Voluntary wheel running prevents salt-induced endothelial dysfunction: role of oxidative stress

Diets high in salt can lead to endothelial dysfunction, a nontraditional risk factor for cardiovascular disease (CVD). Exercise is known to reduce CVD risk; however, it remains unknown whether chronic physical activity can attenuate salt-induced endothelial dysfunction independent of blood pressure (BP) and whether these changes are due to an upregulation in endogenous antioxidants. Eight-week-old Sprague-Dawley rats were fed either a normal (NS; 0.49%)- or a high (HS; 4.0%)-salt diet and further divided into voluntary wheel running (NS-VWR, HS-VWR) and sedentary (NS, HS) groups for 6 wk. BP was measured weekly and remained unchanged within groups ( P = 0.373). Endothelium-dependent relaxation (EDR) was impaired in the femoral artery of HS compared with NS (38.6 ± 4.0% vs. 65.0 ± 3.6%; P = 0.013) animals, whereas it was not different between NS and HS-VWR (73.4 ± 6.4%; P = 0.273) animals. Incubation with the antioxidants TEMPOL ( P = 0.024) and apocynin ( P = 0.013) improved EDR in HS animals, indicating a role for reactive oxygen species (ROS). Wheel running upregulated the antioxidant superoxide dismutase-2 (SOD-2) ( P = 0.011) under HS conditions and lowered NOX4 and Gp91-phox, two subunits of NADPH oxidase. Wheel running elevated phosphorylated endothelial nitric oxide synthase (eNOS) ( P = 0.014) in HS-fed rats, demonstrating a role for physical activity and eNOS activity under HS conditions. Finally, there was a reduction in EDR ( P = 0.038) when femoral arteries from NS-VWR animals were incubated with TEMPOL or apocynin, suggesting there may be a critical level of ROS needed to maintain endothelial function. In summary, physical activity protected HS-fed rats from reductions in endothelial function, likely through increased SOD-2 levels and reduced oxidative stress. NEW & NOTEWORTHY Our data suggest that voluntary wheel running can prevent impairments in endothelium-dependent relaxation in the femoral artery of rats fed a high-salt diet. This appears to be independent of blood pressure and mediated through a decrease in expression of NADPH oxidases as a result of physical activity. These data suggest that increased chronic physical activity can protect the vasculature from a diet high in salt, likely through a reduction in oxidative stress.

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P4475Vasodilation- and blood pressure normalization-independent cardioprotective effects of endogenous, physical activity-induced alpha calcitonin gene-related peptide in chronic hypertension

European Heart Journal ◽

10.1093/eurheartj/ehz745.0870 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

T Skaria ◽

K Mitchell ◽

J A Fischer ◽

W Born ◽

M Gassmann ◽

...

Keyword(s):

Physical Activity ◽

Blood Pressure ◽

Cardiac Tissue ◽

Wheel Running ◽

Chronic Hypertension ◽

Voluntary Wheel Running ◽

Cardioprotective Effects ◽

Pressure Independent ◽

And Function ◽

Voluntary Wheel

Abstract Background Alpha calcitonin gene-related peptide (αCGRP) is one of the strongest vasodilators and, as such, is cardioprotective in chronic hypertension when reducing the associated elevated blood pressure. However, we hypothesize that endogenous, physical activity-induced αCGRP has blood pressure independent cardioprotective effects in chronic hypertension. Methods Chronic hypertension was induced in WT and αCGRP−/− mice by one-kidney one-clip surgery. Chronic hypertensive WT and αCGRP−/− mice lived sedentarily or performed voluntary wheel running and were treated simultaneously with either vehicle, αCGRP or αCGRP receptor antagonist CGRP8–37. Cardiac function and tissue phenotype were evaluated echocardiographically and by ddPCR, Western blotting and histology, respectively. Results Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological cardiac remodeling and symptomatic heart failure already in sedentary, chronic hypertensive WT mice. In these mice, voluntary wheel running significantly improved cardiac tissue phenotype and function, that was abolished by CGRP8–37 treatment. In αCGRP−/− mice, αCGRP treatment, in contrast to voluntary wheel running, improved cardiac tissue phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-mediated blunting of pathological cardiac remodeling. Conclusion Endogenous, physical activity-induced αCGRP has blood pressure independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, permanently inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger hypertensive patients. Acknowledgement/Funding Swiss National Science Foundation, Novartis Foundation for Medical-biological Research

