Treadmill running produces both positive and negative physiological adaptations in Sprague-Dawley rats

Exercise training produces a vast array of physiological adaptations, ranging from changes in metabolism to muscle mitochondrial biogenesis. Researchers studying the physiological effects of exercise often use animal models that employ forced exercise regimens that include aversive motivation, which could activate the stress response. This study examined the effect of forced treadmill running (8 wk) on several physiological systems that are sensitive to training and stress. Forced treadmill running produced both positive and negative physiological adaptations. Indicative of positive training adaptations, exercised male Sprague-Dawley rats had a decrease in body weight gain and an increase in muscle citrate synthase activity compared with sedentary controls. In contrast, treadmill running also resulted in the potentially negative adaptations of adrenal hypertrophy, thymic involution, decreased serum corticosteroid binding globulin, elevated lymphocyte nitrite concentrations, suppressed lymphocyte proliferation, and suppressed antigen-specific IgM. Such alterations in neuroendocrine tissues and immune responses are commonly associated with chronic stress. Thus treadmill running produces both positive training adaptations and potentially negative adaptations that are indicative of chronic stress. Researchers employing forced activity need to be aware that this type of exercise procedure also produces physiological adaptations indicative of chronic stress and that these changes could potentially impact other measures of interest.     

Cardiovascular effects of treadmill exercise in physiological and pathological preclinical settings

Exercise adaptations result from a coordinated response of multiple organ systems, including cardiovascular, pulmonary, endocrine-metabolic, immunologic, and skeletal muscle. Among these, the cardiovascular system is the most directly affected by exercise, and it is responsible for many of the important acute changes occurring during physical training. In recent years, the development of animal models of pathological or physiological cardiac overload has allowed researchers to precisely analyze the complex cardiovascular responses to stress in genetically altered murine models of human cardiovascular disease. The intensity-controlled treadmill exercise represents a well-characterized model of physiological cardiac hypertrophy because of its ability to mimic the typical responses to exercise in humans. In this review, we describe cardiovascular adaptations to treadmill exercise in mice and the most important parameters that can be used to quantify such modifications. Moreover, we discuss how treadmill exercise can be used to perform physiological testing in mouse models of disease and to enlighten the role of specific signaling pathways on cardiac function.     

Special feature for the Olympics: effects of exercise on the immune system: exercise effects on mucosal immunity

The present review examines the effects of exercise on mucosal immunity in recreational and elite athletes and the role of mucosal immunity in respiratory illness. Habitual exercise at an intense level can cause suppression of mucosal immune parameters, while moderate exercise may have positive effects. Saliva is the most commonly used secretion for measurement of secretory antibodies in the assessment of mucosal immune status. Salivary IgA and IgM concentrations decline immediately after a bout of intense exercise, but usually recover within 24 h. Training at an intense level over many years can result in a chronic suppression of salivary immunoglobulin levels. The degree of immune suppression and the recovery rates after exercise are associated with the intensity of exercise and the duration or volume of the training. Low levels of salivary IgM and IgA, particularly the IgA1 subclass, are associated with an increased risk of respiratory illness in athletes. Monitoring mucosal immune parameters during critical periods of training provides an assessment of the upper respiratory tract illness risk status of an individual athlete. The mechanisms underlying the mucosal immune suppression are unknown.     

Nutritional modulation of training-induced skeletal muscle adaptations

Skeletal muscle displays remarkable plasticity, enabling substantial adaptive modifications in its metabolic potential and functional characteristics in response to external stimuli such as mechanical loading and nutrient availability. Contraction-induced adaptations are determined largely by the mode of exercise and the volume, intensity, and frequency of the training stimulus. However, evidence is accumulating that nutrient availability serves as a potent modulator of many acute responses and chronic adaptations to both endurance and resistance exercise. Changes in macronutrient intake rapidly alter the concentration of blood-borne substrates and hormones, causing marked perturbations in the storage profile of skeletal muscle and other insulin-sensitive tissues. In turn, muscle energy status exerts profound effects on resting fuel metabolism and patterns of fuel utilization during exercise as well as acute regulatory processes underlying gene expression and cell signaling. As such, these nutrient-exercise interactions have the potential to activate or inhibit many biochemical pathways with putative roles in training adaptation. This review provides a contemporary perspective of our understanding of the molecular and cellular events that take place in skeletal muscle in response to both endurance and resistance exercise commenced after acute and/or chronic alterations in nutrient availability (carbohydrate, fat, protein, and several antioxidants). Emphasis is on the results of human studies and how nutrient provision (or lack thereof) interacts with specific contractile stimulus to modulate many of the acute responses to exercise, thereby potentially promoting or inhibiting subsequent training adaptation.     

