Neutrophil activation, antioxidant supplements and exercise-induced oxidative stress

Neutrophils produce free radicals known as reactive oxygen species (ROS), which assist in the clearance of damaged host tissue. Tissue damage may occur during exercise due to muscle damage, thermal stress and ischaemia/reperfusion. When produced in excess, neutrophil-derived ROS may overwhelm the body's endogenous antioxidant defence mechanisms, and this can lead to oxidative stress. There is increasing evidence for links between oxidative stress and a variety of pathological disorders such as cardiovascular diseases, cancer, chronic inflammatory diseases and post-ischaemic organ injury. A small number of studies have investigated whether there is a link between neutrophil activation and oxidative stress during exercise. In this review, we have summarised the findings of these studies. Exercise promotes the release of neutrophils into the circulation, and some evidence suggests that neutrophils mobilised after exercise have an enhanced capacity to generate some forms of ROS when stimulated in vitro. Neutrophil activation during exercise may challenge endogenous antioxidant defence mechanisms, but does not appear to increase lipid markers of oxidative stress to any significant degree, at least in the circulation. Antioxidant supplements such as N-acetylcysteine are effective at attenuating increases in the capacity of neutrophils to generate ROS when stimulated in vitro, whereas vitamin E reduces tissue infiltration of neutrophils during exercise. Free radicals generated during intense exercise may lead to DNA damage in leukocytes, but it is unknown if this damage is the result of neutrophil activation. Exercise enhances the expression of inducible haem (heme)-oxygenase (HO-1) in neutrophils after exercise, however, it is uncertain whether oxidative stress is the stimulus for this response.

Individual variability in compensatory eating following acute exercise in overweight and obese women

Background While compensatory eating following acute aerobic exercise is highly variable, little is known about the underling mechanisms that contribute to alterations in exercise-induced eating behaviour. Methods Overweight and obese women (BMI = 29.6 ± 4.0kg.m2) performed a bout of cycling individually tailored to expend 400kcal (EX), or a time-matched no exercise control condition in a randomised, counter-balanced order. Sixty minutes after the cessation of exercise, an ad libitum test meal was provided. Substrate oxidation and subjective appetite ratings were measured during exercise/time-matched rest, and during the period between the cessation of exercise and food consumption. Results While ad libitum EI did not differ between EX and the control condition (666.0 ± 203.9kcal vs. 664.6 ± 174.4kcal, respectively; ns), there was marked individual variability in compensatory energy intake (EI). The difference in EI between EX and the control condition ranged from -234.3 to +278.5kcal. Carbohydrate oxidation during exercise was positively associated with post-exercise EI, accounting for 37% of the variance in EI (r = 0.57; p = 0.02). Conclusions These data indicate that capacity of acute exercise to create a short-term energy deficit in overweight and obese women is highly variable. Furthermore, exercise-induced CHO oxidation can explain part of the variability in acute exercise-induced compensatory eating. Post-exercise compensatory eating could serve as an adaptive response to facilitate the restoration of carbohydrate balance.

Spectroscopic correlation analysis of NMR-based metabonomics in exercise science

Spectroscopic studies of complex clinical fluids have led to the application of a more holistic approach to their chemical analysis becoming more popular and widely employed. The efficient and effective interpretation of multidimensional spectroscopic data relies on many chemometric techniques and one such group of tools is represented by so-called correlation analysis methods. Typical of these techniques are two-dimensional correlation analysis and statistical total correlation spectroscopy (STOCSY). Whilst the former has largely been applied to optical spectroscopic analysis, STOCSY was developed and has been applied almost exclusively to NMR metabonomic studies. Using a 1H NMR study of human blood plasma, from subjects recovering from exhaustive exercise trials, the basic concepts and applications of these techniques are examined. Typical information from their application to NMR-based metabonomics is presented and their value in aiding interpretation of NMR data obtained from biological systems is illustrated. Major energy metabolites are identified in the NMR spectra and the dynamics of their appearance and removal from plasma during exercise recovery are illustrated and discussed. The complementary nature of two-dimensional correlation analysis and statistical total correlation spectroscopy are highlighted.

