Journal of Exercise & Organ Cross Talk

Abstract Exercise and the use of anti-inflammatory supplements are effective in controlling inflammation and tissue damage in diabetes. Therefore, the aim of the present study was to investigate the effect of 8 weeks of interval training and royal jelly on the expression of renal inflammatory genes and insulin resistance in diabetic rats. Thirty-two male Wistar rats were used in this study. Diabetes was induced by a high-fat diet for 20 weeks followed by intraperitoneal injection of freshly prepared STZ solution in saline (25 mg/kg). Then the rats were randomly divided into 4 groups: Diabetes (DI), DI+ HIIT, DI+ royal jelly (RJ), and DI+ HIIT+ RJ. Royal jelly groups were given royal jelly at a dose of 100 mg/kg diluted in distilled water and gavage 5 days a week. The exercise program consisted of eight weeks of HIIT training, five sessions per week with a gradual increase in intensity intervals from 22 to 38 meters per minute (80 to 90% of Vo2max) and rest intervals at a speed of 16 to 22 meters per minute (50 to 56% of Vo2max). At the end of the research, rats were euthanized and kidney tissue was removed to measure the expression of TNF-α and NF-κB genes. The DI+HIIT (p=0.0006), DI+RJ (p=0.0011) and DI+HIIT+RJ (p<0.0001) groups showed a significant decrease in HOMA-IR compared to the diabetes control group. The DI+HIIT, DI+RJ and DI+HIIT+RJ groups showed a significant decrease in TNF-α and NF-κB gene expression in kidney tissue compared to the diabetes control group. In conclusion, 8 weeks of HIIT and/or royal jelly supplementation significantly ameliorated insulin resistance and suppressed renal pro-inflammatory gene expression (TNF-α, NF-κB) in diabetic rats, with the combined approach showing the greatest efficacy.

Abstract This study investigated the combined efficacy of interval training and thyme honey in attenuating the expression of inflammatory genes (TNF-α and TGF-β) in renal tissue and improving insulin resistance in diabetic rats. In this experimental study, 32 young male Wistar rats were divided into 4 groups: diabetes mellitus control (DM), diabetes and interval training (DM+HIIT), diabetes and thyme honey (DM+TH), and diabetes and interval training-thyme honey (DM+HIIT+TH). Animals in the training group underwent 40 sessions of training over two months with a gradual increase in the number of intense intervals from 2 to 8 intervals and an intensity of 80 to 95% of maximum running speed. At the same time, the samples in the TH groups received thyme honey at a rate of g/kg 3 and 5 days per week. Insulin resistance index (HOMA-IR) was performed using the formula. TNF- α  and TGF-β gene expression in kidney tissue was evaluated using Real-Time PCR. Based on the results of the present study, DM+HIIT significantly reduced HOMA-IR compared to the diabetes group (p<0.05). However, the DM+HIIT+TH group did not yield a greater improvement in HOMA-IR than the DM+HIIT group alone. Also, TNF-α and TGF-β genes in the DM+HIIT, DM+TH and DM+HIIT+TH groups showed a significant decrease compared to the diabetes group (p<0.05). In conclusion, our findings provide strong evidence that both interval training and thyme honey supplementation independently ameliorate diabetic nephropathy by downregulating key pro-fibrotic and inflammatory mediators. While the combination therapy was highly effective at suppressing inflammatory genes, it did not provide a synergistic benefit for insulin sensitivity compared to exercise alone. These results suggest that interval exercise is the primary driver of improved insulin sensitivity in this model.

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 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 This study examined the acute hormonal and myokine responses to traditional and circuit resistance training in young males with distinct BMI-based groups. Twenty sedentary men aged 20–30 years were classified as high-BMI (BMI >29.9) or low-BMI (BMI <18.5). Each participant completed both traditional resistance training (TRT) and circuit resistance training (CRT) protocols in a crossover design, with a one-week washout period. Sessions included multi-joint upper and lower body exercises at comparable intensities. Blood samples were taken immediately before and after each session. Serum levels of testosterone, cortisol, myostatin, and follistatin were assessed using ELISA kits. A repeated-measures ANOVA was used to compare within- and between-group changes across time and training modality. Baseline cortisol levels were significantly higher in low-BMI individuals (P=0.037), while testosterone levels showed no initial difference between groups (P>0.05). Post-TRT, testosterone levels increased significantly in high-BMI individuals compared to low-BMI individuals (P=0.017), with both training types elevating testosterone and cortisol across all participants (P<0.05). CRT led to a significant reduction in myostatin and increase in follistatin in high-BMI individuals (P<0.05), while only follistatin increased significantly in low-BMI individuals after TRT (P<0.05). These results suggest that CRT promotes superior anabolic signaling in high-BMI individuals, while TRT is more effective at enhancing testosterone response. Myokine and hormonal responses appear to be body-type-dependent and training-modality-specific. Practitioners designing hypertrophy-focused programs should tailor training protocols to the athlete’s BMI-based group to optimize muscle adaptation and endocrine outcomes. And also, trainers should individualize hypertrophy programs based on body composition to optimize both hormonal responses and muscle adaptation.

