Effects Of Voluntary Wheel Running Research Articles

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.

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.

Voluntary wheel running access produces opposite effects in male and female rats on both palatable diet consumption and associated ventral striatal opioid- and dopamine-related gene expression.

The relationship between physical activity levels and feeding behaviors has been a focus of preclinical research for decades, yet this interaction has only recently been explored for potential sex differences. The aim of the present study was to isolate sex-dependent effects of voluntary wheel running (RUN) vs. sedentary locked wheel (SED) home cage conditions on palatability-driven feeding behavior using a 2-diet choice task between standard chow and a high-fat diet. The sex-dependent effects of physical activity on feeding behavior were examined following a within-subject novel reversal design of physical activity conditions (i.e., RUN > SED > RUN), to assess temporal sensitivity of the interaction. Following the final 2 weeks of reestablished and sustained RUN vs. SED conditions in separate groups of both males and females, reward-related opioid and dopamine gene expression within the nucleus accumbens (Acb) brain region were analyzed. Results demonstrated that the initial RUN > SED transition led to sex-dependent effects of SED condition, as males increased, and females decreased their high fat consumption, compared to their respective high fat consumption during previous RUN condition phase. Following reintroduction to the RUN condition, males decreased, and females increased their high fat consumption, compared to their separate SED control group. Last, sex-dependent shifts in ventral striatal opioid- and dopamine-related gene expression were observed to parallel the behavioral effects. The major findings of the study reveal that SED and RUN home cage conditions shift palatability-driven feeding in the opposite direction for males and females, these effects are sensitive to reversal, and these sex-dependent feeding behaviors track sex-dependent changes to critical reward-related gene expression patterns in the Acb. Considering the present high rates of sedentary behavior and obesity, furthering our understanding of the interaction between physical activity (or lack thereof) and feeding behavior should be a priority, especially in the context of these divergent sex-dependent outcomes.

Sex-specific effects of voluntary wheel running on behavior and the gut microbiota-immune-brain axis in mice

Physical exercise has been positioned as a promising strategy to prevent and/or alleviate anxiety and depression, but the biological processes associated with its effects on mental health have yet to be entirely determined. Although the prevalence of depression and anxiety in women is about twice that of men, very few studies have examined whether physical exercise could affect mental health differently according to sex. This study examined, in singly-housed mice, the sex-specific effects of voluntary exercise on depressive- and anxiety-like behaviors as well as on different markers along the gut microbiota-immune-brain axis. Male and female C57BL/6N mice had voluntary access to running wheels in their home-cages for 24 days or were left undisturbed in identical home-cages without running wheels. Behaviors were then examined in the open field, splash, elevated plus maze, and tail suspension tests. Gene expression of pro-inflammatory cytokines, microglia activation-related genes, and tight junction proteins was determined in the jejunum and the hippocampus, while microbiota composition and predicted function were verified in cecum contents. Voluntary exercise reduced anxiety-like behaviors and altered grooming patterns in males exclusively. Although the exercise intervention resulted in changes to brain inflammatory activity and to cecal microbiota composition and inferred function in both sexes, reductions in the jejunal expression of pro-inflammatory markers were observed in females only. These findings support the view that voluntary exercise, even when performed during a short period, is beneficial for mental and intestinal health and that its sex-specific effects on behavior could be, at least in part, related to some components of the gut microbiota-immune-brain axis.

Sex-Dependent Effects Of Voluntary Wheel Running On Hindpaw Sensitivity And Bilateral Hippocampal Methylation In Mice Exposed To Early Life Stress

Sex-Dependent Effects Of Voluntary Wheel Running On Hindpaw Sensitivity And Bilateral Hippocampal Methylation In Mice Exposed To Early Life Stress

Effect of voluntary wheel running on autophagy status in lung tissue of high-fat diet-fed rats

Here, we aimed to explore the therapeutic effect of voluntary wheel running (VWR) in high-fat diet-fed rats on pulmonary tissue injury via the modulation of autophagic response. Thirty-two rats were allocated into four groups; normal diet (Control); VWR; high-fat-diet (HFD), and HFD + VWR. After three months, pathological effect of HFD on pulmonary tissue was investigated. The levels of tumour necrosis factor (TNF)-α were detected in the bronchoalveolar lavage fluid (BALF). We monitored the expression of interleukin (IL)-6 and autophagy-related genes in lung tissues. H&E staining showed pathological changes in HFD group coincided with the increase of TNF-α levels in the bronchoalveolar fluid compared to the normal rats. Our results showed the up-regulation of IL-6, becline-1, LC3 and P62 in the HFD group compared to the Control group. VWR inhibited HFD-induced changes and could decrease HFD-induced changes via the regulation of autophagy status.

