Mobilizing serum factors and immune cells through exercise to counteract age-related changes in cancer risk.

An increasing body of evidence suggests that age-related immune changes and chronic inflammation contribute to cancer development. Recognizing that exercise has protective effects against cancer, promotes immune function, and beneficially modulates inflammation with ageing, this review outlines the current evidence indicating an emerging role for exercise immunology in preventing and treating cancer in older adults. A specific focus is on data suggesting that muscle- derived cytokines (myokines) mediate anti-cancer effects through promoting immunosurveillance against tumourigenesis or inhibiting cancer cell viability. Previous studies suggested that the exercise-induced release of myokines and other endocrine factors into the blood increases the capacity of blood serum to inhibit cancer cell growth in vitro. However, little is known about whether this effect is influenced by ageing. Prostate cancer is the second most common cancer in men. We therefore examined the effects of serum collected before and after exercise from healthy young and older men on the metabolic activity of androgen-responsive LNCaP and androgen-unresponsive PC3 prostate cancer cells. Exercise-conditioned serum collected from the young group did not alter cell metabolic activity, whereas post-exercise serum (compared with pre-exercise serum) from the older men inhibited the metabolic activity of LNCaP cancer cells. Serum levels of candidate cancer-inhibitory myokines oncostatin M and osteonectin increased in both age groups following exercise. Serum testosterone increased only in the younger men postexercise, potentially attenuating inhibitory effects of myokines on the LNCaP cell viability. The data from our study and the evidence in this review suggest that mobilizing serum factors and immune cells may be a key mechanism of how exercise counteracts cancer in the older population.

The Effect of Carbohydrate Ingestion Following Eccentric Resistance Exercise on AKT/mTOR and ERK Pathways: A Randomized, Double-Blinded, Crossover Study.

PURPOSE: To determine the acute effects of carbohydrate (CHO) ingestion following a bout of maximal eccentric resistance exercise on key anabolic kinases of mammalian target of rapamycin and extracellular signal-regulated kinase (ERK) pathways. The authors' hypothesis was that the activation of anabolic signaling pathways known to be upregulated by resistance exercise would be further stimulated by the physiological hyperinsulinemia resulting from CHO supplementation. METHODS: Ten resistance-trained men were randomized in a crossover, double-blind, placebo (PLA)-controlled manner to ingest either a noncaloric PLA or 3 g/kg of CHO beverage throughout recovery from resistance exercise. Muscle biopsies were collected at rest, immediately after a single bout of intense lower body resistance exercise, and after 3 hr of recovery. RESULTS: CHO ingestion elevated plasma glucose and insulin concentrations throughout recovery compared with PLA ingestion. The ERK pathway (phosphorylation of ERK1/2 [Thr202/Tyr204], RSK [Ser380], and p70S6K [Thr421/Ser424]) was markedly activated immediately after resistance exercise, without any effect of CHO supplementation. The phosphorylation state of AKT (Thr308) was unchanged postexercise in the PLA trial and increased at 3 hr of recovery above resting with ingestion of CHO compared with PLA. Despite stimulating-marked phosphorylation of AKT, CHO ingestion did not enhance resistance exercise-induced phosphorylation of p70S6K (Thr389) and rpS6 (Ser235/236 and Ser240/244). CONCLUSION: CHO supplementation after resistance exercise and hyperinsulinemia does not influence the ERK pathway nor the mTORC1 target p70S6K and its downstream proteins, despite the increased AKT phosphorylation.

A Systematic Review and Meta-Analysis of the Safety, Feasibility, and Effect of Exercise in Women With Stage II+ Breast Cancer.

OBJECTIVE: To systematically evaluate the safety, feasibility, and effect of exercise among women with stage II+ breast cancer. DATA SOURCES: CINAHL, Cochrane, Ebscohost, MEDLINE, Pubmed, ProQuest Health and Medical Complete, ProQuest Nursing and Allied Health Source, Science Direct and SPORTDiscus were searched for articles published before March 1, 2017. STUDY SELECTION: Randomized, controlled, exercise trials involving at least 50% of women diagnosed with stage II+ breast cancer were included. DATA EXTRACTION: Risk of bias was assessed and adverse event severity was classified using the Common Terminology Criteria. Feasibility was evaluated by computing median (range) recruitment, withdrawal, and adherence rates. Meta-analyses were performed to evaluate exercise safety and effects on health outcomes only. The influence of intervention characteristics (mode, supervision, duration and timing) on exercise outcomes were also explored. DATA SYNTHESIS: There were no differences in adverse events between exercise and usual care (risk difference: <0.01 ([95% CI: -0.01, 0.01], P=0.38). Median recruitment rate was 56% (1%-96%), withdrawal rate was 10% (0%-41%) and adherence rate was 82% (44%-99%). Safety and feasibility outcomes were similar, irrespective of exercise mode, supervision, duration, or timing. Effects of exercise for quality of life, fitness, fatigue, strength, anxiety, depression, body mass index and waist circumference compared with usual care were significant (standardized mean difference range: 0.17-0.77, P<0.05). CONCLUSION: The findings support the safety, feasibility, and effects of exercise for those with stage II+ breast cancer, suggesting that national and international exercise guidelines appear generalizable to women with local, regional, and distant breast cancer.

Divergent effects of cold water immersion versus active recovery on skeletal muscle fiber type and angiogenesis in young men.