Abstract Epidemiological evidence indicates that obesity is associated with accelerated prostate cancer progression and elevated mortality rates. However, the underlying physiological mechanisms linking obesity to prostate cancer pathogenesis remain unclear. This study aimed to examine the effects of six weeks of moderate-intensity aerobic training combined with cannabidiol (CBD) supplementation on prostate protein kinase B (Akt) gene expression in high-fat diet (HFD)-induced obese male rats. Forty male Wistar rats (240 ± 20 g) were randomly assigned to five experimental groups: healthy control, HFD, HFD+exercise, HFD+CBD, HFD+exercise and CBD (n=8 per group). CBD was administered via oral gavage at 100 mg/kg, five days per week for six weeks. The aerobic exercise protocol consisted of treadmill running at progressive intensities, ranging from 15 m/min for 30 min to 27 m/min for 60 min, five days per week for six weeks. Following the intervention, prostate tissue was extracted for quantitative analysis of Akt gene expression. Statistical analysis revealed that aerobic exercise significantly modulated Akt gene expression (P=0.015). Similarly, CBD administration exerted a significant effect on Akt expression (P=0.004). However, no significant interactive effect was observed between aerobic exercise and CBD (P=0.068). These findings suggest that both aerobic exercise and CBD independently influence Akt signaling pathways, potentially through anti-inflammatory mechanisms, which may contribute to prostate cancer prevention. Further research is warranted to elucidate the precise molecular interactions involved.

Abstract Metabolic syndrome (MetS) elevates thrombotic risk through dysregulated coagulation factors, including plasminogen activator inhibitor-1 (PAI-1) and fibrinogen, driven by visceral adiposity and metabolic dysfunction. High-intensity interval training (HIIT) improves cardiometabolic health, but its effects on hemostatic markers in MetS remain underexplored. Twenty-four men with MetS (ATP-III criteria; age 44.4 ± 5.4 years, BMI 31.7 ± 2.3 kg·m⁻²) were randomized to HIIT (n=12) or control (n=12). HIIT comprised 3 sessions/week for 8 weeks (4 × 4-min intervals at 90% HRmax, interspersed with 3-min active recovery at 70% HRmax). Fasting plasma PAI-1, fibrinogen, insulin resistance (HOMA-IR), body composition, and lipid profiles were assessed pre/post-intervention. HIIT significantly reduced PAI-1 (−30.7%, p<0.001) and fibrinogen (−21.8%, p<0.001) versus controls. Concurrent improvements occurred in HOMA-IR (−20.6%, p<0.001), body fat (−3.8%, p<0.05), systolic/diastolic BP (−7.5%/−5.2%, p<0.05), LDL-c (−5.6%), triglycerides (−9.4%), and HDL-c (+3.0%; all p<0.05). Control group exhibited no significant changes. HIIT attenuates prothrombotic risk in MetS, evidenced by reductions in PAI-1 and fibrinogen. These hemostatic improvements are mechanistically linked to ameliorated metabolic dysfunction, highlighting HIIT’s role in modulating adipose tissue–vascular cross talk.

Abstract This study investigated the effects of intense endurance training (HIET) combined with egg white and wheat germ supplementation on immune, respiratory, and cardiopulmonary function in endurance runners. In this quasi-experimental study, 24 male endurance runners from Saqqez City were randomly assigned to either a training + supplement group (n=12) or a training + placebo group (n=12). Both groups underwent 8 weeks of HIET (3 sessions/week, 60 min/session, 70-90% heart rate reserve). The supplement group consumed 15g egg white powder (75 kcal) and 17.5g wheat germ powder (78 kcal) daily, approximately 2 hours before training. The placebo group received starch powder. Cardiopulmonary function (VO2max, FEV1), cardiac biomarkers (NT-proBNP, left ventricular stroke volume - LVSV), and inflammatory markers (IL-6) were assessed pre- and post-intervention. Data were analyzed using ANCOVA (SPSS v26, α=0.05), controlling for baseline values. Significant improvements were observed in the supplement group compared to the placebo group for VO2max (F(1,21)=29.482, p<0.001, η²=0.510) and FEV1 (F(1,21)=60.308, p<0.001, η²=0.742). IL-6 levels decreased significantly in the supplement group relative to the placebo group, which showed an increase (F(1,21)=7.848, p=0.011, η²=0.272). No significant between-group differences were found for NT-proBNP (F(1,21)=3.627, p=0.071, η²=0.147) or LVSV (F(1,21)=0.061, p=0.807, η²=0.003). Eight weeks of HIET combined with egg white and wheat germ supplementation significantly enhanced maximal oxygen consumption and expiratory function while attenuating exercise-induced inflammation in endurance runners, compared to HIET alone. These findings suggest potential benefits of this supplement combination for improving cardiopulmonary performance and modulating immune responses during intense endurance training.