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Circadian pattern of total and free corticosterone concentrations, corticosteroid-binding globulin, and physical activity in mice selectively bred for high voluntary wheel-running behavior

General and Comparative Endocrinology ◽

10.1016/j.ygcen.2008.01.020 ◽

2008 ◽

Vol 156 (2) ◽

pp. 210-217 ◽

Cited By ~ 87

Author(s):

Jessica L. Malisch ◽

Creagh W. Breuner ◽

Fernando R. Gomes ◽

Mark A. Chappell ◽

Theodore Garland

Keyword(s):

Physical Activity ◽

Wheel Running ◽

Circadian Pattern ◽

Voluntary Wheel Running ◽

Corticosteroid Binding Globulin ◽

Voluntary Wheel

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Voluntary wheel running ameliorates vascular smooth muscle hyper-contractility in type 2 diabetic db/db mice

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-058 ◽

2007 ◽

Vol 32 (4) ◽

pp. 711-720 ◽

Cited By ~ 9

Author(s):

Karyn A. Esser ◽

Wen Su ◽

Sergey Matveev ◽

Vicki Wong ◽

Li Zeng ◽

...

Keyword(s):

Physical Activity ◽

Smooth Muscle ◽

Blood Glucose ◽

Vascular Smooth Muscle ◽

Wheel Running ◽

Voluntary Wheel Running ◽

Voluntary Physical Activity ◽

Type 2 Diabetic ◽

Voluntary Wheel

Physical activity reduces cardiovascular disease related mortality in diabetic patients. However, it is unknown if the diabetic state reduces voluntary physical activity and, if so, if the voluntary physical activity at the reduced level is sufficient to improve cardiovascular risk factors. To address these two specific questions, we investigated voluntary wheel running performance in an obese and type 2 diabetic mouse model, the db/db mice. In addition, we determined the effects of running on body mass, blood glucose, insulin, plasma free fatty acids, cholesterol, and vascular smooth muscle hyper-contractility. Our results showed that daily running distance, time, and speed were significantly reduced in the db/db mice to about 23%, 32%, and 71%, respectively, of that in non-diabetic control mice. However, this low level of running was sufficient to induce a reduction in the vascular smooth muscle hyper-contractility, cholesterol, and some plasma free fatty acids, as well as to delay the decrease in blood insulin. These changes occurred in the absence of weight loss and a detectable decrease in blood glucose. Thus, the results of this study demonstrated that voluntary wheel running activity was dramatically reduced in db/db mice. However, the low levels of running were beneficial, in the absence of effects on obesity or blood glucose, with significant reductions in cardiovascular risk factors and potential delays in β-cell dysfunction.

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PhenylethanolamineN-Methyltransferase Gene Expression in the Heart and Blood Pressure Response to Oxytocin Treatment in Rats Exposed to Voluntary Wheel Running

Annals of the New York Academy of Sciences ◽

10.1196/annals.1410.031 ◽

2008 ◽

Vol 1148 (1) ◽

pp. 302-307 ◽

Cited By ~ 6

Author(s):

Jan Bakos ◽

Peter Bobryshev ◽

Andrej Tillinger ◽

Richard Kvet��ansk�� ◽

Daniela Jezova

Keyword(s):

Gene Expression ◽

Blood Pressure ◽

Wheel Running ◽

Blood Pressure Response ◽

Pressure Response ◽

Voluntary Wheel Running ◽

Methyltransferase Gene ◽

Voluntary Wheel

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Chronic environmental or genetic elevation of galanin in noradrenergic neurons confers stress resilience in mice

10.1101/2020.04.24.060608 ◽

2020 ◽

Author(s):

Rachel P. Tillage ◽

Genevieve E. Wilson ◽

L. Cameron Liles ◽

Philip V. Holmes ◽

David Weinshenker

Keyword(s):

