Voluntary Wheel Running Research Articles

Physical activity mitigates serotonin and oxidative stress-associated mesenteric arterial endothelial dysfunction in obesity

Introduction: Serotonin (5-HT) signaling may play a role in modulating vascular endothelial function. Obesity-induced oxidative stress causes the development of cardiovascular disease (CVD). We aimed to investigate the protective effect of voluntary wheel running (EX) on serotonin receptor (5-HT1B) and oxidative stress in the mesenteric artery of obese mice. Methods: Mice were randomly divided into four groups. They were fed a control low-fat diet (LF) or high-fat diet (HF; 45% of calories from fat) and provided with voluntary wheel running (LF-EX or HF-EX) or a sedentary condition. The protein expressions of phosphorylated-endothelial nitric oxide synthase (p-eNOS), 5-HT1B receptor, Akt, and proteins regulating oxidative stress were quantified by Western blot analysis. Statistical comparisons between groups were performed with two-way ANOVA with Fisher’s LSD test. Results: The protein expressions of p-eNOS, 5-HT1B receptor, and p-Akt in HF were lower compared to LF, but EX increased the protein levels ( P < 0.05). NOX2 in HF was higher compared to LF, but EX decreased it ( P < 0.05). SOD1, SOD2, and UCP2 in HF were lower compared to LF, but EX increased the protein levels ( P < 0.05). There was no difference in expressions of Akt, Gαq/11, NOX4, and VDUP1 between groups. Conclusion: Voluntary wheel running improves e-NOS-mediated vascular endothelial function possibly via increased 5-HT1B receptors and reduced oxidative stress, which could mitigate the risk of obesity-induced CVD. This study was supported by grants from the Cardiovascular Research Foundation Asia (#16215 to Y. P.) and the University of Houston (Small Grant Program to Y. P.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exercise Mitigates Angiotensin II-Mediated Sympathetic Nerve-Macrophage Interaction in Aortic Adventitia Leading to Vascular Remodeling

Large artery stiffness is a significant risk factor for cardiovascular diseases. Our previous study suggested that angiotensin II (Ang II) stimulates sympathetic innervation in aortic adventitia (AA) leading to elevated mean arterial blood pressure and increased arterial fibrosis, while voluntary wheel-running (VWR) reduces them. The aim of this study is to explore mechanism under Ang II-induced the aortic remodeling through sympathetic nerves and immune cell interactions using transcriptomics. We isolated cells in AA from Ang II (1.5 mg/kg/day) vs. Vehicle (Saline) infused C57BL/6 male mice (n=3 of each group), and we performed single-cell RNA-sequencing (scRNAseq). We profiled 23,419 cells after quality control and filtering steps and annotated 9 cell types in the AA employing a uniform manifold approximation and projection (UMAP) to visualize the remaining cells and the Leiden cluster algorithm. Firstly, we identified the Adrb2 gene for β2-adrenergic receptor (β2-ADR) was predominantly expressed in macrophages/monocytes as compared to other cell types, and significantly more expressed in macrophages vs. monocytes (adjusted p-value, <0.05). We validated the transcriptomic results using immunostaining for β2-ADR and synapsin with CD68 in AA. In addition, Ang II increased AA macrophage proportion which displays M1 phenotype (pro-inflammatory) (adjusted p-value, <0.05). These findings suggest that Ang II promotes M1 like macrophages which interact with sympathetic nerves in AA. Next, we performed Gene Ontology (GO) enrichment test in macrophages and fibroblasts. Ang II Macrophages were enriched in GO terms with inflammation and cytokines, and Ang II fibroblasts were enriched in GO terms involved in extracellular matrix deposition. The GO results indicate that Ang II induced inflammatory macrophages activates fibroblasts to accumulate ECM deposition in AA. Congruent with the scRNAseq results, we found that number of macrophages, ECM accumulation, and vascular stiffness measured by pulse wave velocity were increased with Ang II vs. Vehicle (all, p <0.05), whereas interestingly VWR ameliorated the Ang II effects. This study provides the evidence that Ang II promotes aortic remodeling by interaction between sympathetic nerves and macrophage which results in ECM deposition in AA using transcriptomics approach, while VWR countermeasure to these detrimental effects. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Physical activity alleviates obesity-associated mesenteric arterial endothelial dysfunction: Role of adiponectin receptor

