Journal of Exercise & Organ Cross Talk

Abstract Sedentary obesity is associated with chronic inflammation, oxidative stress, and impaired angiogenesis, leading to endothelial dysfunction. Interval training and CoQ10 each improve redox balance and vascular health, possibly via inter-organ crosstalk, but their combined effects in sedentary obese men are unclear. Sixty sedentary obese men (30–45 years) were randomized into four groups (n=15): control, CoQ10 (100 mg/day), moderate-intensity intermittent training (3×/week, 8 weeks), and training + CoQ10. Serum VEGF, TAC, and H₂O₂ were measured pre/post-n via ELISA and colorimetric assays. Data were analyzed with repeated-measures ANOVA (α=0.05). Effect sizes (partial η²) were reported. Training significantly raised VEGF (p < 0.001, η² = 0.363) and TAC (p < 0.001, η² = 0.290), while strongly reducing H₂O₂ (p < 0.001, η² = 0.520). CoQ10 showed no significant main or interactive effects on TAC or H₂O₂; however, a significant three-way interaction (time × exercise × supplement) was observed for VEGF (p = 0.001, η² = 0.187). Post-hoc analysis revealed that the exercise-only group showed a greater increase in VEGF compared to the combined group, though the direct comparison between TR and TR+SUP at post-intervention did not reach statistical significance (p > 0.05). Eight weeks of interval training robustly improves VEGF and redox homeostasis in sedentary obese men, possibly through myokines/exerkines enhancing muscle–adipose–endothelial crosstalk and HIF-1α/VEGF signaling. CoQ10 provides no added benefit for most outcomes and may be associated with a modest attenuation of the exercise-induced VEGF response.

Abstract Obesity is associated with chronic low-grade inflammation and elevated oxidative stress. This study investigated the independent and combined effects of an 8-week aerobic interval-style continuous training program and CoQ10 supplementation on serum TGF-β and MDA concentrations in inactive obese men. Sixty inactive obese men (aged 30–45 years) were randomly assigned to four groups (n=15 each): control (CONT), CoQ10 supplementation (SUP; 100 mg/day), training (TR), and combined training + supplementation (TR+SUP). The supervised training protocol was performed three sessions per week for 8 weeks with progressive intensity. Fasting venous blood samples were collected before and after the intervention. Serum MDA was measured using colorimetric assay, and TGF-β was quantified via ELISA. Data was analyzed using two-way repeated-measures ANOVA. Significant time × exercise interactions were observed for both MDA (F(1,56) = 28.793, p < 0.001) and TGF-β (F(1,56) = 30.617, p < 0.001), with reductions in the exercise groups (MDA: exercise groups from 210 nmol/L to 156 nmol/L; TGF-β: from 35 nmol/L to 30 pg/mL). Time × supplementation interactions were also significant but smaller (MDA: η_p² = 0.082; TGF-β: η_p² = 0.068). No significant three-way interaction was detected for either marker. These findings highlight aerobic interval-style continuous training as a cornerstone intervention for mitigating obesity-related oxidative stress and fibrotic signaling. CoQ10 supplementation produced a small independent reduction in both markers, but no synergistic or additive interaction with exercise was observed.