Genotype determining aerobic exercise capacity associates with behavioral plasticity in middle-aged rats

Good aerobic fitness associates positively with cognitive performance and brain health and conversely, low aerobic fitness predisposes to neurodegenerative diseases. To study how genotype together with exercise, started at older age, affects brain and behavior, we utilized rats that differ in inherited aerobic fitness. Rats bred for Low Capacity for Running (LCR) are shown to display less synaptic plasticity and more inflammation in the hippocampus and perform worse than rats bred for a High Capacity for Running (HCR) in tasks requiring flexible cognition. Here we used middle-aged (∼ 16 months) HCR and LCR rats to study how genotype and sex associate with anxiety and neural information filtering, termed sensory gating. Further, we assessed how inherited aerobic capacity associates with hippocampus-dependent learning, measured with contextual fear conditioning task. In females, we also investigated the effects of voluntary wheel running (5 weeks) on these characteristics. Our results indicate that independent of sex or voluntary running, HCR rats were more anxious in open-field tasks, exhibited lower sensory gating and learned more efficiently in contextual fear conditioning task than LCR rats. Voluntary running did not markedly affect innate behavior but slightly decreased the differences between female LCR and HCR rats in fear learning. In conclusion, inherited fitness seems to determine cognitive and behavioral traits independent of sex. Although the traits proved to be rather resistant to change at adult age, learning was slightly improved following exercise in LCR females, prone to obesity and poor fitness.

Characterizing the Effects of Voluntary Wheel Running on Cardiac SERCA Function in Ovariectomized Mice

The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) actively transports Ca2+ into the sarcoplasmic reticulum to facilitate cardiac muscle relaxation. Phospholamban (PLN) allosterically inhibits SERCA, and an imbalance of SERCA2a, dominant cardiac isoform, and PLN content disrupts Ca2+ homeostasis and cardiac contractility. A previous study has shown that ovariectomized (OVX) rats have reduced SERCA activity due to lowered SERCA2a and increased PLN content. Furthermore, it was found that forced treadmill running in OVX rats restored SERCA activity and protein content levels. Here, we investigated whether voluntary wheel running (VWR) would produce similar effects on cardiac SERCA function in OVX mice. Female mice were divided into the following groups for 8 weeks: SHAM; OVX; SHAM + VWR; and OVX + VWR (n = 10/group). SERCA activity and Ca2+ uptake assays were performed in cardiac muscle homogenates. Protein levels of SERCA2, PLN, and pPLN were determined via Western blot analysis. We found statistical interactions for Ca2+ uptake, maximal SERCA activity, and SERCA2a content where VWR increased these parameters in SHAM mice but not in OVX mice. We detected a main effect of OVX on PLN content, and main effects of OVX and VWR on pPLN content. The OVX mice ran significantly less than the SHAM mice, suggesting that estrogen deprivation and lack of regular exercise may blunt the effects of voluntary aerobic exercise on cardiac SERCA function.

Trimethylamine N-oxide aggravated cognitive impairment from APP/PS1 mice and protective roles of voluntary exercise