Introduction: A strong association between cardiovascular disease and obesity has been reported. However, the role of adiponectin in the effect of physical activity on mesenteric circulation and its underlying mechanism has been unknown. We investigated the protective effect of voluntary wheel running (EX) on endothelial function in the mesenteric artery of obese mice and its underlying mechanisms. Methods: C57BL/6J male mice were randomly divided into four groups: (1) control low-fat diet (LF), (2) LF diet with free access to a voluntary running wheel (LF-EX), (3) high-fat diet (HF; 45% of calories from fat), and (4) HF-EX. The protein expressions of total-endothelial nitric oxide synthase (t-eNOS), adiponectin receptors 1 and 2, AMPK, Ob (leptin), inflammatory markers, and proteins regulating apoptosis were quantified by Western blot analysis. Statistical comparisons between groups were performed with two-way ANOVA with Fisher’s LSD test. Results: The protein expressions of t-eNOS, adiponectin receptors 1 and 2, and p-AMPK in HF were lower compared to LF, but EX increased the protein levels ( P < 0.05). Ob in HF was higher compared to LF, but EX decreased it ( P < 0.05). IL-1β, TNF-α, and Caspase-1 in HF were higher compared to LF, but EX decreased the protein levels ( P < 0.05). There was no difference in expressions of AMPK, CHOP, Bcl-2, and GADD153 between groups. Conclusion: Voluntary wheel running alleviates e-NOS-mediated endothelial dysfunction in the mesenteric artery of obese mice possibly via increased adiponectin receptors and decreased inflammation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Alterations in sphingolipid synthesis during training, detraining, and retraining may alter myogenesis in skeletal muscle

The benefits of exercise on metabolic health and its effectiveness at reducing morbidity risk are well established. Exercise training enhances skeletal muscle metabolism and function, but whether such adaptations persist through detraining and how they are potentiated with retraining are not well understood. Recent evidence has highlighted the role sphingolipids play on skeletal muscle size and function, but how exercise affects sphingolipid metabolism is not yet known. We hypothesize that alterations in skeletal muscle sphingolipid metabolism with exercise training are necessary to enhance muscle mass with further exercise retraining. Here, mice were SEDentary (SED; static cages) or exercise-TRAINed (TRAIN; voluntary wheel running) and chow-fed. We performed body composition analysis (using EchoMRI) and skeletal muscle collection [tibialis anterior ( TA), extensor digitorum longus ( EDL), gastrocnemius ( Gas), Soleus ( Sol), plantaris ( Plant), and levator ani ( LA)] following training (4wks), detraining (8wk), and retraining (12wk) in three independent cohorts. Sphingolipid and myogenic gene expression was measured in TA muscle by qPCR. Exercise training concomitantly increased lean and decreased fat percentage ( p<0.05), while increasing Sol muscle mass in TRAIN mice ( p<0.05), compared to SED. This was accompanied by higher sphingolipid metabolism ( Acer1, p<0.05; and Cers1, p=0.058) and myogenic gene expression ( MyoD, Myf5; p<0.05). Following detraining, TRAIN mice had an overall increase in lean-to-fat mass ( p<0.05) while maintaining all individual muscle masses ( p<0.05), compared to SED. This was accompanied by a reduction in gene expression of the sphingolipid receptor S1pr1 and myogenic factor Myf5 ( p<0.05), but no differences in sphingolipid metabolism ( Acer1, Cers1). Lastly, retraining increased lean and decreased fat percentage ( p<0.05) and enhanced the masses of TA, Gas, Sol, and Plant muscles in TRAIN mice ( p<0.05), compared to SED. This was accompanied by a reduced expression of rate limiting sphingolipid synthesis genes Sptlc1 and Sptlc2 and the kinase Sphk1 ( p<0.05), but no differences in Cers1 or myogenic gene expression in TRAIN mice, compared to SED. Overall, our data shows that exercise training and retraining potentiate muscle mass accretion and dynamically regulates sphingolipid metabolism adaptations. These data suggest a potential role for sphingolipids to modulate long-lasting improvements to skeletal muscle. Funding was provided by the University of Illinois Urbana-Champaign. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 2037: Investigating Changes In Satellite Cell Proliferation And Angiogenic Potential In Response To Exercise