Abstract This study aimed to investigate the effects of eight weeks of resistance training (Ex), vitamin D supplementation (VD), and their combination (VD+Ex) on insulin resistance (HOMA IR), glycemic control (HbA1c, fasting glucose), inflammatory markers (interleukin 6 [IL 6] and C reactive protein [CRP]), and anthropometric measures in men with T2DM. In this single blind randomized controlled trial, 40 men with T2DM (aged 40–55 years) were randomly allocated into four groups (n=10 each): placebo control (PI), vitamin D supplementation (2000 IU/day, VD), resistance training (three sessions/week, 60–70% of 1RM, progressive overload, Ex), and combined VD+Ex. All participants maintained their usual diet, lifestyle, and anti diabetic medications. Fasting blood samples were collected pre and post intervention to measure serum glucose, insulin, 25 hydroxy vitamin D, IL 6, and CRP. HOMA IR was calculated. Post hoc analysis showed that the Ex group had significantly lower HOMA IR than the placebo group (p=0.002), and the VD+Ex group had significantly lower HOMA IR compared to both placebo (p<0.001) and VD alone (p=0.001). The comparison between VD+Ex and Ex was not statistically significant (p>0.05). No significant difference in HbA1c was observed (p=0.210). For body fat percentage, both Ex (p=0.043) and VD+Ex (p<0.001 vs. placebo;p=0.009 vs. VD) showed significant reductions. IL 6 levels were significantly lower in the Ex and VD+Ex groups compared to placebo and VD groups (p<0.001 for both). No significant changes were found in CRP levels (p=0.078).

Abstract Western diet (WD) consumption promotes oxidative stress and inflammation and plays a central role in the development of fatty liver disease. This study investigated the effects of high-intensity interval training (HIIT), ketone ester supplementation, and their combination on hepatic Keap1, Nrf2, and NF-κB protein levels in WD-fed mice. Thirty male C57BL/6J mice were randomly assigned to five groups (n=6): normal diet (ND), WD, WD plus ketone ester (WD+KE), WD plus HIIT (WD+HIIT), and WD plus HIIT combined with ketone ester supplementation (WD+HIIT+KE). Except for the ND group, all animals consumed a WD for eight weeks. HIIT was performed for four weeks (three sessions/week), and ketone ester was administered daily by oral gavage. Hepatic protein levels of Keap1, Nrf2, and NF-κB were determined using Western blotting. WD feeding significantly increased hepatic Keap1 and NF-κB protein levels and reduced Nrf2 levels compared with the ND group. HIIT and ketone ester, both independently and in combination, significantly decreased NF-κB and increased Nrf2 protein levels compared with the WD group. In addition, HIIT alone and in combination with ketone ester supplementation significantly reduced hepatic Keap1 levels (p<0.05). Overall, both interventions alleviated WD-induced alterations in hepatic oxidative stress and inflammatory signaling. The combined intervention elicited the most pronounced molecular responses, suggesting potential synergistic effects of HIIT and ketone ester supplementation in attenuating Western diet-induced oxidative stress and inflammation.

Abstract This study aimed to investigate the effects of high-intensity interval training (HIIT) on Adiponectin receptor 1 (AdipR1) gene expression in breast tumor tissue and serum levels of glutathione peroxidase (GPX) and glutathione reductase (GR) in a murine model of breast cancer. Sixteen female BALB/c mice were inoculated subcutaneously with 4T1 murine mammary carcinoma cells (5 × 10⁵ cells/mouse). One week post-inoculation, mice were randomly assigned to either a tumor-bearing control group (Tumor, n=8) or a tumor-bearing group subjected to HIIT (Tumor+HIIT, n=8). The HIIT protocol was performed on a motor-driven treadmill five days/week for four weeks, consisting of six 2-minute high-intensity intervals (18–25 m/min, 80–90% VO₂max) interspersed with 3-minute active recovery periods (5–9 m/min). Twenty-four hours after the final session, tumor tissues were excised for AdipR1 gene expression analysis via quantitative real-time PCR (2^-ΔΔCT method), and serum samples were collected for assessment of GPX and GR levels using ELISA. Statistical comparisons were performed using independent samples t-tests (p<0.05). HIIT significantly upregulated AdipR1 gene expression in breast tumor tissue compared to the control group (p<0.0001). Serum GPX levels were significantly decreased in the Tumor+HIIT group compared to the Tumor control group (p<0.0001). However, no significant difference was observed in serum GR levels between the two groups (p=0.7499). These findings suggest that HIIT may influence breast cancer progression through adiponectin-mediated pathways and oxidative stress regulation, providing a potential non-pharmacological adjunctive strategy for breast cancer management. Further studies are warranted to elucidate the underlying molecular mechanisms and clinical implications.