Physical Activity ◽

Locus Coeruleus ◽

Wheel Running ◽

Neuropsychiatric Disorders ◽

Noradrenergic Neurons ◽

Stress Resilience ◽

Voluntary Wheel Running ◽

Exercise Induced ◽

Species Specific ◽

Voluntary Wheel

ABSTRACTThe neuropeptide galanin has been implicated in stress-related neuropsychiatric disorders in both humans and rodent models. While pharmacological treatments for these disorders are ineffective for many individuals, physical activity is beneficial for stress-related symptoms. Galanin is highly expressed in the noradrenergic system, particularly the locus coeruleus (LC), which is dysregulated in stress-related disorders and activated by exercise. Galanin expression is elevated in the LC by chronic exercise, and blockade of galanin transmission attenuates exercise-induced stress resilience. However, most research on this topic has been done in rats, so it is unclear whether the relationship between exercise and galanin is species-specific. Moreover, use of intracerebroventricular galanin receptor antagonists in prior studies precluded defining a causal role for LC-derived galanin specifically. Therefore, the goals of this study were twofold. First, we investigated whether physical activity (chronic voluntary wheel running) increases stress resilience and galanin expression in the LC of mice. Next, we used transgenic mice that overexpress galanin in noradrenergic neurons (Gal OX) to determine how chronically elevated noradrenergic-derived galanin, alone, alters anxiogenic-like responses to stress. We found that three weeks of ad libitum access to a running wheel in their home cage increased galanin mRNA in the LC of mice and conferred resilience to a stressor. The effects of exercise were phenocopied by galanin overexpression in noradrenergic neurons, and Gal OX mice were resistant to the anxiogenic effect of optogenetic LC activation. Together, these findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.Significance statementUnderstanding the neurobiological mechanisms underlying behavioral responses to stress is necessary to improve treatments for stress-related neuropsychiatric disorders. Increased physical activity is associated with stress resilience in humans, but the neurobiological mechanisms underlying this effect are not clear. Here we investigate the anxiolytic potential of the neuropeptide galanin from the main noradrenergic nucleus, the locus coeruleus (LC). We show that chronic voluntary wheel running in mice galanin expression in the LC and stress resilience. Furthermore, we show that genetic overexpression of galanin in noradrenergic neurons confers resilience to the anxiogenic effects of foot shock and optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.

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Sex dependent effects of physical activity on diet preference in rats selectively bred for high or low levels of voluntary wheel running

Behavioural Brain Research ◽

10.1016/j.bbr.2018.10.018 ◽

2019 ◽

Vol 359 ◽

pp. 95-103 ◽

Cited By ~ 8

Author(s):

Jenna R. Lee ◽

Melissa A. Tapia ◽

Jane R. Nelson ◽

Justin M. Moore ◽

Graydon B. Gereau ◽

...

Keyword(s):

Physical Activity ◽

Wheel Running ◽

Voluntary Wheel Running ◽

Diet Preference ◽

Low Levels ◽

Voluntary Wheel

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Exercise by lifelong voluntary wheel running reduces subsarcolemmal and interfibrillar mitochondrial hydrogen peroxide production in the heart

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00396.2005 ◽

2005 ◽

Vol 289 (6) ◽

pp. R1564-R1572 ◽

Cited By ~ 89

Author(s):

Sharon Judge ◽

Young Mok Jang ◽

Anthony Smith ◽

Colin Selman ◽

Tracey Phillips ◽

...

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Food Restriction ◽

Wheel Running ◽

Daily Energy Expenditure ◽

Voluntary Wheel Running ◽

Daily Energy ◽

Oxidant Production ◽

Voluntary Wheel

Evidence suggests that mitochondrial dysfunction and oxidant production, in association with an accumulation of oxidative damage, contribute to the aging process. Regular physical activity can delay the onset of morbidity, increase mean lifespan, and reduce the risk of developing several pathological states. No studies have examined age-related changes in oxidant production and oxidative stress in both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria in combination with lifelong exercise. Therefore, we investigated whether long-term voluntary wheel running in Fischer 344 rats altered hydrogen peroxide (H2O2) production, antioxidant defenses, and oxidative damage in cardiac SSM and IFM. At 10–11 wk of age, rats were randomly assigned to one of two groups: sedentary and 8% food restriction (sedentary; n = 20) or wheel running and 8% food restriction (runners; n = 20); rats were killed at 24 mo of age. After the age of 6 mo, running activity was maintained at an average of 1,145 ± 248 m/day. Daily energy expenditure determined by doubly labeled water technique showed that runners expended on average ∼70% more energy per day than the sedentary rats. Long-term voluntary wheel running significantly reduced H2O2 production from both SSM (−10.0%) and IFM (−9.6%) and increased daily energy expenditure (kJ/day) significantly in runners compared with sedentary controls. Additionally, MnSOD activity was significantly lowered in SSM and IFM from wheel runners, which may reflect a reduction in mitochondrial superoxide production. Activities of the other major antioxidant enzymes (glutathione peroxidase and catalase) and glutathione levels were not altered by wheel running. Despite the reduction in mitochondrial oxidant production, no significant differences in oxidative stress levels (4-hydroxy-2-nonenal-modified proteins, protein carbonyls, and malondialdehyde) were detected between the two groups. The health benefits of chronic exercise may be, at least partially, due to a reduction in mitochondrial oxidant production; however, we could not detect a significant reduction in several selected parameters of oxidative stress.