To determine whether trimethylamine N-oxide (TMAO) would aggravate cognitive dysfunction from APP/PS1 mice and the potential protective effects of voluntary wheel running (VWR). TMAO impaired learning and memory abilities, and exercise reversed TMAO induced cognitive impairment. Serum TMAO, choline, betaine and TMA were significantly elevated from TMAO group, while exercise group had decreased TMAO, betaine and TMA level. TMAO group has significantly upregulated BACE1 from both hippocampus and cortex, also increased cathepsin B, p-Tau at Ser396&Ser404, GFAP, p-NF-κB p65 in cortex, while reduced BDNF, synaptophysin and PSD95 in hippocampus, also reduced occludin and ZO-1 from cortex, and reduced occludin from colon. In contrast, BACE1 from both hippocampus and cortex, also cathepsin B and p-Tauser396 from cortex were reduced, BDNF, snaptophysin, and PSD95 from hippocampus, ZO-1 from cortex, and occludin from colon were elevated post exercise compared to TMAO group. Exercise elevated α diversity index of cecal content, and TMAO and exercise affected gut microbiota profiles differentially. In conclusion, TMAO led to gut microbiota dysbiosis, impaired gut-brain integrity, elevated neuroinflammation, Aβ pathology and tau phosphorylation, disordered synaptic function; and exercise could reverse TMAO induced cognitive dysfunction via improving the above markers. The potential deleterious effects of TMAO on cognitive function need to be validated in humans, also dosages of exercise for exerting neuroprotective effects against TMAO induced cognitive impairment.

Exercise on Striatal Dopamine Level and Anxiety-Like Behavior in Male Rats after 2-VO Cerebral Ischemia.

The purpose of this study was to discuss the effect of voluntary wheel running on striatal dopamine levels and anxiety-like behavior in rats with global cerebral ischemia. The male Sprague-Dawley rats were signed on in this study and randomly divided into following 4 groups: Control group (C group), Sham group (S group), ischemia group (I group), and 3 weeks physical exercise before ischemia group (3RI group). The rats in the 3RI group were placed in a voluntary running wheel for three weeks to exercise. Then, the rats in I and 3RI groups received bilateral carotid artery ligation (2-VO) operation. The C and S group did not perform voluntary running exercise and the bilateral common carotid arteries of S group were exposed without ligation. In vivo microdialysis was used in conjunction with high performance liquid chromatography (HPLC) and electrochemical detection to ascertain the level of dopamine in the striatum. Elevated plus maze (EPM) and open field (OF) were used to test anxiety status at 24 hours and 7days after 2-VO cerebral ischemia. Meanwhile, gait and motor coordination evaluations were carried out to eliminate the influence of non-specific motor problems. The results indicated that cerebral ischemia instigate the increase of striatal dopamine in I group rats during acute cerebral ischemia. A 3-week voluntary wheel running significantly enhances the striatal dopamine before ischemia and obstructs a further increase of dopamine during acute cerebral ischemia in 3RI group rats. At 24 hours after ischemia, striatal dopamine returned to pre-ischemic levels in 3RI group. Striatal dopamine in I group were less than pre-ischemic levels at 7 days. Behavioral data indicated that 3-week voluntary wheel running promoted recovery of anxiety-like behavior and gait were not affected by 2-VO cerebral ischemia at 24 hours post-ischemia rats. Therefore, it can be concluded that 3-week physical exercise significantly increased the striatal dopamine and improved anxiety-like behavior by inhibiting the increase of dopamine during acute cerebral ischemia and suppressing the decrease of dopamine after 24 hours and 7 days cerebral ischemia.

Voluntary Wheel Running Reduces Hepatic Dendritic And Cytotoxic T Cells In Western Diet-fed C57Bl/6 J Mice