Abstract The purpose of this study was to examine the effects of eight weeks of resistance, continuous endurance, and interval endurance training on Dectin-1 and Glucagon-Like Peptide-1 levels in overweight women. A total of 40 women, aged between 25 and 35 years with a body mass index (BMI) ranging from 25 to 30 kg/m², voluntarily participated in the study. Participants were randomly assigned to one of four groups: resistance training (n = 10), continuous endurance training (n = 10), interval endurance training (n = 10), and a non-training control group (n = 10). The intervention consisted of three exercise sessions per week over an eight-week period, following structured and group-specific training protocols. Results indicated that all three exercise modalities—resistance, continuous endurance, and interval training— significantly altered Dectin-1 and GLP-1 levels compared to the control group (p < 0.05). Among the training groups, continuous endurance training elicited the greatest reduction in Dectin-1 levels, followed by interval training and then resistance training. However, post hoc analysis revealed no significant difference between resistance and interval training groups for either biomarker. Similarly, GLP-1 levels increased most prominently in the continuous endurance group, followed by the interval and resistance training groups, again with no significant difference between the latter two. In summary, the findings suggest that all three forms of exercise contributed to favorable changes in Dectin-1 and GLP-1 among overweight women. Nonetheless, the magnitude of these changes appears to be influenced by the type and possibly the intensity of the training stimulus, with continuous endurance training demonstrating the most pronounced effects.

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 Dear Editor-in-Chief
While the critical role of macronutrients and established myokines (e.g., BDNF, Irisin) in muscle-brain communication during exercise is increasingly recognized, a significant and underexplored frontier lies in the specific, active modulation of this bidirectional crosstalk by essential micronutrients. This letter proposes a novel conceptual framework: that certain micronutrients act not merely as metabolic co-factors, but as dynamic orchestrators or gatekeepers of the signaling pathways fundamental to muscle-brain communication in response to acute and chronic exercise.
Beyond their classical roles in energy metabolism or antioxidant defense within each organ, compelling emerging evidence suggests specific micronutrients directly influence the production, release, stability, and reception of key signaling molecules traversing the muscle-brain axis: Vitamin D receptors (VDR) are expressed in both skeletal muscle and brain regions crucial for motor control and cognition. Recent work indicates vitamin D sufficiency potentiates exercise-induced BDNF release from muscle and brain, enhances sensitivity to neuroprotective myokines like Irisin, and may regulate muscle-derived kynurenine metabolism, shifting it away from neurotoxic metabolites (e.g., quinolinic acid) towards neuroprotective pathways (Pan et al., 2022). Deficiency may thus disrupt this protective signaling axis.
Certain polyphenols (e.g., flavonoids, curcumin) cross the BBB and exhibit potent anti-inflammatory and antioxidant effects. Novel evidence suggests they may protect neuronal receptors involved in sensing muscle-derived signals (e.g., AMPK activation) from exercise-induced oxidative stress, enhancing signal fidelity. Furthermore, they may modulate microglial activation states triggered by muscle-derived inflammatory signals during intense exercise, preventing excessive neuroinflammation (Gao et al., 2024; Gomez-Pinilla & Nguyen, 2012; Wang et al., 2024).
B-vitamins (particularly B6, B9, B12) are essential co-factors in one-carbon metabolism, critically influencing the synthesis of neurotransmitters (serotonin, dopamine) known to modulate central fatigue, motivation, and motor output. Exercise alters neurotransmitter turnover. Crucially, B-vitamin status impacts the brain's response to peripherally derived signals like IL-6, which has dual pro-inflammatory and anti-inflammatory/neuroprotective roles depending on context and magnitude (Gomez-Pinilla & Nguyen, 2012; Kato et al., 2024). Optimal B-vitamin levels may be key for interpreting muscle-derived IL-6 as an anti-fatigue signal within the CNS.
Therefore, we propose that specific micronutrients (e.g., Vitamin D, B-vitamins, polyphenols) act as dynamic modulators of the muscle-brain signaling axis during exercise, moving beyond their classical metabolic roles. Understanding this "Micronutrient Crosstalk Matrix" offers novel avenues to optimize exercise benefits for brain health and performance through targeted nutrition.

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 Cancer is the leading cause of death worldwide, with breast cancer posing a high risk for women. Immunotherapy has shown efficacy, and exercise is recognized for its role in cancer management. Combining both may enhance therapeutic outcomes. This study examined 30 female BALB/c mice (average weight: 17.76g), divided into five groups (n=6 each). After treadmill acclimation, they underwent two 6-week training protocols and a 4-week protocol post-cancer induction. Data analysis was performed using one-way ANOVA. The findings revealed significant differences in body weight among the EIEA and EIA groups compared to the control group. Similarly, in the heart weight analysis, both EIEA and EIA groups showed significant differences compared to the control (p<0.05). Notably, the combination of exercise and anti-PD-L1 antibody treatment effectively prevented weight loss in both body mass and heart weight. This protective effect may be attributed to the mitigation of cachexia, a common complication in cancer that leads to severe weight loss and muscle wasting. These results suggest that integrating physical activity with immunotherapy could serve as a potential strategy to counteract cancer-induced weight deterioration.