Skeletal muscle adaptation to exercise: a century of progress.

Skeletal muscle physiology and biochemistry is an established field with Nobel Prize-winning scientists, dating back to the 1920s. Not until the mid to late 1960s did there appear a major focus on physiological and biochemical training adaptations in skeletal muscle. The study of adaptations to exercise training reveals a wide range of integrative approaches, from the systemic to the molecular level. Advances in our understanding of training adaptations have come in waves caused by the introduction of new experimental approaches. Research has revealed that exercise can be effective at preventing and/or treating some of the most common chronic diseases of the latter half of the 20th century. Endurance-trained muscle is more effective at clearing plasma triglyceride, glucose, and free fatty acids. However, at the present time, most of the mechanisms underlying the adaptation of human skeletal muscle to exercise still remain to be discovered. Little is known about the regulatory factors (e.g., trans-acting proteins or signaling pathways) directly modulating the expression of exercise-responsive genes. Because so many potential physiological and biochemical signals change during exercise, it will be an important challenge in the next century to move beyond "correlational studies" and to identify responsible mechanisms. Skeletal muscle metabolic adaptations may prove to be a critical component to preventing diseases such as coronary heart disease, type 2 diabetes, and obesity. Therefore, training studies have had an impact on setting the stage for a potential "preventive medicine reformation" in a society needing a return to a naturally active lifestyle of our ancestors.     

Purinergic signaling as a new mechanism underlying physical exercise benefits: a narrative review

In the last years, it has become evident that both acute and chronic physical exercise trigger responses/adaptations in the purinergic signaling and these adaptations can be considered one important mechanism related to the exercise benefits for health improvement. Purinergic system is composed of enzymes (ectonucleotidases), receptors (P1 and P2 families), and molecules (ATP, ADP, adenosine) that are able to activate these receptors. These components are widely distributed in almost all cell types, and they respond/act in a specific manner depending on the exercise types and/or intensities as well as the cell type (organ/tissue analyzed). For example, while acute intense exercise can be associated with tissue damage, inflammation, and platelet aggregation, chronic exercise exerts anti-inflammatory and anti-aggregant effects, promoting health and/or treating diseases. All of these effects are dependent on the purinergic signaling. Thus, this review was designed to cover the aspects related to the relationship between physical exercise and purinergic signaling, with emphasis on the modulation of ectonucleotidases and receptors. Here, we discuss the impact of different exercise protocols as well as the differences between acute and chronic effects of exercise on the extracellular signaling exerted by purinergic system components. We also reinforce the concept that purinergic signaling must be understood/considered as a mechanism by which exercise exerts its effects.     

Oxidative stress and inflammation: liver responses and adaptations to acute and regular exercise

The liver is remarkably important during exercise outcomes due to its contribution to detoxification, synthesis, and release of biomolecules, and energy supply to the exercising muscles. Recently, liver has been also shown to play an important role in redox status and inflammatory modulation during exercise. However, while several studies have described the adaptations of skeletal muscles to acute and chronic exercise, hepatic changes are still scarcely investigated. Indeed, acute intense exercise challenges the liver with increased reactive oxygen species (ROS) and inflammation onset, whereas regular training induces hepatic antioxidant and anti-inflammatory improvements. Acute and regular exercise protocols in combination with antioxidant and anti-inflammatory supplementation have been also tested to verify hepatic adaptations to exercise. Although positive results have been reported in some acute models, several studies have shown an increased exercise-related stress upon liver. A similar trend has been observed during training: while synergistic effects of training and antioxidant/anti-inflammatory supplementations have been occasionally found, others reported a blunting of relevant adaptations to exercise, following the patterns described in skeletal muscles. This review discusses current data regarding liver responses and adaptation to acute and regular exercise protocols alone or combined with antioxidant and anti-inflammatory supplementation. The understanding of the mechanisms behind these modulations is of interest for both exercise-related health and performance outcomes.     

