Exercise In Animal Models Research Articles

Animal models of exercise and obesity.

Animal models have been invaluable in the conduct of nursing research for the past 40 years. This review will focus on specific animal models that can be used in nursing research to study the physiologic phenomena of exercise and obesity when the use of human subjects is either scientifically premature or inappropriate because of the need for sampling tissue or the conduct of longitudinal studies of aging. There exists an extensive body of literature reporting the experimental use of various animal models, in both exercise science and the study of the mechanisms of obesity. Many of these studies are focused on the molecular and genetic mechanisms of organ system adaptation and plasticity in response to exercise, obesity, or both. However, this review will narrowly focus on the models useful to nursing research in the study of exercise in the clinical context of increasing performance and mobility, atrophy and bedrest, fatigue, and aging. Animal models of obesity focus on those that best approximate clinical pathology.

The effects of physical exercise in schizophrenia and affective disorders

Affective and non-affective psychoses are severe and frequent psychiatric disorders. Amongst others, they not only have a profound impact on affected individuals through their symptomatology, but also regarding cognition, brain structure and function. Cognitive impairment influences patients' quality of life as well as their ability to work and being employed. While exercise therapy has been implemented in the treatment of psychiatric conditions since the days of Kraepelin and Bleuler, the underlying mechanisms have never been systematically studied. Since the early 1990s, studies emerged examining the effect of physical exercise in animal models, revealing stimulation of neurogenesis, synaptogenesis and neurotransmission. Based on that body of work, clinical studies have been carried out in both healthy humans and in patient populations. These studies differ with regard to homogenous study samples, sample size, type and duration of exercise, outcome variables and measurement techniques. Based on their review, we draw conclusions regarding recommendations for future research strategies showing that modern therapeutic approaches should include physical exercise as part of a multimodal intervention programme to improve psychopathology and cognitive symptoms in schizophrenia and affective disorders.

Increased Nerve Growth Factor Serum Levels in Top Athletes

The nerve growth factor (NGF) is the main neurotrophin, which, besides being an important growth factor for nerves, plays an important role as a mediator of inflammation. Nerve growth factor has been shown to increase in relation to stress stimuli and in allergic diseases in humans as well as after physical exercise in animal models. This study aims at evaluating NGF serum levels in top athletes, a population sample in which allergic and neuro-immune diseases are reported with a significantly increased prevalence. Observational, cross-sectional, multicenter study. Institutional, tertiary care. Ninety-six Italian pre-Olympic athletes (44 allergic and 52 nonallergic) and 49 matched controls selected within the Italian National Olympic delegation (n = 435). Nerve growth factor serum levels determined through an enzyme-linked immunosorbent assay. Parametric or nonparametric tests were used for comparing NGF serum levels among different study groups depending on value distributions. Nerve growth factor serum levels were significantly higher in athletes than in controls independently from the presence of allergy. Nerve growth factor mean values were 368.3 ± 776.3 pg/mL in the sample of athletes and 174.1 ± 483.7 pg/mL in the control group (P < 0.001). This is the first study showing that intense and prolonged physical exercise is associated with an increase of NGF serum levels in athletes. Whether the increased NGF production might be linked to the prevalent Th2 response observed in allergic diseases and after physical exercise and whether it might be related to the patophysiology of neuro-immune disorders as such amyotrophic lateral sclerosis, reported with a higher prevalence in athletes, should deserve further investigations.

Neurobiological markers of exercise-related brain plasticity in older adults.

The current study examined how a randomized one-year aerobic exercise program for healthy older adults would affect serum levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor type 1 (IGF-1), and vascular endothelial growth factor (VEGF) - putative markers of exercise-induced benefits on brain function. The study also examined whether (a) change in the concentration of these growth factors was associated with alterations in functional connectivity following exercise, and (b) the extent to which pre-intervention growth factor levels were associated with training-related changes in functional connectivity. In 65 participants (mean age=66.4), we found that although there were no group-level changes in growth factors as a function of the intervention, increased temporal lobe connectivity between the bilateral parahippocampus and the bilateral middle temporal gyrus was associated with increased BDNF, IGF-1, and VEGF for an aerobic walking group but not for a non-aerobic control group, and greater pre-intervention VEGF was associated with greater training-related increases in this functional connection. Results are consistent with animal models of exercise and the brain, but are the first to show in humans that exercise-induced increases in temporal lobe functional connectivity are associated with changes in growth factors and may be augmented by greater baseline VEGF.