Is recovery driven by central or peripheral factors? A role for the brain in recovery following intermittent-sprint exercise

Prolonged intermittent-sprint exercise (i.e., team sports) induce disturbances in skeletal muscle structure and function that are associated with reduced contractile function, a cascade of inflammatory responses, perceptual soreness, and a delayed return to optimal physical performance. In this context, recovery from exercise-induced fatigue is traditionally treated from a peripheral viewpoint, with the regeneration of muscle physiology and other peripheral factors the target of recovery strategies. The direction of this research narrative on post-exercise recovery differs to the increasing emphasis on the complex interaction between both central and peripheral factors regulating exercise intensity during exercise performance. Given the role of the central nervous system (CNS) in motor-unit recruitment during exercise, it too may have an integral role in post-exercise recovery. Indeed, this hypothesis is indirectly supported by an apparent disconnect in time-course changes in physiological and biochemical markers resultant from exercise and the ensuing recovery of exercise performance. Equally, improvements in perceptual recovery, even withstanding the physiological state of recovery, may interact with both feed-forward/feed-back mechanisms to influence subsequent efforts. Considering the research interest afforded to recovery methodologies designed to hasten the return of homeostasis within the muscle, the limited focus on contributors to post-exercise recovery from CNS origins is somewhat surprising. Based on this context, the current review aims to outline the potential contributions of the brain to performance recovery after strenuous exercise.

The effects of exercise and adipose tissue lipolysis on plasma adiponectin concentration and adiponectin receptor expression in human skeletal muscle

Objective It has been suggested that adiponectin regulates plasma free fatty acid (FFA) clearance by stimulating FFA uptake and/or oxidation in muscle. We aimed to determine changes in plasma adiponectin concentration and adiponectin receptor 1 and 2 mRNA expression in skeletal muscle during and after prolonged exercise under normal, fasting conditions (high FFA trial; HFA) and following pharmacological inhibition of adipose tissue lipolysis (low FFA trial; LFA). Furthermore, we aimed to detect and locate adiponectin in skeletal muscle tissue. Methods Ten subjects performed two exercise trials (120 min at 50% VO2max). Indirect calorimetry was used to determine total fat oxidation rate. Plasma samples were collected at rest, during exercise and during post-exercise recovery to determine adiponectin, FFA and glycerol concentrations. Muscle biopsies were taken to determine adiponectin protein and adiponectin receptor 1 and 2 mRNA expression and to localise intramyocellular adiponectin. Results Basal plasma adiponectin concentrations averaged 6.57±0.7 and 6.63±0.8 mg/l in the HFA and LFA trials respectively, and did not change significantly during or after exercise. In the LFA trial, plasma FFA concentrations and total fat oxidation rates were substantially reduced. However, plasma adiponectin and muscle adiponectin receptor 1 and 2 mRNA expression did not differ between trials. Immunohistochemical staining of muscle cross-sections showed the presence of adiponectin in the sarcolemma of individual muscle fibres and within the interfibrillar arterioles. Conclusion Plasma adiponectin concentrations and adiponectin receptor 1 and 2 mRNA expression in muscle are not acutely regulated by changes in adipose tissue lipolysis and/or plasma FFA concentrations. Adiponectin is abundantly expressed in muscle, and, for the first time, it has been shown to be present in/on the sarcolemma of individual muscle fibres.

Altering the redox state of skeletal muscle by glutathione depletion increases the exercise-activation of PGC-1α

We investigated the relationship between mitochondrial biogenesis, cell signalling and antioxidant enzymes by depleting skeletal muscle glutathione with diethyl maleate (DEM) which resulted in a demonstrable increase in oxidative stress during exercise. Animals were divided into six groups: (1) sedentary control rats; (2) sedentary rats treated with DEM; (3) exercise control rats euthanized immediately after exercise; (4) exercise rats + DEM; (5) exercise control rats euthanized 4 h after exercise, and; (6) exercise rats + DEM euthanized 4 h after exercise. Exercising animals ran on the treadmill at a 10% gradient at 20 m/min for the first 30 min. The speed was then increased every 10 min by 1.6 m/min until exhaustion. There was a reduction in total glutathione in the skeletal muscle of DEM treated animals compared to the control animals (P<0.05). Within the control group, total glutathione was higher in the sedentary group compared to after exercise (P<0.05). DEM treatment also significantly increased oxidative stress, as measured by increased plasma F2-isoprostanes (P<0.05). Exercising animals given DEM showed a significantly greater increase in peroxisome proliferator activated receptor γ coactivator-1α(PGC-1α) mRNA compared to the control animals that were exercised (P<0.05). This study provides novel evidence that by reducing the endogenous antioxidant glutathione in skeletal muscle and inducing oxidative stress through exercise, PGC-1α gene expression was augmented. These findings further highlight the important role of exercise induced oxidative stress in the regulation of mitochondrial biogenesis.