Effects of exercise on endothelium and endothelium/smooth muscle cross talk: role of exercise-induced hemodynamics

Physical activity, exercise training, and fitness are associated with decreased cardiovascular risk. In the context that a risk factor "gap" exists in the explanation for the beneficial effects of exercise on cardiovascular disease, it has recently been proposed that exercise generates hemodynamic stimuli which exert direct effects on the vasculature that are antiatherogenic. In this review we briefly introduce some of the in vitro and in vivo evidence relating exercise hemodynamic modulation and vascular adaptation. In vitro data clearly demonstrate the importance of shear stress as a potential mechanism underlying vascular adaptations associated with exercise. Supporting this is in vivo human data demonstrating that exercise-mediated shear stress induces localized impacts on arterial function and diameter. Emerging evidence suggests that exercise-related changes in hemodynamic stimuli other than shear stress may also be associated with arterial remodeling. Taken together, in vitro and in vivo data strongly imply that hemodynamic influences combine to orchestrate a response to exercise and training that regulates wall stress and peripheral vascular resistance and contributes to the antiatherogenic impacts of physical activity, fitness, and training.     

Exercise induces renin–angiotensin system unbalance and high collagen expression in the heart of Mas-deficient mice

The renin–angiotensin system (RAS) is involved in the cardiac and vascular remodeling associated with cardiovascular diseases. Angiotensin (Ang) II/AT₁ axis is known to promote cardiac hypertrophy and collagen deposition. In contrast, Ang-(1–7)/Mas axis opposes Ang II effects in the heart producing anti-trophic and anti-fibrotic effects. Exercise training is known to induce cardiac remodeling with physiological hypertrophy without fibrosis. We hypothesize that cardiac remodeling induced by chronic exercise depends on the action of Ang-(1–7)/Mas axis. Thus, we evaluated the effect of exercise training on collagen deposition and RAS components in the heart of FVB/N mice lacking Mas receptor (Mas-KO). Male wild-type and Mas-KO mice were subjected to a moderate-intense swimming exercise training for 6 weeks. The left ventricle (LV) of the animals was sectioned and submitted to qRT-PCR and histological analysis. Circulating and tissue angiotensin peptides were measured by RIA. Sedentary Mas-KO presented a higher circulating Ang II/Ang-(1–7) ratio and an increased ACE2 expression in the LV. Physical training induced in Mas-KO and WT a similar cardiac hypertrophy accompanied by a pronounced increase in collagen I and III mRNA expression. Trained Mas-KO and trained WT presented increased Ang-(1–7) in the blood. However, only in trained-WT there was an increase in Ang-(1–7) in the LV. In summary, we showed that deletion of Mas in FVB/N mice produced an unbalance in RAS equilibrium increasing Ang II/AT₁ arm and inducing deleterious cardiac effects as deposition of extracellular matrix proteins. These data indicate that Ang-(1–7)/Mas axis is an important counter-regulatory mechanism in physical training mediate cardiac adaptations.     

Novel quantitative phenotypes of exercise training in mouse models

Regular physical exercise has beneficial effects in many human disease states, including cardiovascular diseases, cancer, and depression. Exercise training of genetically modified mouse models may provide insight into the molecular mechanisms that underlie the beneficial effects of exercise. Presently, there is relatively little understanding of the normal physiology of mouse exercise. In this paper, we describe a novel computerized voluntary wheel-running system capable of recording and analyzing individual wheel rotations. Using this system, we demonstrate that C57BL/6 mice run considerable distances during the night in short bouts and at a preferred speed: the cruising speed. We find that the vast majority of running occurs around this cruising speed, which is close to the maximum speed at which the animal can run but is significantly higher than the average speeds recorded by simple digital odometers. We describe how these parameters vary with exercise training and demonstrate marked sex differences in the patterns of voluntary exercise. The results of this study have important implications for the design and interpretation of both voluntary and forced exercise experiments in mouse models. The novel parameters described provide more physiological quantitative measures of voluntary exercise activity and training and will extend the physiological utility of exercise training as a phenotyping tool in genetic mouse models.     

Impact of exercise training on cardiovascular disease and risk

Epidemiological studies in large cohorts support the notion that physical fitness is associated with reduced cardiovascular mortality and hospitalization due to cardiovascular disease. During the last 20 years even the concept of resting inactive after a myocardial infarction has dramatically changed and nowadays patients are mobilized and included into exercise training programs very shortly after the insult. Unfortunately, these beneficial effects of exercise training are independent of the genetic background and are only observed in case the training program is not paused for a longer time. Therefore, to take advantage of the effects of exercise training in health care the challenge for the future is to increase exercise compliance by offering interesting and effective exercise training programs. At the physiological and molecular level, exercise training affects several organs like the vascular system and the skeletal muscle. Changes elicited by regular exercise training range in the vascular system from increasing vasodilation due to an elevation of bioavailable nitric oxide to a shift in the catabolic/anabolic balance in the peripheral skeletal muscle. In this review we discuss the healthy benefit of exercise training and the molecular changes triggered by exercise training in the setting of secondary prevention.     