Intranasal insulin-like growth factor I (IGF-I) as a plausible future treatment of depression

Depression remains a highly prevalent and mostly recurrent disorder causing an increased need to optimize and broaden the current therapy options. An enormous body of evidence links the regulation of specific neurotrophic proteins, like the brain-derived neurotrophic factor (BDNF), to depression and it may be assumed that the behavioral effects of antidepressants require functional BDNF signaling in the brain. Another neurotrophin, insulin-like growth factor-I (IGF-I), also produces antidepressant-like behavioral effects. Data have shown that BDNF plus IGF-I are more effective than either neurotrophin alone in activating neurotrophic cascades and promoting survival of hippocampal neurons. In fact, it has been suggested that the increase in hippocampal BDNF following antidepressant treatment or physical exercise in animal models is IGF-I-dependent and that antidepressant treatment increases IGF-I in human cerebrospinal fluid (CSF). Thus, BDNF and IGF-I seem to act synergistically in the same cascade of transmission and neuroplasticity. In order to avoid the pitfalls of systemic application (e.g. possible peripheral side effects) while directly targeting central nervous circuitries, the clinical intranasal administration of IGF-I appears to be a plausible and promising treatment option of depression.

Augmented alpha‐adrenergic vasoconstriction during exercise in human metabolic syndrome

The contribution of α‐adrenergic vasoconstriction during exercise in animal models of metabolic syndrome (MS) is controversial and the relevance to human MS is unclear. We hypothesized humans with MS (n=11) would exhibit greater α‐adrenergic vasoconstriction during exercise compared with healthy controls (n=16) and greater constriction would correlate with higher muscle sympathetic nerve activity (mSNA). We measured forearm blood flow (BF, Doppler ultrasound) and calculated changes in conductance (BF/blood pressure) with local intra‐arterial infusion of adrenergic agonists [phenylephrine (PE, α1), clonidine (CL, α2)] during dynamic forearm exercise (15% maximal effort). mSNA was measured in a subset of subjects (n=15, microneurography of the peroneal nerve). mSNA was higher in MS (66±9 vs 35±4 bursts/100 heart beats, p&lt;0.01) and did not change with exercise. Infusion of PE decreased conductance similarly between groups. In contrast, MS subjects exhibited greater constriction to CL infusion compared with controls (p&lt;0.01). Greater CL‐mediated constriction was associated with higher mSNA (r=0.51, p=0.05). These findings demonstrate greater α2‐adrenergic vasoconstriction during exercise in human MS which is related to higher mSNA. Such relationships may lead to impaired blood flow distribution and blood pressure regulation during exercise in MS. Support: AHA 10PRE3870000, NIH HL091397.

Rehabilitation and Parkinson’s Disease

Rehabilitation and Parkinson’s Disease

Response to Letters Regarding Article, “Cardiac Arrhythmogenic Remodeling in a Rat Model of Long-Term Intensive Exercise Training”

We would like to thank Maass and Maier and Ruiz et al for their interesting comments on our study.1 Maass et al stress the potential benefit of exercise in improving the evolution of certain cardiac diseases, and also the need to analyze the benefits of exercise in animal models. In particular, they comment on the beneficial effects of voluntary exercise through diverse pathological conditions. We fully agree with their cautionary comments, and certainly our results cannot be directly extrapolated to models of voluntary exercise training. Our model attempted to replicate extreme endurance training conditions, often present in endurance sports training. The authors also pointed out the potential damage caused by stress due to the use of electric discharges to stimulate running. Although we recognize this potential limitation (as …

Cognitive and locomotor/exploratory behavior after chronic exercise in the olfactory bulbectomy animal model of depression

Despite the evidence that exercise improves cognitive behavior in animal models, little is known about these beneficial effects in animal models of pathology. We examined the effects of activity wheel (AW) running on contextual fear conditioning (CFC) and locomotor/exploratory behavior in the olfactory bulbectomy (OBX) model of depression, which is characterized by hyperactivity and changes in cognitive function. Twenty-four hours after the conditioning session of the CFC protocol, the animals were tested for the conditioned response in a conditioned and a novel context to test for the effects of both AW and OBX on CFC, but also the context specificity of the effect. OBX reduced overall AW running behavior throughout the experiment, but increased locomotor/exploratory behavior during CFC, thus demonstrating a context-dependent effect. OBX animals, however, displayed normal CFC behavior that was context-specific, indicating that aversively conditioned memory is preserved in this model. AW running increased freezing behavior during the testing session of the CFC protocol in the control animals but only in the conditioned context, supporting the hypothesis that AW running improves cognitive function in a context-specific manner that does not generalize to an animal model of pathology. Blood corticosterone levels were increased in all animals at the conclusion of the testing sessions, but levels were higher in AW compared to sedentary groups indicating an effect of exercise on neuroendocrine function. Given the differential results of AW running on behavior and neuroendocrine function after OBX, further exploration of the beneficial effects of exercise in animal models of neuropathology is warranted.