Cytokine expression and secretion by skeletal muscle cells : regulatory mechanisms and exercise effects

Cytokines are important mediators of various aspects of health and disease, including appetite, glucose and lipid metabolism, insulin sensitivity, skeletal muscle hypertrophy and atrophy. Over the past decade or so, considerable attention has focused on the potential for regular exercise to counteract a range of disease states by modulating cytokine production. Exercise stimulates moderate to large increases in the circulating concentrations of interleukin (IL)-6, IL-8, IL-10, IL-1 receptor antagonist, granulocyte-colony stimulating factor, and smaller increases in tumor necrosis factor-α, monocyte chemotactic protein-1, IL-1β, brain-derived neurotrophic factor, IL-12p35/p40 and IL-15. Although many of these cytokines are also expressed in skeletal muscle, not all are released from skeletal muscle into the circulation during exercise. Conversely, some cytokines that are present in the circulation are not expressed in skeletal muscle after exercise. The reasons for these discrepant cytokine responses to exercise are unclear. In this review, we address these uncertainties by summarizing the capacity of skeletal muscle cells to produce cytokines, analyzing other potential cellular sources of circulating cytokines during exercise, and discussing the soluble factors and intracellular signaling pathways that regulate cytokine synthesis (e.g., RNA-binding proteins, microRNAs, suppressor of cytokine signaling proteins, soluble receptors).

Exercise, Nutrition, and Bone Health

Optimal bone metabolism is the result of hormonal, nutritional, and mechanical harmony, and a deficit in one area is usually impossible to overcome by improvements in others. Exercise during growth influences bone modeling locally at the regions being loaded, whereas calcium is thought to act systemically to influence bone remodeling. Despite acting through different mechanisms, a growing body of research suggests that exercise and calcium may not operate independently. Low dietary calcium intake or reduced bioavailability may minimize the adaptive response to exercise-induced bone loading. Conversely, adequate levels of calcium intake can maximize the positive effect of physical activity on bone health during the growth period of children and adolescents. Research also suggests that adequate levels of calcium intake can maximize bone density at the regions being loaded during exercise. Achieving optimal bone health and minimizing one’s risk of osteoporotic fracture later in life depend on a lifelong approach. This approach relies on the establishment of an optimum level of bone during the growth years, with a subsequent goal to maintain and slow the rate of age-related bone loss thereafter. Exercise, adequate nutrition, and optimal hormone levels are the components that influence the bone outcome. Making healthy nutritional choices, engaging in weight-bearing physical activity, and ensuring optimal hormone levels during growth provides a window of opportunity to build optimal bone mass, to reduce the risk of fracture later in life. Concurrent management of fracture risk with a physical activity prescription, adequate nutrition, and pharmacotherapy for osteoporosis when required offers the best approach to optimal bone health throughout adulthood.

Modulating exercise-induced hormesis: Does less equal more?

