Journal of Exercise & Organ Cross Talk

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

Abstract NAFLD is one of the chronic liver diseases closely related to metabolic disorders. Borage and physical activity improves oxidative indices. Also, Beclin-1 is a key gene in the autophagy process, and Parkin acts as a protective mechanism against liver damage. So, this study aims to investigate the effect of aerobic training and borage extract on the expression of Beclin-1 and Parkin genes in the liver cells in NAFLD. In this experimental study,40male Wistar rats weighing were divided into 4groups. (control, supplement, training), and training+supplement. The data were analyzed using SPSS 25 software. Training and borage extract had no significant effect on Beclin-1 expression (P=0.267), with fold changes of 1.05±0.07 for training, 1.07±0.06 for borage extract, and 1.12±0.08 for training+borage extract, compared to the control. However, Parkin expression increased significantly (P=0.006), with fold changes of 1.15±0.08 for Training, 1.18±0.09 for borage extract, and 1.20±0.10 for training+borage extract. Post hoc confirmed a significant increase in Parkin expression in the training+borage extract group compared to the control (P=0.035). This study showed that it is possible that the consumption of borage extract and aerobic training together and alone have an increasing the expression of Parkin. So, both borage extract and aerobic training have individual benefits for improving liver health by targeting Beclin-1 and PARKIN pathways, and their combination could provide a more robust approach to managing NAFLD by promoting effective autophagy, mitophagy, and mitochondrial function. This dual intervention could reduce liver damage, inflammation, and fibrosis, ultimately improving metabolic outcomes in individuals suffering from NAFLD.

Abstract Osteosarcopenic adiposity (OSA) syndrome significantly impacts hepatic disorders more than each of the tissues alone. The purpose of this study is to evaluate the effects of elastic resistance training modality on hepatic health markers, including fatty liver index (FLI), lipid accumulation product (LAP), hepatic steatosis index (HSI), and Framingham steatosis index (FSI)), in the elderly with OSA. Sixty-three eligible patients aged 60-80 years meet the inclusion criteria, including a) body fat percentage (BFP) ≥32%; b) body mass index (BMI) ≥30 kg/m²; c) T-score of L1-L4, and/or total femur or femoral neck -2.5≤T-score ≤-1.0; d) gait speed (10-meter walk test (10MWT) ≤1 (m/s²); and e) skeletal muscle index (SMI) ≤28% or ≤7.76 kg/m². The participants were randomly assigned to experimental (n=32) or control (n=31) groups. The experimental group completed a 12-week elastic-band resistance training program [3x/week; 60 min/session]. The results showed a statistically significant benefit from the elastic-band resistance training on LAP (P=0.033), FLI (P=0.001), HSI (P=0.008), and FSI (P=0.001). Our findings show that an elastic-band resistance exercise training program can improve hepatic function. This relatively low-cost, highly accessible form of exercise can be easily implemented to enhance the health of this population across a wide range of settings.

Abstract This study investigates the effect of home-based combined exercise on the transforming growth factor-β/Interleukin-17 ratio (TGF-β/IL-17) in maternal serum during the first, second, and third trimesters of pregnancy, as well as in umbilical cord blood. Thirty overweight pregnant women were randomly allocated to control and training groups. Blood samples were collected during each trimester of pregnancy and from the umbilical cord at birth. Fitness-related indicators were assessed in the mother throughout pregnancy. Newborn health indicators were measured at birth. The levels of IL-17 and TGF-β were determined using enzyme-linked immunosorbent assay (ELISA) and specialized kits. The exercise training significantly reduced TGF-β levels (p=0.011, effect size=1.22) and the TGF-β/IL-17 ratio (p=0.045, effect size=0.79) in the third trimester in mothers. Similarly, this ratio decreased in the fetus, accompanied by an increase in IL-17 levels (p = 0.038, effect size = 0.93). These immune changes were associated with improved maternal cardiovascular fitness and higher Apgar scores at 5 minutes for newborns (p<0.05). Obesity and excessive weight gain during pregnancy are linked to inflammatory responses and elevated cytokine levels, which may increase the risk of complications for the mother. This study highlights the long-term benefits of maternal exercise, evidenced by reduced inflammatory responses and improved neonatal health outcomes, as reflected in Apgar scores.

Abstract Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder associated with fat accumulation, sedentary lifestyle, and poor diet. This study examined the effects of aerobic exercise and mealworm protein supplementation on oxidative balance and the expression of FGF21 and mTOR genes in the soleus muscle of rats with NAFLD. Fifteen male Wistar rats (250 ± 50 g, aged 10–12 weeks) were randomly assigned to five groups: healthy control, fatty liver, fatty liver + supplement, fatty liver + exercise, and fatty liver + supplement + exercise. A high-fat diet was used to induce NAFLD. The exercise group performed moderate-intensity treadmill running (12–16 m/min) for eight weeks, five days per week. Mealworm protein (20 mg/kg) was administered via oral gavage. Liver and muscle tissues were analyzed using Real-Time PCR (FGF21, mTOR) and ELISA (TOS, TAC). Combined treatment significantly increased FGF21 expression (~130%; p = 0.022), reduced total oxidant status (~40%; p = 0.001), increased total antioxidant capacity (~45%; p = 0.009), and lowered SGPT and ALP levels (~32% and ~38%, respectively; p < 0.05). mTOR expression showed no significant change (p = 0.113), and the 18% SGOT reduction was not significant (p = 0.169). The combination had greater effects than either treatment alone. Aerobic exercise combined with mealworm protein supplementation improves oxidative balance and FGF21 expression in NAFLD. This integrative strategy may offer a novel therapeutic approach targeting liver-muscle metabolic interactions. Further human studies are recommended.

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.