Extended Swimming Exercise Reduces Inflammatory and Peripheral Neuropathic Pain in Rodents

Physical exercise is often recommended to patients who have chronic pain. However, only a small number of studies report exercise-induced analgesia in the setting of inflammatory pain, and even fewer relate long-term exercise to reductions in neuropathic pain. To address these questions, we evaluated the effect of extended swimming exercise in animal models of inflammatory (intraplantar injection of dilute formalin) and neuropathic (partial peripheral nerve injury) pain. We found that 9 days of swimming exercise in 37 degrees C water for 90 min/d decreased licking and flinching responses to formalin, as compared with nonexercised control animals. In addition, 18 to 25 days of swimming decreased nerve injury-induced cold allodynia and thermal hyperalgesia in rats, and 7 days of swimming decreased nerve injury-induced thermal hyperalgesia in mice. Our data indicate that swimming exercise reduces behavioral hypersensitivity in formalin- and nerve injury-induced animal models of persistent pain. Surprisingly, few animal studies have investigated the effects of extended exercise on chronic pain. Our results support the use of exercise as a nonpharmacological approach for the management of peripheral neuropathic pain.

Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle

Intramuscular triglyceride (IMTG) deposition in skeletal muscle is associated with obesity and type 2 diabetes (T2DM) and is thought to be related to insulin resistance (IR). Curiously, despite enhanced skeletal muscle insulin sensitivity, highly trained athletes and calorie-restricted (CR) monkeys also have increased IMTG. Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate the biosynthesis of cholesterol and fatty acids. SREBP-1 is increased by insulin in skeletal muscle in vitro and in skeletal muscle of IR subjects, but SREBP-1 expression has not been examined in exercise training or calorie restriction. We examined the relationship between IMTG and SREBP-1 expression in animal models of exercise and calorie restriction. Gastrocnemius and soleus muscle biopsies were obtained from 38 Sprague-Dawley rats (18 control and 20 exercise trained). Triglyceride content was higher in the gastrocnemius and soleus muscles of the trained rats. SREBP-1c mRNA, SREBP-1 precursor and mature proteins, and fatty acid synthase (FAS) protein were increased with exercise training. Monkeys (Macaca mulatta) were CR for a mean of 10.4 years, preventing weight gain and IR. Vastus lateralis muscle was obtained from 12 monkeys (6 CR and 6 controls). SREBP-1 precursor and mature proteins and FAS protein were higher in the CR monkeys. In addition, phosphorylation of ERK1/ERK2 was increased in skeletal muscle of CR animals. In summary, SREBP-1 protein and SREBP-1c mRNA are increased in interventions that increase IMTG despite enhanced insulin sensitivity. CR and exercise-induced augmentation of SREBP-1 expression may be responsible for the increased IMTG seen in skeletal muscle of highly conditioned athletes.

Motivating physical activity in animal models

A variety of physical activity models have been developed for animal studies to simulate the range of activities engaged by humans, from intense athletic training and competition to normal activities of daily life. These animal models of exercise cover a spectrum from high‐intensity to low‐intensity exercise with brief to long durations, and either forced or voluntary in nature. The varieties of animal models of exercise adapted for use in rats and mice, the most frequently studied animals, reviewed here include resistance or weight‐lifting exercise, treadmill running, voluntary wheel running, enriched environment, and skills training. The motivational factors used to induce exercise in these various animal models are considered, and the use of rewarding brain stimulation to motivate exercise in animals is described as well as recent findings that suggest that exercise in itself has rewarding aspects. Challenges of future animal studies of exercise are to better understand quantitative and qualitative aspects of the dimension of exercise and physical activity, and to move beyond descriptive reports of whether or not exercise has an effect with research that elucidates the mechanisms of exercise effects in both the central nervous system and periphery

506 Doppler myocardial imaging differentiates myocardial hypertrophy induced either by arterial hypertension or aortic stenosis

Background: Doppler Myokardial Imaging (DMI) has been shown to differentiate myocardial hypertrophy induced by aortic ligation and exercise in animal models. The purpose of this clinical study was to compare the impact of aortic stenosis and arterial hypertension on DMI parameters of regional left ventricular function. Methods: Twenty patients with arterial hypertension (HTN) and twenty patients with aortic stenosis (AOS) and exclusion of arterial hypertension were enrolled in the study. Coronary artery disease was ruled out by coronary angiography and LV angiography was done to measure ejection fraction in both groups. Ten age matched normals served as control. All patients had a conventional echocardiography study including a DMI study with an evaluation of the posterior wall derived from parasternal long axis views. The following parameters were assessed: enddiastolic wall thickness (WTed), peak systolic velocity (pVel), peak systolic strain rate (pSR), LV enddiastolic diameter (LVEDD) and LV ejection fraction (EF). Results: Both patient groups showed a normal EF and there was no difference in WTed. Peak velocity in the AOS group (aortic orifice area 0.6 ± 0.2 cm 2 )w as significantly lower compared to normals but did not differ from the HTN group. In contrast peak strain rate in the AOS group was significantly lower compared to both the HTN group and the normals (see table).