Background: Peripheral Artery Disease (PAD) is an atherosclerotic process leading to vessel obstruction. Supervised walking exercise is a first-line treatment to improve walking ability and quality of life scores of patients. Despite its known benefits, the underlying mechanism is not fully understood. Thus, this study focuses on satellite cells (SCs), known for their role in muscular regeneration but also found to have an under investigated role as mediators of vascular growth through the secretion of cytokines and growth factors. Previous in vivo models have demonstrated increased migration of endothelial cells and smooth muscle cells, as well as blood vessel growth in response to SC activity. Aims: The project aims to enhance the efficacy of exercise therapy through a better understanding satellite cell biology and their pro-vasculogenic ability. Hypothesis: Exercise therapy will enhance SCs proliferation and secretion of paracrine growth factors inducing increased cell migration and vascular growth. Methods: Aortic Ring Assay: Murine thoracic aortic sections were embedded in a Type I collagen matrix in 96-wells. The wells were seeded with Opti-MEM (control), Opti-MEM+0.3% Vascular Endothelial Growth Factors (VEGF)(+ control), SC Conditioned Media (CM) (24hr incubation, 2M cells/plate), or denatured CM (56°C, 1 hr). The total length and number of branches were measured via ImageJ. Flow Cytometry: 18+ months old C57BL/6 were housed with voluntary running wheels with activity counter until day 28. Satellite cells were mechanically and chemically digested and were labeled as: CD11b-, CD45-, CD31-, Sca1-, and α7-integrin+ at 7-day intervals. Results: Aortic Ring Assay: SC CM showed significantly higher total branch length (13381.89±2470.44μm, n=6) (****p<0.0001) and numbers (19.24±3.87, n=6) (**p<0.01) compared to control (2158.18±382.31μm, n=9), (5.76±0.81, n=9). Flow Cytometry: SC proportion on day 21 (2.55±0.14,n=2) was significantly higher than control (1.54±0.298,n=8)(*p<0.05). Conclusion(s): These findings indicate that SC CM induces angiogenesis by secreting pro-angiogenic factors. The angiogenic activities could potentially be heightened through the proliferation of SCs under exercise therapy.

High-intensity exercise training using a rotarod instrument (RotaHIIT)significantly improves exercise capacity in mice.

Voluntary or forced exercise training in mice is used to assess functional capacity as well as potential disease-modifying effects of exercise over a range of cardiovascular disease phenotypes. Compared to voluntary wheel running, forced exercise training enables precise control of exercise workload and volume, and results in superior changes in cardiovascular performance. However, the use of a shock grid with treadmill-based training is associated with stress and risk of injury, and declining compliance with longer periods of training time for many mouse strains. With these limitations in mind, we designed a novel, high-intensity interval training modality (HIIT) for mice that is carried out on a rotarod. Abbreviated as RotaHIIT, this protocol establishes interval workload intensities that are not time or resource intensive, maintains excellent training compliance over time, and results in improved exercise capacity independent of sex when measured by treadmill graded exercise testing (GXT) and rotarod specific acceleration and endurance testing. This protocol may therefore be useful and easily implemented for a broad range of research investigations. As RotaHIIT training was not associated cardiac structural or functional changes, or changes in oxidative capacity in cardiac or skeletal muscle tissue, further studies will be needed to define the physiological adaptations and molecular transducers that are driving the training effect of this exercise modality.

Impact of exercise on uncoupling protein 1 and macrophage phenotype in mesenteric adipose tissue in an animal model of endometriosis

