeted molecular dose? New research on exercise-induced extracellular vesicles (ExEVs) suggests that this concept is evolving from a metaphorical understanding to a mechanistic one. Extracellular vesicles (EVs), particularly exosomes, are increasingly recognized as important facilitators of the signals generated by exercise, known as exerkines. These vesicles carry well-known myokines like IL-6 and irisin, as well as a wide range of other components, including microRNAs (miRNAs), mitochondrial DNA (mtDNA), and metabolites. This cargo is transported to distant organs, enhancing communication between muscles and various systems, including the brain, liver, and cardiovascular system (Magliulo et al., 2022; Nederveen et al., 2021).
Both aerobic and resistance training lead to a substantial increase in the secretion of extracellular vesicles (EVs) from skeletal muscle tissue, as well as a modification of their miRNA profiles, including miR-181a-5p, miR-486-5p, and miR-342-5p. These miRNAs are correlated with enhanced insulin sensitivity, reduced systemic inflammation, and neuronal protection. Consequently, this evidence underscores the role of EVs as stable carriers of exerkines that are less susceptible to enzymatic degradation and capable of delivering them more precisely than free myokines (Li et al., 2026; Silvestri et al., 2026; Wang et al., 2026).
One of the most compelling pieces of translational evidence comes from animal studies. When extracellular vesicles (ExEVs) from trained mice are injected into models of muscle disuse, they effectively preserve muscle mass and enhance regeneration (Fliflet et al., 2026). This serves as a strong proof-of-concept for developing exercise- mimetic therapeutics that can work without the need for actual exercise. In human studies, the profiles of extracellular vesicles following exercise are similarly associated with improved metabolic function and decreased markers of biological aging (Plaza-Florido et al., 2024).
Ongoing methodological obstacles, particularly in the standardization of extracellular vesicle (EV) isolation techniques, such as ultracentrifugation compared to size-exclusion chromatography, as well as in the accurate identification of their sources, whether from muscle, endothelial cells, or platelets. We propose that forthcoming investigations should progress beyond these unresolved issues towards a definitive roadmap: a multi-omics profiling approach—encompassing transcriptomics, proteomics, and lipidomics—of extracellular vesicles (ExEVs) across various exercise modalities (high-intensity interval training versus endurance training), while systematically considering sex-specific responses and age-stratified cohorts ranging from adolescence to older age. This framework would establish the groundwork for the development of vesicle-based "exercise pharmacology" (Nederveen et al., 2021).
This pioneering area not only advances our understanding of the molecular underpinnings of how exercise imparts its benefits, but also establishes a groundbreaking trajectory for therapeutics centered on extracellular vesicles—exosome mimetics formulated to treat obesity, type 2 diabetes, and sarcopenia independently of physical activity. Such developments could significantly reshape the notion of exercise prescription in medical practice.
Given the substantial transformative potential of this field, we recommend that your journal launch a special issue or thematic series on "Exercise-Derived Extracellular Vesicles in Precision Medicine." This initiative would integrate mechanistic, translational, and clinical research to fortify this swiftly evolving sector and delineate its future pathways. We believe that this Letter will be of great interest to your audience and look forward to your thoughtful consideration.

Abstract Skeletal muscle is a highly plastic organ that undergoes significant metabolic and structural stress during exercise, necessitating precise nutritional support for adaptation and recovery. While the roles of macronutrients are well-established, the complex interplay, or "crosstalk," between essential micronutrients is a critical yet dynamic facet of exercise physiology. This review synthesizes current evidence on the synergistic relationships between key vitamins and minerals—specifically vitamin D, calcium, magnesium, the B-vitamins, antioxidants, and iron—in supporting skeletal muscle function during and after exercise. We explore how these micronutrients co-operate in energy production, calcium handling, contraction coupling, antioxidant defense, and anabolic signaling. Recent research continues to elucidate the molecular mechanisms behind this crosstalk, highlighting the role of the gut-muscle axis and the impact of deficiencies on adaptive outcomes. Understanding this intricate network is paramount for developing targeted nutritional strategies that optimize athletic performance, enhance recovery, and support long-term musculoskeletal health.