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Interrelationship of CB1R and OBR pathways in regulation of metabolic, neuroendocrine, and behavioral responses to food restriction and voluntary wheel running

Journal of Applied Physiology ◽

10.1152/japplphysiol.01303.2013 ◽

2014 ◽

Vol 117 (2) ◽

pp. 97-104 ◽

Cited By ~ 3

Author(s):

Abdoulaye Diane ◽

Donna F. Vine ◽

James C. Russell ◽

C. Donald Heth ◽

W. David Pierce ◽

...

Keyword(s):

Physical Activity ◽

Body Weight ◽

Food Restriction ◽

Leptin Receptor ◽

Wheel Running ◽

Behavioral Responses ◽

Voluntary Wheel Running ◽

Cannabinoid 1 Receptor ◽

Clinical Measures ◽

Voluntary Wheel

We hypothesized the cannabinoid-1 receptor and leptin receptor (ObR) operate synergistically to modulate metabolic, neuroendocrine, and behavioral responses of animals exposed to a survival challenge (food restriction and wheel running). Obese-prone (OP) JCR:LA- cp rats, lacking functional ObR, and lean-prone (LP) JCR:LA- cp rats (intact ObR) were assigned to OP-C and LP-C (control) or CBR1-antagonized (SR141716, 10 mg/kg body wt in food) OP-A and LP-A groups. After 32 days, all rats were exposed to 1.5-h daily meals without the drug and 22.5-h voluntary wheel running, a survival challenge that normally culminates in activity-based anorexia (ABA). Rats were removed from the ABA protocol when body weight reached 75% of entry weight (starvation criterion) or after 14 days (survival criterion). LP-A rats starved faster (6.44 ± 0.24 days) than LP-C animals (8.00 ± 0.29 days); all OP rats survived the ABA challenge. LP-A rats lost weight faster than animals in all other groups ( P < 0.001). Consistent with the starvation results, LP-A rats increased the rate of wheel running more rapidly than LP-C rats ( P = 0.001), with no difference in hypothalamic and primary neural reward serotonin levels. In contrast, OP-A rats showed suppression of wheel running compared with the OP-C group ( days 6–14 of ABA challenge, P < 0.001) and decreased hypothalamic and neural reward serotonin levels ( P < 0.01). Thus there is an interrelationship between cannabinoid-1 receptor and ObR pathways in regulation of energy balance and physical activity. Effective clinical measures to prevent and treat a variety of disorders will require understanding of the mechanisms underlying these effects.

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Hippocampal Morphology in a Rat Model of Depression: The Effects of Physical Activity

The Open Neuroimaging Journal ◽

10.2174/1874440001509010001 ◽

2015 ◽

Vol 9 (1) ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Adam Sierakowiak ◽

Anna Mattsson ◽

Marta Gómez-Galán ◽

Teresa Feminía ◽

Lisette Graae ◽

...

Keyword(s):

Physical Activity ◽

Genetic Model ◽

Wheel Running ◽

Ex Vivo ◽

Hippocampal Volume ◽

Antidepressant Effect ◽

Spine Density ◽

Voluntary Wheel Running ◽

Voluntary Wheel

Accumulating in vivo and ex vivo evidences show that humans suffering from depression have decreased hippocampal volume and altered spine density. Moreover, physical activity has an antidepressant effect in humans and in animal models, but to what extent physical activity can affect hippocampal volume and spine numbers in a model for depression is not known. In this study we analyzed whether physical activity affects hippocampal volume and spine density by analyzing a rodent genetic model of depression, Flinders Sensitive Line Rats (FSL), with Magnetic Resonance Imaging (MRI) and ex vivo Golgi staining. We found that physical activity in the form of voluntary wheel running during 5 weeks increased hippocampal volume. Moreover, runners also had larger numbers of thin spines in the dentate gyrus. Our findings support that voluntary wheel running, which is antidepressive in FSL rats, is associated with increased hippocampal volume and spine numbers.

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