Endometriosis is a gynecological disorder characterized by growth of endometrial tissue outside the uterine cavity, with symptoms which may include chronic pelvic pain and infertility resulting in a decreased quality of life. Previous studies in our laboratory demonstrated that endometriosis animals have increased mesenteric adipose tissue (MAT), inflammation, and growth of implanted endometrial vesicles which are decreased by voluntary exercise. The levels of Uncoupling Protein 1 (UCP-1), a mitochondrial protein, are known to be increased by exercise in rodents, promoting thermogenesis and decreasing inflammation. Exercise can also increase expression of peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily. When activated PPARγ polarizes the macrophages into an anti-inflammatory M2 state, which can stimulate white adipose tissue beiging. We hypothesized that voluntary wheel running exercise can increase UCP-1 and M2 macrophages, decreasing MAT and endometrial vesicle size. Aim: To assess the impact of voluntary exercise on UCP-1 expression and macrophage phenotype in MAT of an animal model of endometriosis. Methods: Endometriosis was induced by implanting uterine tissue on the intestinal mesentery of female Sprague Dawley rats while control group only received sutures (SHAM). Exercise rats had access to a running wheel after surgery (ENDO-EX or SHAM-EX), while non-exercised animals didn’t (ENDO and SHAM; n=10-11/group). After sixty days, animals were sacrificed, and MAT was collected to determine CD68, UCP-1 and PPARγ expression by immunofluorescence staining. Results: Vesicles from ENDO-EX animals exhibited significantly decreased average weight (p<0.01) and smaller average total area (p<0.01) compared with the ENDO group. Endometriosis animals showed increased mesenteric adipose tissue when compared to sham group (p<0.01), which was reduced by voluntary exercise (p<0.001). Macrophage infiltration, UCP-1 and PPARγ expression increased with exercise. Conclusions: Increased UCP-1 and anti-inflammatory M2 macrophages following exercise may result in browning of MAT which can have a role in reducing the development of vesicles in the endometriosis model. These findings suggest that exercise may be a potential complementary therapeutic strategy for managing endometriosis symptoms. This work was supported by R15AT009915, R16GM149365, T32GM144896, PRI MD Summer Program and Porter Physiology Development Fellowship. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Meta Analysis of Whole-Body and Heart Mass Effect Sizes From a Long-Term Artificial Selection Experiment for High Voluntary Exercise

Effect sizes are a quantitative measure of the magnitude and direction of a phenomenon. These estimates can be compiled across multiple studies to summarize the weight of evidence for a particular alternative hypothesis, which is generally termed a meta-analysis. A meta-analytic approach allows one to summarize information from a wide array of similar studies and reach conclusions that may not be apparent on a case-by-case basis (e.g., to determine the overall effectiveness of a drug). Meta-analyses may be particularly useful in selection experiments, where the magnitude of a correlated response is necessarily expected to increase across generations, perhaps eventually reaching a plateau. Here, we examined the effect of artificial selection for high voluntary wheel running on heart mass in mice, which was expected to increase with selection for aerobic exercise behavior. The experiment spans nearly 30 years and 100 generations. All 4 of the replicate High Runner (HR) lines reached selection limits around generations 17-27, running approximately 2.5-3-fold more revolutions per day than the 4 non-selected Control (C) lines. These selection limits cannot be explained simply by a complete loss of heritability. Functional studies have tried to elucidate subordinate traits that affect motivational and/or ability for endurance exercise and have shown that HR mice differ from C in several other behavioral, physiological, and morphological traits. Several studies of heart ventricle mass have reported larger values in HR mice (with body mass as a covariate), but the differences often do not reach statistical significance (p<0.05). We compiled Least-Square Means, standard errors, F-statistics, degrees of freedom, and p-values from multiple studies. We also recorded pertinent information, such as: covariates used, age, generation, and whether other main effects were present (e.g., sex, wheel access). We calculated a common measure of effect size (Pearson’s R) and associated confidence intervals. This work is part of a larger meta-analysis to quantify effects of selection on various traits across multiple levels of biological organization. Preliminary results indicate that, despite a lack of statistical significance in many generations, HR mice have evolved larger hearts and smaller bodies relative to Controls. Moreover, a plateau in effect sizes for both of these traits coincide with the generational range during which the selection limit for wheel-running behavior was reached. NSF IOS-2038528. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Late-life aerobic exercise reverses DNA damage and telomere dysfunction in non-atheroprone aortic regions with advanced age