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
The topic of the interaction between gut microbiota and skeletal muscle and its influence on the regulation of muscle mass is new. There is evidence that the composition and diversity of gut microbiota plays a role in skeletal muscle metabolism and function, especially in catabolic (sarcopenia and cachexia) or anabolic (exercise or in athletes) situations. Signals generated by gut-microbiota interactions, such as microbial metabolites, gut peptides, lipopolysaccharides, and interleukins, modulate systemic inflammation and insulin sensitivity, which in turn regulate muscle function.
Potential mechanisms by which the gut microbiota can affect muscle mass suggest that it can regulate the sensitivity of skeletal muscle to anabolic stimuli and contribute to the reduction or increase of muscle mass depending on the physiological state.
In addition, the use of probiotic strategies to prevent muscle mass loss or promote muscle mass gain in catabolic or anabolic states may be helpful. Probiotics, particularly lactic acid bacteria and bifidobacteria, have shown potential in limiting sarcopenia, cachexia, or promoting muscle health and function in rodent studies. However, more research is needed to identify specific strains that can optimize muscle mass and performance in humans (Chew et al., 2023).
Overall, this line of research suggests that a combination of strategies, including probiotics, personalized nutrition, and traditional supplementation, may be the best approach to maintaining muscle function in people of all ages. However, further studies are needed to better understand the role of gut microbiota in muscle metabolism and to identify optimal probiotic strategies for muscle health.
Researchers in this field also discuss challenges in studying the effects of probiotics on muscle mass and function, including variations in study design, participant characteristics, and measurement methods. They suggest future research directions, such as investigating the use of strict anaerobic bacteria and a mixture of probiotics or fecal microbiota transplantation (FMT) to more efficiently colonize the host's microbial ecosystem. In addition, they suggest the combination of probiotic strains with other nutritional agents to optimize their effects on the microbiota and muscles (Gizard et al., 2020).
Consequently, while probiotics have shown promising effects on muscle mass and performance in animal studies, their efficacy in humans remains unclear. Further research is needed to determine specific strains and protocols that can effectively modulate gut microbiota and improve muscle health in different populations.

Abstract Toll-like receptor 4 (TLR4) is found in the membrane of skeletal muscle cells. A variety of factors can activate TLR4. It has been shown that TLR4 expression reduce after aerobic training, but more studies considering the influences of different types of training on TLR4 expression are necessary. The purpose of this study was to evaluate the influence of 8 weeks of aerobic training on muscle TLR4 Expression in rats. Twenty Male Wistar rats (200±20 g) divided into four groups: control, training, high fat diet (HFD) and HFD+exerise. High fat diet was made by adding 10% animal oil, 2% cholesterol and 0.5% colic acid to standard rodent chow. Training group performed a swimming training protocol (1 h/day, and 5 days/week for 8 weeks). Forty eight hours after the final session of training, the rats were sacrificed and their gastrocnemius muscle was removed for determination of TLR4 expression. Training significantly decreased TLR4 messenger RNA and protein expression (p<0.05). Levels of TLR4 expression in the HFD group was significantly (p<0.05) higher tahn control ones. Our result displayed that training in rats induceed a critical suppression in the TLR4 signaling in muscle. These data give noticeable progress in our knowledge of the events that link physical training to an improvement in inflammation.

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 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.