Abstract This randomized controlled trial evaluated the effects of combined mobile-based digital education ("DiabetiFit Pro") and aerobic-resistance exercise on treatment adherence, glycemic control, and tissue markers (lipotoxicity, sarcopenia, and necrosis) among underserved type 2 diabetes patients. In this 12-week RCT, 250 patients (mean age 54.3±10.7 years; HbA1c 9.2%) from underserved Iranian regions were randomized to intervention (n=125; 3 weekly sessions: 10-min app-based education +35-50 min ACSM-guided exercise) or control (n=125; usual care). Primary outcomes were HbA1c and MMAS-8 adherence scores. Secondary outcomes included glycemic variability and tissue biomarkers. Analysis used ITT with ANCOVA, regression, and χ² (α=0.05). Intervention produced superior HbA1c reduction (-1.70% vs -0.70% control; between-group diff: -1.00%, η²=0.18, p<.001) and adherence gains (+1.30 vs +0.40 points; η²=0.16, p<.001). High adherence increased from 23.2% to 48.8% (χ²=22.45, p<.001). Dose-response: modules completed explained 11.5% HbA1c variance (β=-0.34); app hours predicted 16.8% adherence variance (β=0.41). Favorable lipotoxicity/ sarcopenia improvements observed. Combined digital education-exercise interventions significantly enhance adherence, glycemic control, and tissue health in underserved T2DM populations, demonstrating dose-response efficacy and clinical meaningfulness per ADA standards. Health systems should scale such integrated mHealth platforms.

Abstract The aim of the present study was to investigate the effect of sprint interval training on markers of bone metabolism and bone density in Male Wistar Rats under unhealthy high fat, sugar, salt Diet. The study design was an 8-week protocol consisting of three groups: Control (CO), Western diet (WD) and Western diet+Sprint interval training (SIT) (WD/SIT). WD rats received a high-fat, sugar, and salt diet, while WD/SIT rats followed the same diet combined with sprint interval training. The one-way ANOVA revealed significant differences between groups for all variables (p<0.05). Effect sizes (η²) ranged from 0.47 to 0.99, indicating large effects for bone density (η²=0.99), ALP(η²=0.77), phosphorus (η²=0.74), and calcium (η²=0.47). Post-hoc analysis by LSD test showed that the WD group exhibited a significantly lower femur bone density percentage (24.09±2.32) compared to both the control (58.40±1.64) and WD/SIT (47.67±1.60) groups (p<0.001). Regarding bone metabolism markers, the WD/SIT group demonstrated significantly reduced serum ALP levels (195.67±20.83IU/L) compared to the control (248.33±29.30IU/L) and WD (253.17±38.46IU/L) groups (p<0.001). For serum phosphorus, the WD/SIT group (5.68±0.58 mg/dL) was significantly lower than the control (7.68±0.63 mg/dL) and WD (8.58±0.78mg/dL) groups (p<0.001). Furthermore, serum calcium levels in the control group (10.27±0.80 mg/dL) were significantly higher than in the WD/SIT (8.92±0.61 mg/dL) and WD (9.18±0.28 mg/dL) groups (p<0.01). These results indicate that a high-calorie, high-salt diet had a negative effect on bone metabolism. However, sprint interval training partially attenuated these adverse effects.