Abstract Dear Editor-in-Chief
With the alarming rise in cancer cases, which is now recognized as the leading cause of death, the importance of exercise in cancer management is gaining significant recognition (Ahmadi Hekmatikar et al., 2023). In a study titled "Exerkines in health, resilience, and disease," Chow et al. (2022) shed light on the crucial role of exerkines in relation to various diseases, highlighting the positive impact of exercise, particularly in cancer (Chow et al., 2022). However, Brooks et al. (2022), in a letter to the editor addressing the aforementioned study by Chow et al., noted that lactate, a notable myokine and exerkine, was not mentioned. They emphasized the pivotal role of lactate as an important secretory product of exercise (Brooks et al., 2022). In this regard, our recent study, which was published in the journal Support Care Cancer (Ahmadi Hekmatikar, 2023), presented a critique of the article by Depenbusch et al. 2023. We highlighted that lactate, an important myokine secreted during exercise, can potentially pose a risk to tumors (Depenbusch et al., 2023). Our study emphasized that lactate may contribute to tumor angiogenesis and immunosuppression. Therefore, caution should be exercised when designing exercise programs for cancer patients (Ahmadi Hekmatikar, 2023) In a previous study published in support Care Cancer (Lavín-Pérez et al., 2023), we found that moderate-intensity physical activity does not negatively impact the immunological changes in breast cancer patients. However, upon further examination of the role of lactate, it became evident that more research is needed. Our study aims to provide researchers with a detailed exploration of the role of lactate in cancer, offering a valuable perspective for future investigations.
  Lactate and immune checkpoint: lactate leads to immune 
system suppression (How)
One of the most crucial treatment strategies currently pursued by oncology researchers is immune checkpoint blockade (Sharma et al., 2023). Within the tumor microenvironment, PD-1 and its ligand PD-L1 play a crucial role in tumor progression and survival by evading immune surveillance aimed at neutralizing the tumor (Keir et al., 2008). In the cancer immune cycle, the immune checkpoint PD-1 and its ligand PD-L1 collaborate to facilitate immune escape and promote tumor progression (Keir et al., 2008). In this context, a study revealed that lactate can enhance the expression of PD-L1 on tumor cells, suggesting that lactate may have a protective effect against tumors by increasing PD-L1 expression (Feng et al., 2017). Furthermore, another study strongly emphasized that the lactate-induced activation of the PD-1/PD-L1 pathway can induce immunosuppression by promoting lymphocyte apoptosis in AKI (Xu et al., 2021). Additionally, it has been discovered that lactate metabolism is essential for the function of anti-tumor immune cells (Ahmadi Hekmatikar et al., 2023; Heuser et al., 2023). There are two main perspectives regarding the role of lactate in immune evasion. The first perspective suggests that lactate, by increasing PD-L1 expression, contributes to immune evasion and facilitates tumor growth. The second perspective proposes that lactate derived from the tumor inhibits the proliferation of human T lymphocytes (Ahmadi Hekmatikar et al., 2019; Heuser et al., 2023; Rami et al., 2023; Tayebi et al., 2020).
Lactate and tumor angiogenesis
One characteristic of cancerous tumors is their ability to induce angiogenesis in their surrounding environment, facilitating their growth and metastasis to other parts of the body (Bokhari & Hamar, 2023). This angiogenesis is triggered by an upregulation in the expression of the vascular endothelial growth factor (VEGF) gene (Bokhari & Hamar, 2023). While it is known that tumors promote angiogenesis through the establishment of signaling cascades in their vicinity, a more comprehensive examination of this topic reveals the involvement of lactate in tumor angiogenesis (Pérez-Tomás & Pérez-Guillén, 2020). Lactate appears to play a role in enhancing the expression of VEGF, potentially explaining the association between lactate and tumor angiogenesis (Ahmadi Hekmatikar, 2024; Ahmadi Hekmatikar & Moqhadasi, 2024; Pérez-Tomás & Pérez-Guillén, 2020).
Why exercise?
The first perspective
One of the fundamental characteristics of exercise is the elevation of blood lactate levels during physical exercise (Ahmadi Hekmatikar et al., 2024; Brooks, 2018). It was previously believed that lactate production occurred as a consequence of oxygen deprivation in skeletal muscle contractions. However, it is now understood that lactate is continually generated and utilized in various cells even under fully aerobic conditions. In fact, lactate, as a metabolic byproduct of glycolysis and a substrate for downstream pathways like mitochondrial respiration, can be considered an interface between glycolytic and aerobic pathways (Brooks, 2018). In a study titled "Physiological Significance of Elevated Levels of Lactate by Exercise Training in the Brain and Body," it was discovered that exercise can increase lactate levels in the bloodstream. Moreover, this rise in lactate was found to have implications for angiogenesis. Physical exercise stimulates the production of vascular endothelial growth factor (VEGF) and promotes angiogenesis through the lactate receptor known as HCAR1 (Lee et al., 2023). 