Hormesis enco 16 mpasses the notion that low levels of stress stimulate or upregulate 17 existing cellular and molecular pathways that improve the capacity of cells and organisms to 18 withstand greater stress. This notion underlies much of what we know about how exercise 19 conditions the body and induces long-term adaptations. During exercise, the body is 20 exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and 21 mechanical stress. These stressors activate biochemical messengers, which in turn activate 22 various signaling pathways that regulate gene expression and adaptive responses. 23 Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and 24 cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress 25 and inflammation. However, reactive oxygen species and inflammatory mediators are key 26 signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. 27 Conversely, withholding dietary carbohydrate and restricting muscle blood flow during 28 exercise may augment adaptations to exercise. In this review article, we combine, integrate, 29 and apply knowledge about the fundamental mechanisms of exercise adaptation. We also 30 critically evaluate the rationale for using interventions that target these mechanisms under 31 the overarching concept of hormesis. There is currently insufficient evidence to establish 32 whether these treatments exert dose-dependent effects on muscle adaptation. However, 33 there appears to be some dissociation between the biochemical/molecular effects and 34 functional/performance outcomes of some of these treatments. Although several of these 35 treatments influence common kinases, transcription factors and proteins, it remains to be 36 determined if these interventions complement or negate each other, and whether such 37 effects are strong enough to influence adaptations to exercise.

Systematic review and meta-analysis of the effects of exercise for those with cancer-related lymphedema

Objective: To evaluate the effects of exercise on cancer-related lymphedema and related symptoms, and to determine the need for those with lymphedema to wear compression during exercise. Data Sources: CINAHL, Cochrane, Ebscohost, MEDLINE, Pubmed, ProQuest Health and Medical Complete, ProQuest Nursing and Allied Health Source, Science Direct and SPORTDiscus databases were searched for trials published prior to 1 January, 2015. Study Selection: Randomised and non-randomised, controlled trials, and single group pre-post studies published in English-language were included. Twenty-one (exercise) and four (compression and exercise) studies met inclusion criteria. Data Extraction: Data was extracted into tabular format using predefined data fields by one reviewer and assessed for accuracy by a second reviewer. Study quality was evaluated using the Effective Public Health Practice Project assessment tool. Data Synthesis: Data was pooled using a random effects model to assess the effects of acute and long-term exercise on lymphedema and lymphedema-associated symptoms, with subgroup analyses for exercise mode and intervention length. There was no effect of exercise (acute or intervention) on lymphedema or associated symptoms with standardised mean differences from all analyses ranging between −0.2 and 0.1 (p-values ≥0.22). Findings from subgroup analyses for exercise mode (aerobic, resistance, mixed, other) and intervention duration (>12 weeks or ≤12 weeks) were consistent with these findings; that is, no effect on lymphedema or associated symptoms. There were too few studies evaluating the effect of compression during regular exercise to conduct a meta-analysis. Conclusions: Individuals with secondary lymphedema can safely participate in progressive, regular exercise without experiencing a worsening of lymphedema or related-symptoms. However, the results also do not suggest any improvements will occur in lymphedema. At present, there is insufficient evidence to support or refute the current clinical recommendation to wear compression garments during regular exercise.

The use of metabolomics to monitor simultaneous changes in metabolic variables following supramaximal low volume high intensity exercise

High Intensity Exercise (HIE) stimulates greater physiological remodeling when compared to workload matched low-moderate intensity exercise. This study utilized an untargeted metabolomics approach to examine the metabolic perturbations that occur following two workload matched supramaximal low volume HIE trials. In a randomized order, 7 untrained males completed two exercise protocols separated by one week; 1) HIE150%: 30 x 20s cycling at 150% VO2peak, 40s passive rest; 2) HIE300%: 30 x 10s cycling at 300% VO2peak, 50 s passive rest. Total exercise duration was 30 minutes for both trials. Blood samples were taken at rest, during and immediately following exercise and at 60 minutes post exercise. Gas chromatography-mass spectrometry (GC-MS) analysis of plasma identified 43 known metabolites of which 3 demonstrated significant fold changes (HIE300% compared to the HIE150% value) during exercise, 14 post exercise and 23 at the end of the recovery period. Significant changes in plasma metabolites relating to lipid metabolism [fatty acids: dodecanoate (p=0.042), hexadecanoate (p=0.001), octadecanoate (p=0.001)], total cholesterol (p=0.001), and glycolysis [lactate (p=0.018)] were observed following exercise and during the recovery period. The HIE300% protocol elicited greater metabolic changes relating to lipid metabolism and glycolysis when compared to HIE150% protocol. These changes were more pronounced throughout the recovery period rather than during the exercise bout itself. Data from the current study demonstrate the use of metabolomics to monitor intensity-dependent changes in multiple metabolic pathways following exercise. The small sample size indicates a need for further studies in a larger sample cohort to validate these findings.