Abstract Hepatic gene expression of inflammatory and growth factors such as IL-8 and bFGF2 may be modulated in melanoma metastasis. Non-pharmacological interventions like exercise and anti-inflammatory supplements represent potential complementary strategies for modification. This study aimed to investigate the effects of aerobic exercise, pineapple extract supplementation, and their combination on the hepatic expression of CXCL2/IL-8 HOMOLOG and bFGF2 genes in a murine melanoma model. Melanoma-bearing mice were allocated into four groups (n=5 per group): Control, Aerobic Exercise, Pineapple Extract Supplement, and Aerobic Exercise+Pineapple Extract. After the intervention period, liver tissue was analyzed for CXCL2/IL-8 HOMOLOG and bFGF2 gene expression via one-way ANOVA and Tukey HSD test. Pearson correlation assessed the relationship between the two genes. A significant difference was observed in CXCL2/IL-8 HOMOLOG gene expression between groups (F=4.211, p=0.0239). Post hoc analysis revealed that only the combined Aerobic Exercise + Pineapple Extract group showed a significant decrease in hepatic CXCL2/IL-8 HOMOLOG compared to the Cancer Control group (p=0.0251). In contrast, no significant difference was found in bFGF2 gene expression across groups (F=1.425, p=0.2745). Correlation analysis indicated a significant negative relationship between CXCL2/IL-8 HOMOLOG and bFGF2 exclusively in the Cancer Control group (r=-0.948, p=0.013). The combination of aerobic exercise and pineapple extract supplementation significantly reduces hepatic CXCL2/IL-8 HOMOLOG expression in melanoma-bearing mice, suggesting a potential synergistic effect in modulating the hepatic inflammatory microenvironment. The distinct lack of effect on bFGF2 and the specific negative correlation in controls highlight pathway-selective responses.

Abstract Physical inactivity is a major global determinant of non-communicable diseases, particularly in industrial and occupational environments where structural and environmental barriers limit regular engagement in physical activity. Although the health benefits of aerobic exercise are well established, less attention has been given to the physiological specificity of exercise intensity and its translation into feasible health promotion strategies in real world settings. Current evidence indicates that moderate intensity running (approximately 50–70% heart rate reserve, 46–63% VO₂max, or Borg RPE 12–14) induces coordinated multisystem signaling responses that support metabolic regulation and inflammatory balance. These responses include favorable modulation of myokines, adipokines, neurotrophic factors, and immunoregulatory mediators involved in metabolic homeostasis. Particular attention is given to the context dependent role of interleukin 6, highlighting the distinction between its transient exercises induced signaling effects and the chronic elevations associated with metabolic and inflammatory diseases. In addition to mechanistic insights, this review discusses translational considerations such as adherence, safety, and long term sustainability of moderate intensity running programs in occupational populations. The HamGhadam (Step for Good) initiative implemented by Gol Gohar Mining and Industrial Company is presented as a descriptive workplace case example illustrating how structured physical activity programs can be incorporated into corporate wellness initiatives. The manuscript does not claim empirical validation of the program’s effectiveness but highlights its potential as a practical model for workplace health promotion. Overall, smart running is framed as a biologically efficient and potentially scalable strategy that conceptually bridges molecular exercise biology with population level physical activity promotion.

Abstract This study investigated the effects of high intensity interval training (HIIT), Nano-selenium supplementation, and their combination on the expression of LDHA, LDHB, and the LDHA/LDHB ratio in mice breast tumor tissue. Female mice (n=32) were inoculated with mammary adenocarcinoma cells (4T1) and randomly assigned to four groups (n=8 each): tumor control (Tu), tumor+HIIT (Tu+Ex), tumor + Nano-selenium (Tu+Nsel, 2 mg/kg/day orally), and tumor+HIIT+Nano-selenium (Tu+Ex+Nsel). HIIT was performed on a treadmill (30 min/day, 5 days/week) for four weeks. One-way ANOVA revealed significant differences among groups for LDHA expression (F=38.66, p<0.0001). Compared to the Tu group, all intervention groups (Tu+Ex,Tu+Nsel, and Tu+Ex+Nsel) showed a significant increase in LDHA expression (p<0.05). The greatest increase was observed in the combined treatment group (Tu+Ex+Nsel), which was significantly higher than both Tu+Ex and Tu+Nsel (p<0.001). For the LDHA/LDHB ratio, a significant overall effect was found (F=163.87, p<0.0001). The Tu+Nsel group exhibited a significant increase in the ratio compared to the Tu group (p<0.05), whereas both Tu+Ex and Tu+Ex+Nsel showed a significant decrease in the ratio (p<0.05). The ratio in the Tu+Nsel group was also significantly higher than in the two exercise containing groups (p<0.05). HIIT and Nano-selenium independently upregulate LDHA expression in breast tumor tissue, with an additive effect when combined. However, only Nano-selenium alone increased the LDHA/LDHB ratio, while exercise-based interventions (with or without Nano-selenium) decreased this ratio. These findings suggest that exercise and Nano-selenium differentially shift the balance between LDHA and LDHB, potentially influencing tumor lactate metabolism and the tumor microenvironment.