The activation of innate immunity and recruitment of infiltrating macrophages are critical components of non-alcoholic steatohepatitis (NASH). In mice, voluntary wheel running (VWR) has improved hepatic steatosis and markers of inflammation; however, few studies have evaluated the effects of VWR on hepatic macrophages and hepatic immune cells linked to the development of NASH. PURPOSE: To determine the preventative effects of voluntary wheel running on hepatic macrophages and hepatic immune cells in mice fed a Western diet for 18 weeks. METHODS: Male, 8-week old, C57Bl/6 J mice (n = 56; 14/group) were randomly assigned to either a normal diet (ND) or Western diet (WD; 45% lard, 17% fructose, 0.75% cholesterol), followed by again randomly dividing each dietary group into either a sedentary (SED) or VWR group. Following 18-weeks, the relative percentage of hepatic macrophages (F4/80intCD11b+Ly6C- Kupffer cell, F4/80intCD11b+Ly6C+ infiltrating macrophage, and F4/80+CD11b+CD11c+ dendritic cell) and hepatic immune cells (CD45+CD19+ B-cell, CD45+CD4+ T-cell, and CD45+CD8+ cytotoxic T-cell) were isolated and cell populations were identified by flow cytometry. Differences between the four groups (ND + SED, ND + VWR, WD + SED, and WD + VWR) were identified by one-way ANOVA. RESULTS: No significant differences in either macrophage or immune cell populations were observed between ND + SED and ND + VWR. When compared to ND + SED, WD + SED had significantly (p < 0.05) higher percentage of cytotoxic T-cells (3.4 ± 0.5% vs. 8.2 ± 1.9%), dendritic cells (2.1 ± 0.4% vs. 8.6 ± 2.0%), and infiltrating macrophages (0.6 ± 0.5% vs. 1.6 ± 1.9%). In contrast, WD + VWR had lower percentages of cytotoxic T-cells (3.9 ± 0.5%) and dendritic cells (5.4 ± 1.1%) such that the percentage of cells were not significantly different than ND + SED and ND + VWR. Infiltrating macrophages remained relatively unchanged (1.4 ± 0.2%) in WD + VWR. Despite the positive changes in WD + VWR, the percentage of cytotoxic T-cells (p = 0.056) and dendritic cells (p = 0.387) were not significantly different than WD + SED mice. CONCLUSIONS: In mice fed a Western diet for 18 weeks, voluntary wheel running reduced the relative percentage of dendritic cells and cytotoxic T cells in the liver. Supported by SIUE Seed Grants for Transitional and Exploratory Projects.

Exercise Attenuates Tumor Growth Via Beta-2-Adrenergic Receptor Signaling In Murine Lymphoma

PURPOSE: Voluntary exercise has been shown to reduce tumor burden in several murine cancer models. The frequent mobilization and redistribution of effector lymphocytes (e.g. NK-cells, CD8+ T-cells) with exercise has been shown to enhance the presence of tumor infiltrating lymphocytes, potentially contributing to reductions in tumor growth. We have shown in humans that non-selective β1 + 2 adrenergic receptor (AR) blockade abrogates effector lymphocyte mobilization, whereas selective β1-AR blockade augments the response. We therefore hypothesize that β1 + 2-AR blockade will inhibit, whereas selective β1-AR blockade will enhance, the anti-tumor effects of exercise in an exercise-sensitive mouse model of lymphoma. METHODS: 8-12 week old male Balb/C mice were injected subcutaneously in the flank with 1 x 106 A20 lymphoma cells and assigned to either sedentary or exercise conditions. Groups were then further divided to include one of three different types of chow: (1) standard NIH chow, (2) NIH chow milled with a non-selective β1 + 2-AR antagonist (nadolol), and (3) NIH chow milled with a selective β1-AR antagonist (bisoprolol). Tumor progression was assessed with calipers every 3-4 days for 6 weeks. RESULTS: At week 6, sedentary mice consuming normal chow (3974.63 ± 557.80 mm3), nadolol chow (2943.94 ± 716.75 mm3), or bisoprolol chow (3088.62 ± 611.21 mm3) had comparable tumor burden. Exercising mice consuming normal chow or bisoprolol chow had significantly reduced tumor burden at week 6 relative to sedentary mice (882.56 ± 461.10 and 1398.50 ± 550.32 mm3, respectively; p < 0.0001). Interestingly, exercising mice consuming nadolol chow had tumor burden significantly greater than other exercising mice and were comparable to sedentary groups (3136.25 ± 883.93 mm3; p < 0.01). CONCLUSIONS: These data indicate that the protective effects of voluntary wheel running on murine lymphoma growth are β2-AR but not β1-AR dependent. Whether these effects are due to catecholamine signaling in the tumor or to a greater level of tumor infiltration by mobilized effector lymphocytes remains to be determined. These findings may have implications for patients taking β-blockers during cancer treatment and provide insight into the mechanisms underpinning immune cell mobilization and tumor infiltration with exercise.

Proteomic analysis of the effect of high-fat-diet and voluntary physical activity on mouse liver.