The second perspective
Drawing from previous research, oncology and exercise physiology researchers are striving to establish appropriate physical exercise strategies for individuals with cancer, recognizing that physical exercise is a cost-free intervention that can play a significant role in disease management (Ahmadi Hekmatikar et al., 2023; Chow et al., 2022; Depenbusch et al., 2023; Lavín-Pérez et al., 2023). The importance of physical exercise during cancer is underscored by its potential to mitigate fatigue, alleviate side effects of treatment and medication, and address general physiological mechanisms. However, the tumor microenvironment operates in a sophisticated and intricate manner, necessitating a deep exploration of its underlying mechanisms to develop tailored exercise regimens. Oncology researchers are placing their focus on immunotherapy, as enhancing the performance of tumor-specific immune cells holds promise for researchers. In a meta-analysis study, we asserted that physical exercise does not suppress tumor-specific immune cells, yet it does not significantly increase their levels either (Lavín-Pérez et al., 2023). Furthermore, we reported in another study that low-intensity physical exercise during cancers, viewed  
through the lens of "exerkines and cancer management," can be beneficial. However, caution must be exercised with moderate to high-intensity exercise, as it may contribute to disease progression. One aspect we emphasized was the significance of lactate (Ahmadi Hekmatikar et al., 2023). Lastly, in our study titled "Correspondence: Work Smart or Work Hard in Patients with Metastatic Breast Cancer: Emphasizing the Importance of Immunological and Lactate Changes," we highlighted that physical exercise induces lactate secretion, and the detrimental impact of lactate on tumors has been identified. Consequently, physical exercise recommendations should be approached with caution (Ahmadi Hekmatikar, 2023).
Low-intensity, moderate and high-intensity exercise
The American College of Sports Medicine recommends low-intensity exercise (20-40% VO₂max, 35-45% HRmax) for beginners. Studies show lactate levels typically increase by 1-2 mmol after such activity. However, responses vary based on fitness level, glycogen stores, and oxygen availability. Moderate exercise (40-60% VO₂max, 55-70% HRmax) can elevate lactate by 2-6.5 mmol (Zinman et al., 2003). Some studies also report lactate reduction after prolonged training. Lactate monitoring during moderate-intensity exercise provides insights into physiological adaptation (Andersen et al., 2023; Andersson et al., 2021; Falz et al., 2019; Wiecek et al., 2017; Yuxin et al., 2021). High-intensity exercise (≥64% VO₂max) leads to greater lactate accumulation (4.5-13.2 mmol). Trained individuals may experience lower increases compared to untrained counterparts. Long-term high-intensity training may reduce resting lactate levels. Resting lactate levels in cancer patients can be significantly elevated, but post-exercise lactate increases are generally lower than in healthy individuals. Exercise interventions may help regulate lactate metabolism and reduce fatigue in cancer patients. However, responses vary based on training intensity and individual health conditions. Overall, lactate dynamics depend on exercise intensity, fitness level, and metabolic factors. Further research is needed to optimize exercise prescriptions for different populations, including cancer patients (Andersen et al., 2023; Andersson et al., 2021; Falz et al., 2019; Wiecek et al., 2017; Yuxin et al., 2021).
Conclusion and research gap
In our study, we have demonstrated the detrimental effects of lactate on tumors. Additionally, we have taken a more specialized approach by examining the relationship between lactate and exercise. It is evident that physical exercise leads to increased lactate levels and angiogenesis. Therefore, we strongly recommend that in order to develop appropriate physical exercise strategies for cancer patients, it is crucial to delve into the deeper and more fundamental mechanisms underlying the interaction between exercise and cancer, rather than solely focusing on surface level mechanisms. Considering that immunotherapy is a key focus of cancer treatment for oncology researchers, the role of lactate secreted during exercise becomes particularly significant. It has been established that lactate can negatively impact the immune system's performance in two ways: 1) by increasing the expression of anti-PD-L1, allowing tumors to evade immune surveillance, and 2) by directly suppressing T cells. Furthermore, lactate can also contribute to angiogenesis and facilitate tumor growth (See figure 1). Therefore, our study has opened a specialized and important avenue in the field of sports oncology, presenting these significant hypotheses that can guide future research and aid in developing more effective training strategies:

Can physical exercise -induced elevation of lactate contribute to tumor growth?
Can physical exercise -induced elevation of lactate impact the expression of PD-L1 in tumors?
Can physical exercise-induced elevation of lactate affect tumor specific immune cells?

Can physical exercise -induced elevation of lactate lead to tumor angiogenesis?

What intensity of physical exercise can be effective for cancer patients, considering lactate and its relationship with tumors?

 By addressing these questions, we can gain valuable insights and uncover numerous aspects through this newly opened window.


 
 

Abstract Intense and high-speed intermittent training is recognized as an effective method for achieving rapid and extensive physiological and functional adaptations. However, it is important to consider that a single session of such exercises can exert significant physiological stress, potentially leading to adverse effects. Therefore, this study investigated the effects of a repeated sprint training (RSA) session on serum adropin, inflammatory, and blood coagulation factors. Ten healthy young men (age: 23.60 ± 2.01 years, weight: 68.60 ± 7.21 kg, body mass index: 22.00 ± 2.10 kg/m2) participated in this study. Blood samples were collected before, immediately after, and 20 minutes following the exercise protocol for measuring of adropin protein, fibrinogen, CRP, WBC, RBC, Hgb, and Hct levels. The exercise protocol consisted of 20 repetitions of different running speeds in a distance of 20 meters, with a 20-second rest period after each repetition (20*20*20). A significant increase in adropin, fibrinogen, WBCs, RBC, Hgb and, Hct levels was observed immediately after the exercise (p < 0.05). But only Adropin levels remained significantly higher than before the exercise after 20 minutes following the exercise. Therefore, even after exercise, adropin levels can remain elevated, allowing for the continuation of its positive effects. However, it is important to note that the increase in fibrinogen levels may require further investigation, particularly in relation to the use of anticoagulant agents. Therefore, when considering the implementation of these intense activities for inactive individuals, it is crucial to exercise caution and carefully assess the potential risks involved.

Abstract In Diabetes (Di) exercise training especially high-intensity interval training (HIIT) reduce blood lipids and improve anti-inflammatory status. In this study, we aimed to investigate the impact of high-intensity interval training on ASC inflammasome, lipid profile, and their correlation in diabetic rat models. Twenty rats were divided into four groups, including a control group, HIIT, Di, and Di+HIIT (n=5 in each group). Diabetes was induced using a combination of a high-fat diet (HFD) and STZ. Wistar rats in the exercise groups were subjected to high-intensity interval training for eight weeks. After sample collection, liver tissue was removed and weighed. Serum levels of lipid profile were measured by special kit. Protein expression of the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) in liver tissue was determined by Western blot. The results of the present study showed that diabetes induction significantly increased LDL, cholesterol, triglyceride and ASC levels and decreased HDL levels (p<0.05), whereas HIIT exercise training with diabetes somewhat adjusted the lipid profile and decreased the ASC inflammasome levels (p<0.05). In the correlation analysis, only the correlation between ASC and triglycerides was confirmed in the Di+HIIT group (p=0.043, r=0.997). Diabetes induction adversely affects lipid profiles and increases ASC inflammasome levels. However, high-intensity interval training (HIIT) appears to mitigate these effects by improving the lipid profile and reducing ASC levels. Notably, a significant positive correlation between ASC and triglycerides was observed in the diabetic rats undergoing HIIT, suggesting a link between inflammation and lipid metabolism.

Abstract This study aims to investigate the effectiveness of the USRPT system combined with beta-alanine supplementation on the physical performance of elite young soccer players. Forty-four young soccer players were purposefully selected and divided into four groups of 11 players: Exercise-only (placebo), Exercise with a supplementation, supplementation-only, and a control group. After a 10-minute warm-up, subjects performed the 25-minute USRPT protocol in three weekly sessions, followed by regular team training. The supplementation group consumed 4 grams of beta-alanine daily for six weeks, split into two doses 60 minutes before and after each training session. Body composition, aerobic fitness (Half-time test), anaerobic power (RAST test), 20-meter sprint, muscle endurance, and Borg's Rate of Perceived Exertion (RPE) were measured in the pre-test and post-test. The repeated measures ANOVA revealed a significant difference in aerobic power, anaerobic power, muscular endurance, and fatigue drag index between the exercise-placebo and exercise-plus-supplementation groups after 40 days (P=0.001). No significant differences were found between the supplementation and control groups in other variables (P>0.05). This research found that the USRPT system effectively improves aerobic and anaerobic power in soccer players. It also suggests that when combined with USRPT, beta-alanine supplementation reduces fatigue and enhances performance. Beta-alanine boosts sports performance by increasing Carnosine in muscle cells and offering antioxidant benefits. Coaches and athletes aiming to improve physical performance may consider using beta-alanine alongside targeted training.

Abstract Research indicates that a sedentary lifestyle significantly contributes to the development of post-COVID syndrome (PCS), characterized by persistent symptoms following acute COVID-19 infection. Engaging in regular physical activity is essential not only for mitigating these risks but also for enhancing recovery from COVID-19. Studies have shown that individuals who maintained high levels of PA before and after infection experienced fewer and less severe symptoms associated with PCS. Specifically, exercise training has been identified as a critical intervention for improving muscle function and modulating adipokine levels—signaling proteins released by adipose tissue that play a role in inflammation and metabolic regulation. Given the complex pathogenesis of PCS, which involves various physiological and psychological factors, it is imperative to incorporate structured exercise regimens into rehabilitation programs for affected individuals. Aerobic endurance training has demonstrated significant benefits in improving exercise capacity, reducing fatigue, and enhancing overall quality of life in PCS patients. Furthermore, high levels of PA are associated with improved immune function and lower rates of reinfection. In conclusion, promoting mandatory physical activity during and after pandemic conditions is vital for reducing the burden of post-COVID syndrome and enhancing public health outcomes. This review underscores the necessity for healthcare providers to advocate for exercise as a primary strategy in managing post-COVID symptoms and preventing future chronic diseases linked to sedentary behavior during different pandemics.