Abstract Dear Editor-in-Chief
 
Recently, telocytes (TCs) have been identified in various organs of the body, which are unique stromal cells (Manetti et al., 2019). Telopodes (very long and thin cytoplasmic projections) in TCs connect directly with other TCs and adjacent structures (including blood vessels, nerve endings, smooth muscles, glandular elements) through direct homo- and heterocellular junctions, or extracellular vesicles. Studies also show that TC damage and dysfunction is involved in the pathogenesis of inflammatory and fibrotic diseases, especially aging, and may be considered as therapeutic agents in the future (Chaitow, 2017). On the other hand, the evidence suggests that sarcopenia and fertility-related aging syndromes, due to their complex etiology, make pharmacological or nutritional prescriptions ineffective in their prevention and treatment (Kwak & Kwon, 2019). Therefore, the use of multidimensional strategies such as exercise programs with nutritional interventions may be more effective in preventing these age-related diseases (Nascimento et al., 2019; Pascual-Fernández et al., 2020). Research suggests that TCs may play a critical role in such matters as cross-talk preservation, regenerative mechanisms, and support for localized stem cell differentiation. In 2021, Ravalli et al. examined the presence of TCs in the anterior tibialis muscle of healthy rats under the endurance training protocol compared with sedentary rats. TCs in this study included CD34/CD117 and CD34/vimentin, which were identified by double-positive immunofluorescence staining technique. They showed that TCs in sedentary rats decreased significantly after 16 weeks. In contrast, trained rats showed a constant number of TCs after 16 weeks. In short, it can be stated that the protective relationship between TCs and regular sports activity may present new opportunities in the field of regenerative medicine and supports the hypothesis that a possible adaptative stimulus for TCs in sarcopenia and other musculoskeletal disorders is the promotion of physical activity (Ravalli et al., 2021; Rocha et al., 2021).
In order to support the repair and reconstruction of skeletal muscle, studies performed by transmission electron microscopy also show that there is a close spatial relationship between TCs and satellite cells in adult skeletal muscle. This association is probably due to the intracellular signaling mechanism of endocrine and paracrine, and although their exact function in skeletal muscle regeneration has not yet been fully understood, TCs containing vascular endothelial growth factor and platelet-derived growth factor receptor beta has been discovered in the interstitial part of skeletal muscle. In this way, TCs play an important role in promoting satellite cell self-renewal, vascular stability, facilitating angiogenesis, and preventing fibrosis (Cretoiu & Popescu, 2014; Manetti et al., 2019; Yin et al., 2013).
It is important to note that as age increases, skeletal muscle mass and potential for post-injury regeneration decrease. However, the role of intrinsic changes in satellite cells in these reductions has been controversial because studies have documented a decrease in the number of satellite cells with increasing age in mice. On the other hand, some results indicate that there is not significant reduction in this case. Moreover, evidence suggests that the potential for innate regeneration of satellite cell pools is impaired with age. Although the number of satellite cells in old muscle decreases, the inherent myogenic potential and self-renewal capacity of satellite cells remain unchanged. Factors that can play a role in the activation and differentiation of satellite cells are: paired/homeodomain box transcription factors PAX3 and PAX7 and basic helix-loop-helix myogenic regulatory factors (MRFs) such as MYF5, MRF4, MYOD (Myogenic determination gene number 1) and myogenin (Arpke et al., 2021; Mierzejewski et al., 2020).
Unlike satellite cells and fibroblasts, skeletal muscle TCs express the c-kit cell surface marker. TC-specific antigenic markers are not yet fully understood; however, CD34 is currently used as the most reliable marker to detect TCs at the site of light microscopy, also known as TCs/CD34 + stromal cells (Manetti et al., 2019; Yin et al., 2013). The positive effects of regular physical activity on the number of satellite cells have been expressed, at the same time, skeletal muscle that contracts and relaxes is likely to be affected by the mechanical support of TCs during exercise (Ceccarelli et al., 2017; Kondo & Kaestner, 2019). Studies have shown evidence and conclusions about TCs, although, little research has been done on TCs in mammalian skeletal muscle tissue. At present, there is no direct experimental evidence and results that conclusively support a TCs-satellite cells morpho-functional interaction following skeletal muscle injury (Manetti et al., 2019). However, due to the beneficial role of exercise on satellite cells and TCs in the prevention of age-related muscle disorders, there are still many issues that need to be addressed, including identifying TC-specific biomarkers and their role in sarcopenia. Therefore, the role of regular physical activity on new interstitial cells such as TCs will be a new treatment for age-related diseases such as sarcopenia, which requires further investigations (Ravalli et al., 2021; Wang et al., 2016).