Nonalcoholic fatty liver disease (NALFD), characterized by an abnormal accumulation of triglycerides in hepatocytes, is closely linked to insulin resistance, metabolic syndrome, and changes in lipogenesis in the liver. The accumulation of hepatic lipids can lead to a range of pathologies from mild steatosis to severe cirrhosis. Endurance exercise is known to ameliorate the adverse health effects of NAFLD. Therefore, we aimed to investigate the effect of voluntary wheel running (VWR) on the metabolic changes in the livers of high-fat diet (HFD)-induced NAFLD mice and used LC-MS/MS (Liquid chromatography–mass spectrometry) to determine whether the tested intervention affected the protein expression profiles of the mouse livers. Male C57BL/6 mice were randomly divided into three groups: control (CON), high-fat diet sedentary group (HFD), high-fat diet VWR group (HFX). HFX group performed voluntary wheel running into individually cages, given a high-fat diet for 12 weeks. Food consumption, body weight, and running distance were measured every week. Using 2D (2-dimensional)-gel electrophoresis, we detected and quantitatively analyzed the protein expression with >2.0-fold change in the livers of HFD-fed mice, HFD-fed exercise (HFX) mice, and chow-fed mice. Body weight was significantly increased in HFD compared to CON (P < 0.05). The 2D-gel electrophoresis analysis indicated that there was a difference between CON and HFD groups, showing 31 increased and 27 decreased spots in the total 302 paired spots in the HFD group compared to CON. The analysis showed 43 increased and 17 decreased spots in the total 258 spots in the HFX group compared to CON. Moreover, 12 weeks of VWR showed an increase of 35 and a decrease of 8 spots in a total of 264 paired spots between HFD and HFX. LC-MS/MS of HFD group revealed that proteins involved in ketogenesis, lipid metabolism, and the metabolism of drugs and xenobiotics were upregulated, whereas detoxifying proteins, mitochondrial precursors, transport proteins, proteasomes, and proteins involved in amino acid metabolism were downregulated. On the other hand, VWR counteracted the protein expression profile of HFD-fed mice by upregulating molecular chaperones, gluconeogenesis-, detoxification-, proteasome-, and energy metabolism-related proteins. This study provided a molecular understanding of the HFD- and exercise-induced protein marker expression and presented the beneficial effects of exercise during pathophysiological conditions.

Beneficial effects of voluntary wheel running on activity rhythms, metabolic state, and affect in a diurnal model of circadian disruption

Emerging evidence suggests that disruption of circadian rhythmicity contributes to development of comorbid depression, cardiovascular diseases (CVD), and type 2 diabetes mellitus (T2DM). Physical exercise synchronizes the circadian system and has ameliorating effects on the depression- and anxiety-like phenotype induced by circadian disruption in mice and sand rats. We explored the beneficial effects of voluntary wheel running on daily rhythms, and the development of depression, T2DM, and CVD in a diurnal animal model, the fat sand rat (Psammomys obesus). Voluntary exercise strengthened general activity rhythms, improved memory and lowered anxiety- and depressive-like behaviors, enhanced oral glucose tolerance, and decreased plasma insulin levels and liver weight. Animals with access to a running wheel had larger heart weight and heart/body weight ratio, and thicker left ventricular wall. Our results demonstrate that exercising ameliorates pathological-like daily rhythms in activity and blood glucose levels, glucose tolerance and depressive- and anxiety-like behaviors in the sand rat model, supporting the important role of physical activity in modulating the “circadian syndrome” and circadian rhythm-related diseases. We suggest that the utilization of a diurnal rodent animal model may offer an effective way to further explore metabolic, cardiovascular, and affective-like behavioral changes related to chronodisruption and their underlying mechanisms.

The effects of voluntary wheel running during weight-loss on biomarkers of hepatic lipid metabolism and inflammation in C57Bl/6J mice.