Abstract The global increase in the older population has resulted in escalating healthcare costs and burdens on governments and families. Understanding biological age (BA) as distinct from chronological age (CA) holds significant potential in accurately assessing individuals' health status and susceptibility to diseases. During exercise, myokines like irisin and lactate are released from skeletal muscles, facilitating cross-talk with organs such as the brain and heart. This may improve physical fitness, reducing frailty and BA. This research aimed to develop a comprehensive BA prediction model integrating genetic and epigenetic factors. The study involved 59 healthy adults, comprising 31 males and 28 females, with average ages of 58.2 ± 7 years and 50.1 ± 8.5 years, respectively. Assessments of physical fitness and completion of the Frailty Index (FI34) questionnaire were conducted to capture genetic and epigenetic influences. Feature selection, principal component analysis (PCA), and multiple linear regression (MLR) were employed to tailor BA prediction models for each gender. We identified seven significant biomarkers for males, including FI34, percent of skeletal muscle mass (SM), handgrip strength (GS), flexibility via sit-and-reach test (SR), peak torque of quadriceps muscles (PTQ), cardiopulmonary fitness (VO₂max), and basal metabolic rate (BMR). Conversely, females exhibited six key biomarkers: FI34, SM, GS, waist-to-hip ratio (WHR), peak torque of hamstring muscles (PTH), and percentage of body fat (PBF). We have successfully developed a comprehensive model for estimating BA by integrating key biomarkers representing epigenetic and genetic impacts. Estimating BA is crucial for precise health evaluations and disease risk assessments.

Abstract Recent studies highlight the role of molecular pathways, such as oxidative stress response and mitochondrial function, in COPD. This study explores the role of the PGC-1α gene, a key regulator of mitochondrial biogenesis and energy metabolism, using a rat model and bioinformatics analysis of human lung tissue samples. This study utilized a combined approach, analyzing gene expression in rat lung tissue alongside bioinformatics analysis of public human datasets. A total of 42 male Wistar rats were divided into seven groups, receiving treatments including cigarette smoke extract (CSE), nano-selenium (SeNPs), and aerobic interval training (AIT). PGC-1α expression levels were evaluated using quantitative Real-Time PCR (qRT-PCR) and analyzed using one-way ANOVA, followed by Dunnett’s post hoc test for multiple comparisons to determine significance across groups. The CSE+SeNPs+AIT group exhibited significantly higher PGC-1α expression compared to controls (p = 0.0289), indicating a potential protective role of SeNPs and exercise against oxidative stress. Bioinformatics analysis identified 250 differentially expressed genes (DEGs), with PGC-1α emerging as a critical hub gene associated with pathways like oxidative stress response and mitochondrial regulation. Protein-protein interaction (PPI) analysis further highlighted the centrality of PGC-1α in COPD pathophysiology. This study underscores the importance of PGC-1α in regulating mitochondrial function and oxidative stress in COPD. The findings suggest that PGC-1α could serve as a potential therapeutic target, offering insights into the development of interventions aimed at improving respiratory health in COPD patients. Future research should focus on validating these findings in clinical settings and exploring the therapeutic potential of PGC-1α modulation.

Abstract Resistance exercises and nutritional strategy are the best ways to prevent with age- related muscle atrophy (sarcopenia) by improving the physiological function of skeletal muscle. This study investigated the effect of 8 weeks of Water resistance training with consumption of dark chocolate on the changes and correlation of IGF-1 and FOXO3 in elderly women. In this study, 40 sedentary elderly women with an age range of 60-73 years were randomly divided into four groups: 1. water resistance training, 2. water resistance training + dark chocolate, 3. dark chocolate, 4. control. The subjects of the training groups did water resistance training for eight weeks. During these 8 weeks, the dark chocolate groups consumed 30 grams of 83% dark chocolate every day, and the control group received neither exercise nor Dark chocolate. Blood sampling was done 48 hours before the study and after the end of the last training session. Expressions of IGF-1 and FOXO3 were measured by real time-PCR method. After 8 weeks of water resistance training and consumption of dark chocolate, the expression of insulin-like growth factor 1 (IGF-1) gene increased significantly compared to the pretest (p<0.05). However, FOXO3 did not change significantly (p>0.05). These findings underscore the potential of targeted exercise and dietary interventions in enhancing muscle health among the elderly, although further research is needed to understand the implications of unchanged FOXO3 in this context.