Interactive processes link the multiple symptoms of fatigue in sport competition

Muscle physiologists often describe fatigue simply as a decline of muscle force and infer this causes an athlete to slow down. In contrast, exercise scientists describe fatigue during sport competition more holistically as an exercise-induced impairment of performance. The aim of this review is to reconcile the different views by evaluating the many performance symptoms/measures and mechanisms of fatigue. We describe how fatigue is assessed with muscle, exercise or competition performance measures. Muscle performance (single muscle test measures) declines due to peripheral fatigue (reduced muscle cell force) and/or central fatigue (reduced motor drive from the CNS). Peak muscle force seldom falls by >30% during sport but is often exacerbated during electrical stimulation and laboratory exercise tasks. Exercise performance (whole-body exercise test measures) reveals impaired physical/technical abilities and subjective fatigue sensations. Exercise intensity is initially sustained by recruitment of new motor units and help from synergistic muscles before it declines. Technique/motor skill execution deviates as exercise proceeds to maintain outcomes before they deteriorate, e.g. reduced accuracy or velocity. The sensation of fatigue incorporates an elevated rating of perceived exertion (RPE) during submaximal tasks, due to a combination of peripheral and higher CNS inputs. Competition performance (sport symptoms) is affected more by decision-making and psychological aspects, since there are opponents and a greater importance on the result. Laboratory based decision making is generally faster or unimpaired. Motivation, self-efficacy and anxiety can change during exercise to modify RPE and, hence, alter physical performance. Symptoms of fatigue during racing, team-game or racquet sports are largely anecdotal, but sometimes assessed with time-motion analysis. Fatigue during brief all-out racing is described biomechanically as a decline of peak velocity, along with altered kinematic components. Longer sport events involve pacing strategies, central and peripheral fatigue contributions and elevated RPE. During match play, the work rate can decline late in a match (or tournament) and/or transiently after intense exercise bursts. Repeated sprint ability, agility and leg strength become slightly impaired. Technique outcomes, such as velocity and accuracy for throwing, passing, hitting and kicking, can deteriorate. Physical and subjective changes are both less severe in real rather than simulated sport activities. Little objective evidence exists to support exercise-induced mental lapses during sport. A model depicting mind-body interactions during sport competition shows that the RPE centre-motor cortex-working muscle sequence drives overall performance levels and, hence, fatigue symptoms. The sporting outputs from this sequence can be modulated by interactions with muscle afferent and circulatory feedback, psychological and decision-making inputs. Importantly, compensatory processes exist at many levels to protect against performance decrements. Small changes of putative fatigue factors can also be protective. We show that individual fatigue factors including diminished carbohydrate availability, elevated serotonin, hypoxia, acidosis, hyperkalaemia, hyperthermia, dehydration and reactive oxygen species, each contribute to several fatigue symptoms. Thus, multiple symptoms of fatigue can occur simultaneously and the underlying mechanisms overlap and interact. Based on this understanding, we reinforce the proposal that fatigue is best described globally as an exercise-induced decline of performance as this is inclusive of all viewpoints.

Consecutive days of cold water immersion: effects on cycling performance and heart rate variability.

We investigated performance and heart rate (HR) variability (HRV) over consecutive days of cycling with post-exercise cold water immersion (CWI) or passive recovery (PAS). In a crossover design, 11 cyclists completed two separate 3-day training blocks (120 min cycling per day, 66 maximal sprints, 9 min time trialling [TT]), followed by 2 days of recovery-based training. The cyclists recovered from each training session by standing in cold water (10 °C) or at room temperature (27 °C) for 5 min. Mean power for sprints, total TT work and HR were assessed during each session. Resting vagal-HRV (natural logarithm of square-root of mean squared differences of successive R-R intervals; ln rMSSD) was assessed after exercise, after the recovery intervention, during sleep and upon waking. CWI allowed better maintenance of mean sprint power (between-trial difference [90 % confidence limits] +12.4 % [5.9; 18.9]), cadence (+2.0 % [0.6; 3.5]), and mean HR during exercise (+1.6 % [0.0; 3.2]) compared with PAS. ln rMSSD immediately following CWI was higher (+144 % [92; 211]) compared with PAS. There was no difference between the trials in TT performance (-0.2 % [-3.5; 3.0]) or waking ln rMSSD (-1.2 % [-5.9; 3.4]). CWI helps to maintain sprint performance during consecutive days of training, whereas its effects on vagal-HRV vary over time and depend on prior exercise intensity.

Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease

Objectives In non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is intricately linked with a number of metabolic alterations. We studied substrate utilisation in NAFLD during basal, insulin-stimulated and exercise conditions, and correlated these outcomes with disease severity. Methods 20 patients with NAFLD (mean±SD body mass index (BMI) 34.1±6.7 kg/m2) and 15 healthy controls (BMI 23.4±2.7 kg/m2) were assessed. Respiratory quotient (RQ), whole-body fat (Fatox) and carbohydrate (CHOox) oxidation rates were determined by indirect calorimetry in three conditions: basal (resting and fasted), insulin-stimulated (hyperinsulinaemic–euglycaemic clamp) and exercise (cycling at an intensity to elicit maximal Fatox). Severity of disease and steatosis were determined by liver histology, hepatic Fatox from plasma β-hydroxybutyrate concentrations, aerobic fitness expressed as , and visceral adipose tissue (VAT) measured by computed tomography. Results Within the overweight/obese NAFLD cohort, basal RQ correlated positively with steatosis (r=0.57, p=0.01) and was higher (indicating smaller contribution of Fatox to energy expenditure) in patients with NAFLD activity score (NAS) ≥5 vs <5 (p=0.008). Both results were independent of VAT, % body fat and BMI. Compared with the lean control group, patients with NAFLD had lower basal whole-body Fatox (1.2±0.3 vs 1.5±0.4 mg/kgFFM/min, p=0.024) and lower basal hepatic Fatox (ie, β-hydroxybutyrate, p=0.004). During exercise, they achieved lower maximal Fatox (2.5±1.4 vs. 5.8±3.7 mg/kgFFM/min, p=0.002) and lower (p<0.001) than controls. Fatox during exercise was not associated with disease severity (p=0.79). Conclusions Overweight/obese patients with NAFLD had reduced hepatic Fatox and reduced whole-body Fatox under basal and exercise conditions. There was an inverse relationship between ability to oxidise fat in basal conditions and histological features of NAFLD including severity of steatosis and NAS

Antioxidant supplementation reduces skeletal muscle mitochondrial biogenesis

Purpose: Exercise increases the production of reactive oxygen species (ROS) in skeletal muscle, and athletes often consume antioxidant supplements in the belief they will attenuate ROS-related muscle damage and fatigue during exercise. However, exercise-induced ROS may regulate beneficial skeletal muscle adaptations, such as increased mitochondrial biogenesis. We therefore investigated the effects of long-term antioxidant supplementation with vitamin E and alpha-lipoic acid on changes in markers of mitochondrial biogenesis in the skeletal muscle of exercise-trained and sedentary rats. Methods: Male Wistar rats were divided into four groups: 1) sedentary control diet, 2) sedentary antioxidant diet, 3) exercise control diet, and 4) exercise antioxidant diet. Animals ran on a treadmill 4 d.wk(-1) at similar to 70% V (over dot)O(2max) for up to 90 min.d(-1) for 14 wk. Results: Consistent with the augmentation of skeletal muscle mitochondrial biogenesis and antioxidant defenses, after training there were significant increases in peroxisome proliferator-activated receptor F coactivator 1 alpha (PGC-1 alpha) messenger RNA (mRNA) and protein, cytochrome C oxidase subunit IV (COX IV) and cytochrome C protein abundance, citrate synthase activity, Nfe2l2, and SOD2 protein (P < 0.05). Antioxidant supplementation reduced PGC-1 alpha mRNA, PGC-1 alpha and COX IV protein, and citrate synthase enzyme activity (P < 0.05) in both sedentary and exercise-trained rats. Conclusions: Vitamin E and alpha-lipoic acid supplementation suppresses skeletal muscle mitochondrial biogenesis, regardless of training status.