Proteomics applied to exercise physiology: a cutting-edge technology

Exercise research has always drawn the attention of the scientific community because it can be widely applied to sport training, health improvement, and disease prevention. For many years numerous tools have been used to investigate the several physiological adaptations induced by exercise stimuli. Nowadays a closer look at the molecular mechanisms underlying metabolic pathways and muscular and cardiovascular adaptation to exercise are among the new trends in exercise physiology research. Considering this, to further understand these adaptations as well as pathology attenuation by exercise, several studies have been conducted using molecular investigations, and this trend looks set to continue. Through enormous biotechnological advances, proteomic tools have facilitated protein analysis within complex biological samples such as plasma and tissue, commonly used in exercise research. Until now, classic proteomic tools such as one- and two-dimensional polyacrylamide gel electrophoresis have been used as standard approaches to investigate proteome modulation by exercise. Furthermore, other recently developed in gel tools such as differential gel electrophoresis (DIGE) and gel-free techniques such as the protein labeling methods (ICAT, SILAC, and iTRAQ) have empowered proteomic quantitative analysis, which may successfully benefit exercise proteomic research. However, despite the three decades of 2-DE development, neither classic nor novel proteomic tools have been convincingly explored by exercise researchers. To this end, this review gives an overview of the directions in which exercise-proteome research is moving and examines the main tools that can be used as a novel strategy in exercise physiology investigation.     

Can we optimise the exercise training prescription to maximise improvements in mitochondria function and content?

Background

While there is agreement that exercise is a powerful stimulus to increase both mitochondrial function and content, we do not know the optimal training stimulus to maximise improvements in mitochondrial biogenesis.

Scope of review

This review will focus predominantly on the effects of exercise on mitochondrial function and content, as there is a greater volume of published research on these adaptations and stronger conclusions can be made.

Major conclusions

The results of cross-sectional studies, as well as training studies involving rats and humans, suggest that training intensity may be an important determinant of improvements in mitochondrial function (as determined by mitochondrial respiration), but not mitochondrial content (as assessed by citrate synthase activity). In contrast, it appears that training volume, rather than training intensity, may be an important determinant of exercise-induced improvements in mitochondrial content. Exercise-induced mitochondrial adaptations are quickly reversed following a reduction or cessation of physical activity, highlighting that skeletal muscle is a remarkably plastic tissue. Due to the small number of studies, more research is required to verify the trends highlighted in this review, and further studies are required to investigate the effects of different types of training on the mitochondrial sub-populations and also mitochondrial adaptations in different fibre types. Further research is also required to better understand how genetic variants influence the large individual variability for exercise-induced changes in mitochondrial biogenesis.

General significance

The importance of mitochondria for both athletic performance and health underlines the importance of better understanding the factors that regulate exercise-induced changes in mitochondrial biogenesis. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

Neurobiology of exercise

Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.     

Special feature for the Olympics: effects of exercise on the immune system: effects of exercise on the immune system in the elderly population

Immunosenescence is characterized by impaired cellular immune function concomitant with increased inflammatory activity. Immune dysfunction is associated with increased mortality risk in elderly people. An important part of human ageing is characterized by a decline in the ability of individuals to adapt to environmental stress. Exercise has been suggested as a prototype for studying the effects of stress factors on the cellular immune system. Studies of interactions between an acute bout of exercise and immune function may be a useful and an ethically acceptable tool to investigate cell trafficking, immune mobilization/deficiency and the acute phase response during physical stress situations in relation to human ageing. Elderly humans have a preserved ability to recruit T lymphocytes and NK cells in response to an acute bout of exercise. Physical exercise training programs do not result in major restoration of the senescent immune system in humans. However, highly conditioned elderly humans seem to have a relatively better preserved immune system, although it is not possible to conclude if this is linked to training or other lifestyle-related factors.     

Cigarette Smoke Inhibits Brain Mitochondrial Adaptations of Exercised Mice

Physical exercise and smoking are environmental factors that generally cause opposite health-promoting adaptations. Both physical exercise and smoking converge on mitochondrial adaptations in various tissues, including the pro-oxidant nervous system. Here, we analyzed the impact of cigarette smoking on exercise-induced brain mitochondrial adaptations in the hippocampus and pre-frontal cortex of adult mice. The animals were exposed to chronic cigarette smoke followed by 8 weeks of moderate-intensity physical exercise that increased mitochondrial activity in the hippocampus and pre-frontal cortex in the non-smoker mice. However, mice previously exposed to cigarette smoke did not present these exercise-induced mitochondrial adaptations. Our results suggest that smoking can inhibit some brain health-promoting changes induced by physical exercise.     

Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome

The aetiology of chronic fatigue syndrome (CFS) remains controversial and a number of hypotheses have been put forward to explain it. Research into the condition is hindered by the considerable heterogeneity seen across patients but several reports have highlighted disturbances to cholinergic mechanisms in terms of central nervous system activity, neuromuscular function and autoantibodies to muscarinic cholinergic receptors. This paper examines an altogether separate function for acetylcholine and that is its role as an important and generalized vasodilator. Most diseases are accompanied by a blunted response to acetylcholine but the opposite is true for CFS. Such sensitivity is normally associated with physical training so the finding in CFS is anomalous and may well be relevant to vascular symptoms that characterise many patients. There are several mechanisms that might lead to ACh endothelial sensitivity in CFS patients and various experiments have been designed to unravel the enigma. These are reported here.     

Invited review: Physiological and pathophysiological responses to intermittent hypoxia.

This mini-review summarizes the physiological adaptations to and pathophysiological consequences of intermittent hypoxia with special emphasis given to the pathophysiology associated with obstructive sleep apnea. Intermittent hypoxia is an effective stimulus for evoking the respiratory, cardiovascular, and metabolic adaptations normally associated with continuous chronic hypoxia. These adaptations are thought by some to be beneficial in that they may provide protection against disease as well as improve exercise performance in athletes. The long-term consequences of chronic intermittent hypoxia may have detrimental effects, including hypertension, cerebral and coronary vascular problems, developmental and neurocognitive deficits, and neurodegeneration due to the cumulative effects of persistent bouts of hypoxia. Emphasis is placed on reviewing the available data on intermittent hypoxia, making extensions from applicable information from acute and chronic hypoxia studies, and pointing out major gaps in information linking the genomic and cellular responses to intermittent hypoxia with physiological or pathophysiological responses.     

Effects of Pulse Current on Endurance Exercise and Its Anti-Fatigue Properties in the Hepatic Tissue of Trained Rats

Fatigue is synonymous with a wide spectrum of familiar physiological conditions, from pathology and general health, to sport and physical exercise. Strenuous, prolonged exercise training causes fatigue. Although several studies have investigated the effects of electrical stimulation frequency on muscle fatigue, the effects of percutaneous pulse current stimulation on fatigue in the hepatic tissue of trained rats is still unclear. In order to find an effective strategy to prevent fatigue or enhance recovery, the effects of pulse current on endurance exercise and its anti-fatigue properties in exercised rats were studied. Rats were subjected to one, three or five weeks of swimming exercise training. After exercise training, rats in the treated group received daily applications of pulse current. All rats were sacrificed after one, three or five weeks of swimming exercise, and the major biochemical indexes were measured in serum and liver. The results demonstrate that pulse current could prolong the exhaustion swimming time, as well as decrease serum ALT, AST and LD levels and liver MDA content. It also elevated serum LDH activity, liver SOD activity and glycogen content. Furthermore, pulse current increased the expression of Bcl-2 and decreased the expression of Bax. Taken together, these results show that pulse current can elevate endurance capacity and facilitate recovery from fatigue.     

Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity

Physical activity has been recently documented to play a fundamental physiological role in the regulation of autophagy in several tissues. It has also been reported that autophagy is required for exercise itself and for training-induced adaptations in glucose homeostasis. These autophagy-mediated metabolic improvements are thought to be largely dependent on the activation of the metabolic sensor PRKAA1/AMPK. However, it is unknown whether these important benefits stem from systemic adaptations or are due solely to alterations in skeletal muscle metabolism. To address this we utilized inducible, muscle-specific, atg7 knockout mice that we have recently generated. Our findings indicate that acute inhibition of autophagy in skeletal muscle just prior to exercise does not have an impact on physical performance, PRKAA1 activation, or glucose homeostasis. However, we reveal that autophagy is critical for the preservation of mitochondrial function during damaging muscle contraction. This effect appears to be gender specific affecting primarily females. We also establish that basal oxidative stress plays a crucial role in mitochondrial maintenance during normal physical activity. Therefore, autophagy is an adaptive response to exercise that ensures effective mitochondrial quality control during damaging physical activity.