The aim of this study was to determine the effect of voluntary wheel running (VWR) during weight-loss on hepatic lipid and inflammatory biomarkers using a murine model. To induce obesity, male C57Bl/6 mice were fed a 60% high-fat diet (HF) for 10 weeks. At 10 weeks, weight-loss was promoted by randomizing HF-fed mice to a normal diet (ND) either with (WL + VWR) or without (WL) access to running wheels for 8 weeks. Age-matched dietary control mice were fed either a ND or HF for 18 weeks. Following weight-loss, WL + VWR had a lower body mass compared to all groups despite an average weekly caloric consumption comparable to HF mice. WL + VWR had an increased adiponectin concentration when compared to WL, but no difference between WL and WL + VWR was observed for plasma glucose and lipid biomarkers. When compared to HF, the lower hepatic total lipids in both WL and WL + VWR were associated with increased pAMPK:AMPK and reduced pACC-1:ACC-1 ratios. When compared to WL, WL + VWR resulted in lower hepatic cholesterol and trended to lower hepatic triglyceride. In both WL and WL + VWR, pNF-κB p65:NF-κB p65 ratio was lower than HF and comparable to ND. TGFβ1 and BAMBI protein levels were evaluated as biomarkers for hepatic fibrosis. No differences in TGFβ1 was observed between groups; however, WL and WL + VWR had BAMBI protein levels comparable to ND. Overall, the addition of voluntary exercise resulted in greater weight-loss and improvements in hepatic cholesterol and triglyceride levels; however, limited improvements in hepatic inflammation were observed when compared to weight-loss by diet alone.

Therapeutic effects of voluntary wheel running on cancer cachexia-induced cardiac dysfunction: Approach from the perspective of Cardio-oncology

Therapeutic effects of voluntary wheel running on cancer cachexia-induced cardiac dysfunction: Approach from the perspective of Cardio-oncology

Effect of voluntary wheel running on gut microbiota composition in developing mice.

Background: exercise can increase the species and quantity of beneficial gut microbiota, enrich the diversity of microflora, and promote the development of symbiotic bacteria, especially in the stage of ontogeny. However, there is little evidence of the short-term voluntary exercise effect on the gut microbiota in developing mice. Material and method: therefore, we used short-term voluntary wheel running model to study the gut microbiota of developing mice (1 month old), and detected the fecal samples by 16S rRNA gene sequencing. Results: the results showed that after 4 weeks of voluntary wheel running, the body weight of the running group was significantly lower than that of the control group. Conclusion: there was a significant separation between the running group and the control group in beta diversity measures. At the family level, the clostridiales flora of the running group was higher than that of the control group. Compared with the control group, the abundance of parabacteroides flora and anaerovorax flora increased significantly, and the abundance of anaerotruncus flora and odoribacter flora decreased significantly in the running group. These results showed that gut microbiota be affected after short-term voluntary wheel running in developing mice.

Voluntary exercise prevents abnormal muscle mitochondrial morphology in cancer cachexia mice.

This study aimed to examine the effects of voluntary wheel running on cancer cachexia‐induced mitochondrial alterations in mouse skeletal muscle. Mice bearing colon 26 adenocarcinoma (C26) were used as a model of cancer cachexia. C26 mice showed a lower gastrocnemius and plantaris muscle weight, but 4 weeks of voluntary exercise rescued these changes. Further, voluntary exercise attenuated observed declines in the levels of oxidative phosphorylation proteins and activities of citrate synthase and cytochrome c oxidase in the skeletal muscle of C26 mice. Among mitochondrial morphology regulatory proteins, mitofusin 2 (Mfn2) and dynamin‐related protein 1 (Drp1) were decreased in the skeletal muscle of C26 mice, but exercise resulted in similar improvements as seen in markers of mitochondrial content. In isolated mitochondria, 4‐hydroxynonenal and protein carbonyls were elevated in C26 mice, but exercise blunted the increases in these markers of oxidative stress. In addition, electron microscopy revealed that exercise alleviated the observed increase in the percentage of damaged mitochondria in C26 mice. These results suggest that voluntary exercise effectively counteracts mitochondrial dysfunction to mitigate muscle loss in cachexia.

Physiologic and molecular characterization of a novel murine model of metastatic head and neck cancer cachexia.