Cellular senescence, a state of cell cycle arrest, contributes to arterial aging. The dominant factor driving cellular senescence is DNA damage. Moreover, telomeres, a repeated DNA sequence at the end of chromosomes, are especially vulnerable to DNA damage induced by DNA-damaging stimuli such as atheroprone shear stress. Although the adoption of aerobic exercise in later life is an effective strategy to mitigate arterial aging, its direct relationship with DNA damage and telomere dysfunction has yet to be elucidated. Additionally, the impact of late-life aerobic exercise, particularly in regions exposed to atheroprone and non-atheroprone shear stress, may not yield uniform benefits, requiring further exploration. We sought to investigate the effects of late-life aerobic exercise on DNA damage and telomere dysfunction in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in aortic regions exposed to distinct shear stress patterns such as the major aortic arch, minor aortic arch, and thoracic aorta. Fifteen male C57BL6 (22-23 mo) were given access to voluntary running wheel (VWR) for 4 weeks. They were classified as high-running (HR), moderate-running (MR), and low-running (LR) groups based on their habitual VWR distances (n=5 per group). Habitual VWR distance was greater in HR and MR compared to LR (75.9±11.2 and 21.3±1.6 vs. 5.8±2 m/day; P≤0.0003). Maximal treadmill running distance improved in HR, did not change in MR, and diminished in the LR (HR, MR vs. LR; P≤0.035) and was correlated to habitual VWR distance at 1-month post-intervention (R2=0.252, P=0.056). Immunofluorescence-fluorescent in situ hybridization was performed to detect the abundance of 53BP1 foci, a marker of DNA damage, and colocalization to telomeres, a measure of telomere-specific DNA damage known as telomere dysfunction-induced foci (TIF). The percentage of ECs containing 53BP1 foci and TIF was lower in the non-atheroprone aortic regions, i.e. major aortic arch and thoracic aorta, of HR compared to LR (P≤0.002), but there was no difference in the atheroprone, i.e. minor aortic arch (P≥0.899). A strong to moderate correlation was observed between 53BP1 foci and habitual VWR distance in major aortic arch and thoracic aorta (R2=0.584 and R2=0.54, P≤0.002) but only between VWR and TIF in the thoracic aorta (R2=0.356, P=0.019). The 53BP1 foci and TIF in VSMCs were comparable across groups in all aortic regions (P≥0.102). Likewise, Telomere length in ECs and VSMCs were similar across groups regardless of aortic region (P≥0.296). In conclusion, our findings suggest that increased level of habitual aerobic exercise in later life has a beneficial impact on DNA damage and telomere dysfunction in ECs, particularly in aortic regions exposed to extended periods of non-atheroprone shear stress. Notably, the volume of aerobic exercise was inversely associated with DNA damage and telomere dysfunction. These effects were independent of telomere length. The improvement in DNA damage and telomere dysfunction associated with habitual aerobic exercise were specific to ECs, as VSMCs remained unaffected in all aortic regions and results were independent of telomere length. Funded in part by awards from National Institutes of Health Awards R01 AG060395, R01 AG077751, R01 AG076748, T32 HL007576, T32 HL139451, Veteran's Affairs Merit Review Award I01 BX004492 and Nora Eccles Treadwell Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Voluntary wheel running reduces tumor growth and increases capillarity in the heart during doxorubicin chemotherapy in a murine model of breast cancer.

Introduction: The possible beneficial effects of physical activity during doxorubicin treatment of breast cancer need further investigation as many of the existing studies have been done on non-tumor-bearing models. Therefore, in this study, we aim to assess whether short-term voluntary wheel-running exercise during doxorubicin treatment of breast cancer-bearing mice could induce beneficial cardiac effects and enhance chemotherapy efficacy. Methods: Murine breast cancer I3TC cells were inoculated subcutaneously to the flank of female FVB mice (n = 16) that were divided into exercised and non-exercised groups. Two weeks later, doxorubicin treatment was started via intraperitoneal administration (5mg/kg weekly for 3weeks). Organs were harvested a day after the last dose. Results: The tumor volume over time was significantly different between the groups, with the exercising group having lower tumor volumes. The exercised group had increased body weight gain, tumor apoptosis, capillaries per cardiomyocytes, and cardiac lactate dehydrogenase activity compared to the unexercised group, but tumor blood vessel density and maturation and tumor and cardiac HIF1-α and VEGF-A levels did not differ from those of the non-exercised group. Discussion: We conclude that even short-term light exercise such as voluntary wheel running exercise can decrease the subcutaneous mammary tumor growth, possibly via increased tumor apoptosis. The increase in cardiac capillaries per cardiomyocytes may also have positive effects on cancer treatment outcomes.

Osterix-driven LINC complex disruption in vivo diminishes osteogenesis at 8 weeksbut not at 15 weeks.