Abstract Cancer is now the leading global cause of death, with breast cancer being particularly deadly for women. This study investigates how physical activity combined with anti-PD-L1 antibody administration affects tumor weight and lifespan in mice with breast cancer. In this study, 30 male and female BALB/c mice, averaging 17.76 grams in weight, were selected and divided into the following groups: PCG (n=6), EIC (n=6), EIE (n=6), EIA (n=6), and EIE+A (n=6). Following an acclimation period on the treadmill, mice underwent two initial 4-week training protocols, followed by a 2-week protocol after cancer induction. A one-way analysis of variance (ANOVA) was performed to analyze the research variables. Statistical analysis showed no significant changes in survival time or tumor weight in the PCG, EIC, and EIE groups of breast cancer mice. However, the EIA and EIE+A groups demonstrated significant improvements in both survival and tumor weight reduction (p<0.05). The findings of this study suggest that the combination of physical activity and anti-PDL-1 antibody administration may lead to tumor apoptosis by enhancing positive immunological effects, which could be effective for better cancer management. However, it is recommended that future studies investigate the immunological and physiological effects of the tumor microenvironment with the combination of physical activity and anti-PDL-1 antibody administration.

Abstract Most of the intracellular and extracellular factors that play a vital role in regulating energy metabolism and determining cell fate converge in the mitochondria. To promote or hinder cell survival through regulating the function and maintaining the mitochondrial structure. The decline of mitochondrial function and homeostasis with aging is the basis of the pathogenesis of aging-related diseases, especially in skeletal muscles. One of the important components of mitochondrial quality control that helps maintain the homeostasis of myocytes is autophagy, which is an important biological and evolutionary process, and its vital function is the removal of defective organelles. Although it has been proven that regular sports activities act as autophagy stimulators and play a role in maintaining the cellular homeostasis of skeletal muscle fibers and regulating intracellular metabolism. However, cellular autophagic responses to exercise in skeletal muscle appear to be different in different exercise protocols and disease models. How exercise activity modulates autophagy in skeletal muscle and how the effect of exercise is regulated by the autophagy signaling pathway are still poorly understood. The importance of understanding the obscure angles of this process can be an important goal in preventing the pathology of age-related diseases in skeletal muscle.

Abstract This study aims to investigate the effect of resistance-aerobic exercise and curcumin consumption on brain wnt/β-catenin expression and their correlation with muscle-enriched myokine musclin in rats with glioblastoma multiforme. Fourty male Wistar rats were used in this study. After getting familiarized with the research environment, the rats were randomly divided into five groups of eight: healthy control, tumor control, tumor + resistance-aerobic exercise, tumor + Nano-curcumin supplement, and tumor + aerobic-resistance exercise + Nano-curcumin supplement. For tumor induction, glioblastoma stereotaxic injection was utilized in the frontal cortex. The exercise training group did aerobic training and resistance training 3 days a week for 4 weeks. Nano curcumin supplement was gavage with a dose of 80 mg/kg for 4 weeks, 5 days a week. The brain histology changes of the groups with GBM injection confirmed brain tumor induction compared to the healthy control group (p<0.05). The expression of wnt/β-catenin genes in all tumor groups showed a significant increase compared to the healthy control group. Treatment with resistance-aerobic exercise and curcumin (especially the combination of both) revealed the greatest decrease in the expression of wnt/β-catenin genes compared to the tumor group. Wnt mRNA had a negative correlation with musclin mRNA in Tumor+N. cur group (r=-0.905, p=0.001). It seems that the use of nano supplements along with combined resistance-aerobic exercise can control the wnt/β-catenin signaling pathway in brain tumor tissue. In addition, the cross talk between muscle and brain should be more studied with considering different myokine.

Abstract Impaired cell internal settings and excessive proliferation causes the occurrence of diverse ranges of syndrom and diseases. The pathological stress underlying these conditions triggers persistent flux through multiple intracellular signaling pathways amongst MAPK/ERK as master regulator. Regarding the anti-inflammatory effects of muscle contraction induced myokines and nano-curcumin supplementation, we aimed to investigate the effects of aerobic training and nano-curcumin supplementation on RAS and ERK gene expression in rat muscle tissue. In this experimental study, 32 male wistar rats (aged 4-6 weeks, 130-150 g) were randomly assigned into 4 groups, including Control (C), Moderate Intensity Continious Training (MICT), Nano-Curcumin Supplementation (NCS) and Moderate Intensity Continious Training + Nano-curcumin (MICT+NCS). The training groups implemented the MICT protocol consisted of running at a velocity of 18-20 m/min, 5 days a week and for a total time of 4 weeks. The Supplement groups received 80 mg/kg/day through oral gavage. Regarding the results of one-way ANOVA, 4 weeks of moderate intensity aerobic exercise and Nano-curcumin supplementation led to a significant difference in the RAS (P=0.001) and ERK (P=0.01) gene expression levels in muscle tissue of rats among the study groups. Also, the results of the Bonferronie test showed that implementation of 4 weeks of MICT along with nano-curcumin supplementation alleviated the RAS/ERK gene expression levels, meanwhile nano-curcumin more efficiently down-regulated the pathway; suggesting that nano-curcumin can be an effective ergogenic aid for improving anti-inflmmatory properties through RAS/ERK signaling pathway.