BackgroundCancer cachexia is a metabolic disorder characterized by the progressive loss of fat and lean mass that results in significant wasting, ultimately leading to reduced quality of life and increased mortality. Effective therapies for cachexia are lacking, potentially owing to the mismatch in clinically relevant models of cachexia. Specifically, cachexia observed in a clinical setting is commonly associated with advanced or late‐stage cancers that are metastatic, yet pre‐clinical metastatic models of cachexia are limited. Furthermore, the prevalence of cachexia in head and neck cancer patients is high, yet few pre‐clinical models of head and neck cancer cachexia exist. In addition to these shortcomings, cachexia is also heterogeneous among any given cancer, whereas patients with similar disease burden may experience significantly different degrees of cachexia symptoms. In order to address these issues, we characterize a metastatic model of human papilloma virus (HPV) positive head and neck squamous cell carcinoma that recapitulates the cardinal clinical and molecular features of cancer cachexia.MethodsMale and female C57BL/6 mice were implanted subcutaneously with oropharyngeal squamous cell carcinoma cells stably transformed with HPV16 E6 and E7 together with hRas and luciferase (mEERL) that metastasizes to the lungs (MLM). We then robustly characterize the physiologic, behavioural, and molecular signatures during tumour development in two MLM subclones.ResultsMice injected with MLM tumour cells rapidly developed primary tumours and eventual metastatic lesions to the lungs. MLM3, but not MLM5, engrafted mice progressively lost fat and lean mass during tumour development despite the absence of anorexia (P < 0.05). Behaviourally, MLM3‐implanted mice displayed decreased locomotor behaviours and impaired nest building (P < 0.05). Muscle catabolism programmes associated with cachexia, including E3 ubiquitin ligase and autophagy up‐regulation, along with progressive adipose wasting and accompanying browning gene signatures, were observed. Tumour progression also corresponded with hypothalamic and peripheral organ inflammation, as well as an elevation in neutrophil‐to‐lymphocyte ratio (P < 0.05). Finally, we characterize the fat and lean mass sparing effects of voluntary wheel running on MLM3 cachexia (P < 0.05).ConclusionsThis syngeneic MLM3 allograft model of metastatic cancer cachexia is reliable, consistent, and readily recapitulates key clinical and molecular features and heterogeneity of cancer cachexia. Because few metastatic models of cachexia exist—even though cachexia often accompanies metastatic progression—we believe this model more accurately captures cancer cachexia observed in a clinical setting and thus is well suited for future mechanistic studies and pre‐clinical therapy development for this crippling metabolic disorder.

Voluntary Wheel Running Partially Attenuates Early Life Stress-Induced Neuroimmune Measures in the Dura and Evoked Migraine-Like Behaviors in Female Mice.

Migraine is a complex neurological disorder that affects three times more women than men and can be triggered by endogenous and exogenous factors. Stress is a common migraine trigger and exposure to early life stress increases the likelihood of developing chronic pain disorders later in life. Here, we used our neonatal maternal separation (NMS) model of early life stress to investigate whether female NMS mice have an increased susceptibility to evoked migraine-like behaviors and the potential therapeutic effect of voluntary wheel running. NMS was performed for 3 h/day during the first 3 weeks of life and initial observations were made at 12 weeks of age after voluntary wheel running (Exercise, -Ex) or sedentary behavior (-Sed) for 4 weeks. Mast cell degranulation rates were significantly higher in dura mater from NMS-Sed mice, compared to either naïve-Sed or NMS-Ex mice. Protease activated receptor 2 (PAR2) protein levels in the dura were significantly increased in NMS mice and a significant interaction of NMS and exercise was observed for transient receptor potential ankyrin 1 (TRPA1) protein levels in the dura. Behavioral assessments were performed on adult (>8 weeks of age) naïve and NMS mice that received free access to a running wheel beginning at 4 weeks of age. Facial grimace, paw mechanical withdrawal threshold, and light aversion were measured following direct application of inflammatory soup (IS) onto the dura or intraperitoneal (IP) nitroglycerin (NTG) injection. Dural IS resulted in a significant decrease in forepaw withdrawal threshold in all groups of mice, while exercise significantly increased grimace score across all groups. NTG significantly increased grimace score, particularly in exercised mice. A significant effect of NMS and a significant interaction effect of exercise and NMS were observed on hindpaw sensitivity following NTG injection. Significant light aversion was observed in NMS mice, regardless of exercise, following NTG. Finally, exercise significantly reduced calcitonin gene-related peptide (CGRP) protein level in the dura of NMS and naïve mice. Taken together, these findings suggest that while voluntary wheel running improved some measures in NMS mice that have been associated with increased migraine susceptibility, behavioral outcomes were not impacted or even worsened by exercise.