Abstract Dear Editor-in-Chief
As our field continues to map the intricate networks of exercise-induced organ crosstalk, the concept of "intelligent substrate utilization" remains a compelling yet incompletely understood frontier. While much focus has been placed on the acute actions of individual myokines and exerkines, a more integrated, systems-level perspective is emerging‒one that positions chronic exercise adaptation as the remodeling of an endocrine matrix. This matrix, I propose, governs a form of metabolic intelligence characterized by the dynamic, context-dependent allocation and utilization of energetic substrates across organs. Recent breakthroughs are beginning to decode the spatiotemporal logic of this system, moving beyond simple linear pathways to reveal complex networks that enable the body to adapt fuel metabolism with remarkable precision. Three key advances, in particular, illuminate new variables and pathways that underpin this intelligent substrate utilization.
First, the "Myokine-mediated Multi-organ Metabolic Network" theory provides a comprehensive framework for understanding how myokines act not in isolation but as a coordinated signaling hub. This work meticulously maps interactions from skeletal muscle to over a dozen organs, orchestrating programs across six biological axes, including energy substrate flux. Crucially, the framework highlights how myokines function as pleiotropic modulators within an integrated system, a property that fundamentally reshapes our view of substrate allocation. It suggests that the "intelligence" of the system lies not in any single molecule but in the emergent properties of this multi-target network (Chen et al., 2025). Second, a landmark systems genetics study, leveraging multi-tissue data from the MoTrPAC consortium, reveals that endurance training fundamentally remodels the entire
inter-organ endocrine network. This work demonstrates that the strength and specificity of endocrine signals between tissues are significantly altered with training. Notably, subcutaneous white adipose tissue (scWAT) emerged as a major endocrine hub, and extracellular matrix factors, along with secretory WNT signaling molecules, were identified as central mediators of training adaptations. These discoveries offer a crucial new variable‒the network-wide remodeling of endocrine crosstalk‒demonstrating that "intelligent" substrate use is a learned property of the whole system, not a pre-programmed one. The bidirectional and training-dependent plasticity of tissue-pair signaling adds a new layer of complexity to how we model metabolic control during exercise (Ahn et al., 2025).
Finally, the identification of novel metabolic signaling molecules, termed "metabokines" and "lipokines," expands the classic myokine paradigm to include bioactive metabolites and lipids as direct mediators of inter-organ signaling. These molecules are not mere energy sources but are sophisticated signals that coordinate systemic adaptations. This reframes substrate utilization itself as a mode of communication: the very act of metabolizing a substrate can generate a signal that informs and directs systemic metabolic priorities (Gad et al., 2024). These three insights‒the multi-organ myokine network, the training-induced remodeling of the endocrine matrix, and the signaling roles of metabolites‒converge to describe a system with genuine adaptive intelligence. Chronic exercise, through this lens, is not simply a stressor but an educational process for the body's metabolic network, teaching it to anticipate demands and allocate resources with greater efficiency and precision.
I write this letter to the Journal of Exercise and Organ Crosstalk because it stands at the ideal intersection to champion such a systems-level, integrative approach. Pursuing these ideas will require not only advanced multi-omics but also sophisticated computational modeling to predict network-level adaptive strategies. This is the central challenge for our field: to decode the syntax of exercise-induced communication.