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is a crucial connective component between the nuclear envelope and the cytoskeleton involving various cellular processes including nuclear positioning, nuclear architecture, and mechanotransduction. How LINC complexes regulate bone formation in vivo, however, is not well understood. To start bridging this gap, here we created a LINC disruption murine model using transgenic mice expressing Cre recombinase enzyme under the control of the Osterix (Osx-Cre) which is primarily active in pre-osteoblasts and floxed Tg(CAG-LacZ/EGFP-KASH2) mice. Tg(CAG-LacZ/EGFP-KASH2) mice contain a lox-STOP-lox flanked LacZ gene which is deleted upon cre recombination allowing for the overexpression of an EGFP-KASH2 fusion protein. This overexpressed protein disrupts endogenous Nesprin-Sun binding leading to disruption of LINC complexes. Thus, crossing these two lines results in an Osx- driven LINC disruption (ODLD) specific to pre-osteoblasts. In this study, we investigated how this LINC disruption affects exercise-induced bone accrual. ODLD cells had decreased osteogenic and adipogenic potential in vitro compared to non-disrupted controls and sedentary ODLD mice showed decreased bone quality at 8 weeks. Upon access to a voluntary running wheel,ODLD animals showed increased running time and distance; however, our 6-week exercise intervention did not significantly affect bone microarchitecture and bone mechanical properties.

Voluntary Wheel Running Reduces Cardiometabolic Risks in Female Offspring Exposed to Lifelong High-Fat, High-Sucrose Diet.

Maternal and postnatal overnutrition has been linked to an increased risk of cardiometabolic diseases in offspring. This study investigated the impact of adult-onset voluntary wheel running to counteract cardiometabolic risks in female offspring exposed to a life-long high-fat, high-sucrose (HFHS) diet. Dams were fed either an HFHS or a low-fat, low-sucrose (LFLS) diet starting from 8 wk before pregnancy and continuing throughout gestation and lactation. Offspring followed their mothers' diets. At 15 wk of age, they were divided into sedentary (Sed) or voluntary wheel running (Ex) groups, resulting in four groups: LFLS/Sed ( n = 10), LFLS/Ex ( n = 5), HFHS/Sed ( n = 6), HFHS/Ex ( n = 5). Cardiac function was assessed at 25 wk, with tissue collection at 26 wk for mitochondrial respiratory function and protein analysis. Data were analyzed using two-way ANOVA. Although maternal HFHS diet did not affect the offspring's body weight at weaning, continuous HFHS feeding postweaning resulted in increased body weight and adiposity, irrespective of the exercise regimen. HFHS/Sed offspring showed increased left ventricular wall thickness and elevated expression of enzymes involved in fatty acid transport (CD36, FABP3), lipogenesis (DGAT), glucose transport (GLUT4), oxidative stress (protein carbonyls, nitrotyrosine), and early senescence markers (p16, p21). Their cardiac mitochondria displayed lower oxidative phosphorylation (OXPHOS) efficiency and reduced expression of OXPHOS complexes and fatty acid metabolism enzymes (ACSL5, CPT1B). However, HFHS/Ex offspring mitigated these effects, aligning more with LFLS/Sed offspring. Adult-onset voluntary wheel running effectively counteracts the detrimental cardiac effects of a lifelong HFHS diet, improving mitochondrial efficiency, reducing oxidative stress, and preventing early senescence. This underscores the significant role of physical activity in mitigating diet-induced cardiometabolic risks.

Swimming Exercise Protocol and Care Methods for Pregnant Rats.

The developmental origins of health and disease concept highlights the impact of early environments on chronic non-communicable diseases like diabetes, cardiovascular disease, and cancer. Studies using animal models have investigated how maternal factors such as undernutrition, overnutrition, obesity, and exposure to chemicals or hypoxia affect fetal development and offspring health, leading to issues like low birth weight, high blood pressure, dyslipidemia, and insulin resistance. Given the increasing prevalence of overweight and obesity among reproductive-age women, effective interventions are critical. Maternal exercise during pregnancy has emerged as a key intervention, benefiting both mother and offspring and reducing the risk of disease. This study compares the differences of three exercise models on pregnant rats: voluntary wheel running, motorized treadmills, and swimming. Swimming is the most beneficial option due to its safe and controlled intensity levels. This protocol details the rat breeding methods, swimming training during pregnancy, and post-breeding nursing protocols. This model, suitable for various rat and mouse species, is useful for studying the benefits of maternal exercise on offspring health and intergenerational wellness.

Voluntary exercise preserves visual function and reduces inflammatory response in an adult mouse model of autosomal dominant retinitis pigmentosa

Whole-body physical exercise has been shown to promote retinal structure and function preservation in animal models of retinal degeneration. It is currently unknown how exercise modulates retinal inflammatory responses. In this study, we investigated cytokine alterations associated with retinal neuroprotection induced by voluntary running wheel exercise in a retinal degeneration mouse model of class B1 autosomal dominant retinitis pigmentosa, I307N Rho. I307N Rho mice undergo rod photoreceptor degeneration when exposed to bright light (induced). Our data show, active induced mice exhibited significant preservation of retinal and visual function compared to inactive induced mice after 4 weeks of exercise. Retinal cytokine expression revealed significant reductions of proinflammatory chemokines, keratinocyte-derived chemokine (KC) and interferon gamma inducible protein-10 (IP-10) expression in active groups compared to inactive groups. Through immunofluorescence, we found KC and IP-10 labeling localized to retinal vasculature marker, collagen IV. These data show that whole-body exercise lowers specific retinal cytokine expression associated with retinal vasculature. Future studies should determine whether suppression of inflammatory responses is requisite for exercise-induced retinal protection.

Preexposure to running attenuates rats' running-based flavour avoidance: Testing associative blocking with a cover cues or context change.

Voluntary running in activity wheels by rats leads to a Pavlovian conditioned aversion to the flavour consumed immediately before the running, causing the rats to avoid that flavour. This learning process, known as running-based flavour avoidance learning (FAL), is weakened when the rats have had repeated exposure to the wheels before. According to the associative account, the association between the background context and running established during the preexposure phase blocks the conditioning of the target flavour because the running is highly predictable by the background context from the outset of the FAL phase. Experiments 1 and 2 examined this account by introducing another flavour as a cue signalling wheel access during the preexposure phase. In the framework of the associative account, the introduction of this cue should impede the formation of the context-running association during the preexposure phase, thereby hindering the contextual blocking of aversive conditioning for the target flavour in the FAL phase. This would result in unweakened FAL. Although the results of Experiment 1 align with this prediction, in Experiment 2, when highly distinct flavours were used as the target and second cues, the preexposure effect was not eliminated. This contradicts the predictions of the associative account, indicating that Experiment 1 may have been influenced by stimulus generalisation. In Experiment 3, changing background contexts between the preexposure and FAL phases had no impact on the preexposure effect, contrary to the predictions of the associative account. In general, the associative account was not supported.

Endurance exercise preserves physical function in adult and older male C57BL/6 mice: high intensity interval training (HIIT) versus voluntary wheel running (VWR).

Exercise has been shown to improve physical function, mitigate aspects of chronic disease and to potentially alter the trajectory of age-related onset of frailty and sarcopenia. Reliable and valid preclinical models are necessary to elucidate the underlying mechanisms at the intersection of age, exercise, and functional decline. The purpose of this study was to compare, head to head, the effects of two common pre-clinical models of endurance exercise: high intensity interval training (HIIT) and voluntary wheel running (VWR). The hypothesis was that a prescribed and regimented exercise program, HIIT, would prove to be a superior training method to unregulated voluntary exercise, VWR. To investigate this hypothesis, we evaluated adult (n = 24, designated 10m, aged 6 months at the beginning of the study, 10 months at its completion) and older adult (n = 18, designated 26m, aging from 22 months to 26 months over the course of the study) C57BL/6 male mice. These mice were randomly assigned (with selection criteria) to a 13-week program of voluntary wheel running (VWR), high intensity interval training (HIIT), or sedentary control (SED). The functional aptitude of each mouse was determined pre- and post-training using our composite CFAB (comprehensive functional assessment battery) scoring system consisting of voluntary wheel running (volitional exercise and activity rate), treadmill (endurance), rotarod (overall motor function), grip meter (forelimb strength), and inverted cling (whole body strength/endurance). To measure sarcopenia, we tracked body mass, body composition (with EchoMRI), plantar flexor torque (in 10m), and measured muscle wet mass post-training. Overall, adult CFAB scores decreased while body mass and percent body fat increased as they matured; however, exercise significantly mitigated the changes (p < 0.05) compared to SED. Older adults demonstrated preservation of function (CFAB) and reduced body fat (p < 0.05) compared to SED. To conclude, both types of exercise maintained physical function equally in older mice.

Enhancement of motor functional recovery in thoracic spinal cord injury: voluntary wheel running versus forced treadmill exercise.

JOURNAL/nrgr/04.03/01300535-202503000-00028/figure1/v/2024-06-17T092413Z/r/image-tiff Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group (10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury.

Exploring the role of adipokines in exercise-induced inhibition of tumor growth

The integration of exercise prescriptions into cancer adjuvant therapy presents challenges stemming from the ambiguity surrounding the precise mechanism through which exercise intervention mitigates the risk of hepatocellular carcinoma (HCC) mortality and recurrence. Elucidation of this specific mechanism has substantial social and clinical implications. In this study, tumor-bearing mice engaged in voluntary wheel running exhibited a notable decrease in tumor growth, exceeding 30%. Microarray analysis revealed an upregulation of cytokine-related pathways as a potential explanation for this effect. The inclusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to enhance tumor cell proliferation, while the absence of GM-CSF resulted in a marked inhibition of tumor cell growth. The findings suggest that exercise-induced serum from mice can impede the proliferation of mouse tumor cells, with the adipokine chemerin inhibiting the growth factor GM-CSF. Additionally, exercise was found to stimulate chemerin secretion by brown adipose tissue. Chemerin suppression led to a reduction in the inhibition of tumor cell proliferation. The results of this study suggest that exercise may stimulate the release of adipokines from brown adipose tissue, transport them through the blood to the distant tumor microenvironment, and downregulate GM-CSF expression, alleviating tumor immunosuppression in the tumor microenvironment, thereby inhibiting at HCC progression. These findings provide a theoretical basis for incorporating exercise prescription into cancer treatment.

The sinking platform test: a novel paradigm to measure persistence in animal models.

Persistence is the propensity to maintain goal-directed actions despite adversities. While this temperamental trait is crucial to mitigate depression risk, its neurobiological foundations remain elusive. Developing behavioral tasks to capture persistence in animal models is crucial for understanding its molecular underpinnings. Here, we introduce the Sinking Platform Test (SPT), a novel high-throughput paradigm to measure persistence. Mice were trained to exit a water-filled tank by ascending onto a platform above water level. Throughout the training, mice were also occasionally exposed to "failure trials," during which an operator would submerge a platform right after the mouse climbed onto it, requiring the mouse to reach and ascend a newly introduced platform. Following training, mice were subjected to a 5-min test exclusively consisting of failure trials. Male and female mice exhibited comparable persistence, measured by the number of climbed platforms during the test. Furthermore, this index was increased by chronic administration of fluoxetine or imipramine; conversely, it was reduced by acute and chronic haloperidol. Notably, six weeks of social isolation reduced SPT performance, and this effect was rescued by imipramine treatment over the last two weeks. A 4-week regimen of voluntary wheel running also improved persistence in socially isolated mice. Finally, comparing transcriptomic profiles of the prefrontal cortex of mice with high and low SPT performance revealed significant enrichment of immediate-early genes known to shape susceptibility for chronic stress. These findings highlight the potential of SPT as a promising method to uncover the biological mechanisms of persistence and evaluate novel interventions to enhance this response.

Exercise mitigates flow recirculation and activates metabolic transducer SCD1 to catalyze vascular protective metabolites.

Exercise promotes pulsatile shear stress in the arterial circulation and ameliorates cardiometabolic diseases. However, exercise-mediated metabolic transducers for vascular protection remain under-investigated. Untargeted metabolomic analysis demonstrated that wild-type mice undergoing voluntary wheel running exercise expressed increased endothelial stearoyl-CoA desaturase 1 (SCD1) that catalyzes anti-inflammatory lipid metabolites, namely, oleic (OA) and palmitoleic acids (PA), to mitigate NF-κB-mediated inflammatory responses. In silico analysis revealed that exercise augmented time-averaged wall shear stress but mitigated flow recirculation and oscillatory shear index in the lesser curvature of the mouse aortic arch. Following exercise, endothelial Scd1-deleted mice (Ldlr-/- Scd1EC-/-) on high-fat diet developed persistent VCAM1-positive endothelium in the lesser curvature and the descending aorta, whereas SCD1 overexpression via adenovirus transfection mitigated endoplasmic reticulum stress and inflammatory biomarkers. Single-cell transcriptomics of the aorta identified Scd1-positive and Vcam1-negative endothelial subclusters interacting with other candidate genes. Thus, exercise mitigates flow recirculation and activates endothelial SCD1 to catalyze OA and PA for vascular endothelial protection.