Resistance training (RT) increases muscle fiber size and induces angiogenesis to maintain capillary density. Cold water immersion (CWI), a common postexercise recovery modality, may improve acute recovery, but it attenuates muscle hypertrophy compared with active recovery (ACT). It is unknown if CWI following RT alters muscle fiber type expression or angiogenesis. Twenty-one men strength trained for 12 wk, with either 10 min of CWI ( n = 11) or ACT ( n = 10) performed following each session. Vastus lateralis biopsies were collected at rest before and after training. Type IIx myofiber percent decreased ( P = 0.013) and type IIa myofiber percent increased with training ( P = 0.012), with no difference between groups. The number of capillaries per fiber increased from pretraining in the CWI group ( P = 0.004) but not the ACT group ( P = 0.955). Expression of myosin heavy chain genes ( MYH1 and MYH2), encoding type IIx and IIa fibers, respectively, decreased in the ACT group, whereas MYH7 (encoding type I fibers) increased in the ACT group versus CWI ( P = 0.004). Myosin heavy chain IIa protein increased with training ( P = 0.012) with no difference between groups. The proangiogenic vascular endothelial growth factor protein decreased posttraining in the ACT group versus CWI ( P < 0.001), whereas antiangiogenic Sprouty-related, EVH1 domain-containing protein 1 protein increased with training in both groups ( P = 0.015). Expression of microRNAs that regulate muscle fiber type (miR-208b and -499a) and angiogenesis (miR-15a, -16, and -126) increased only in the ACT group ( P < 0.05). CWI recovery after each training session altered the angiogenic and fiber type-specific response to RT through regulation at the levels of microRNA, gene, and protein expression.

Acute Inflammatory Response to Low-, Moderate-, and High-Load Resistance Exercise in Women With Breast Cancer-Related Lymphedema.

Background Resistance exercise is emerging as a potential adjunct therapy to aid in the management of breast cancer-related lymphedema (BCRL). However, the mechanisms underlying the relationships between the acute and long-term benefits of resistance exercise on BCRL are not well understood. Purpose To examine the acute inflammatory response to upper-body resistance exercise in women with BCRL and to compare these effects between resistance exercises involving low, moderate, and high loads. The impact on lymphedema status and associated symptoms was also compared. Methods A total of 21 women, 62 ± 10 years old, with BCRL participated in the study. Participants completed low-load (15-20 repetition maximum [RM]), moderate-load (10-12 RM), and high-load (6-8 RM) exercise sessions consisting of 3 sets of 6 upper-body resistance exercises. Sessions were completed in a randomized order separated by a 7- to 10-day wash-out period. Venous blood samples were obtained to assess markers of exercise-induced muscle damage and inflammation. Lymphedema status was assessed using bioimpedance spectroscopy and arm circumferences, and associated symptoms were assessed using Visual Analogue Scales for pain, heaviness, and tightness. Measurements were conducted before and 24 hours after the exercise sessions. Results No significant changes in creatine kinase, C-reactive protein, interleukin-6, and tumor necrosis factor-α were observed following the 3 resistance exercise sessions. There were no significant changes in arm swelling or symptom severity scores across the 3 resistance exercise conditions. Conclusions The magnitude of acute exercise-induced inflammation following upper-body resistance exercise in women with BCRL does not vary between resistance exercise loads.

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-1ß, 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).

Ibuprofen supplementation and its effects on NF-κB activation in skeletal muscle following resistance exercise.

Resistance exercise triggers a subclinical inflammatory response that plays a pivotal role in skeletal muscle regeneration. Nuclear factor-κB (NF-κB) is a stress signalling transcription factor that regulates acute and chronic states of inflammation. The classical NF-κB pathway regulates the early activation of post-exercise inflammation; however there remains scope for this complex transcription factor to play a more detailed role in post-exercise muscle recovery. Sixteen volunteers completed a bout of lower body resistance exercise with the ingestion of three 400 mg doses of ibuprofen or a placebo control. Muscle biopsy samples were obtained prior to exercise and at 0, 3 and 24 h post-exercise and analysed for key markers of NF-κB activity. Phosphorylated p65 protein expression and p65 inflammatory target genes were elevated immediately post-exercise independent of the two treatments. These changes did not translate to an increase in p65 DNA binding activity. NF-κB p50 protein expression and NF-κB p50 binding activity were lower than pre-exercise at 0 and 3 h post-exercise, but were elevated at 24 h post-exercise. These findings provide novel evidence that two distinct NF-κB pathways are active in skeletal muscle after resistance exercise. The initial wave of activity involving p65 resembles the classical pathway and is associated with the onset of an acute inflammatory response. The second wave of NF-κB activity comprises the p50 subunit, which has been previously shown to resolve an acute inflammatory program. The current study showed no effect of the ibuprofen treatment on markers of the NF-κB pathway, however examination of the within group effects of the exercise protocol suggests that this pathway warrants further research.

Effect of tocopherol on atherosclerosis, vascular function, and inflammation in apolipoprotein E knockout mice with subtotal nephrectomy.

BACKGROUND/AIMS: Inflammation and endothelial dysfunction contribute to cardiovascular disease, prevalent in chronic kidney disease (CKD). Antioxidant supplements such as tocopherols may reduce inflammation and atherosclerosis. This study aimed to investigate the effect of tocopherol supplementation on vascular function, aortic plaque formation, and inflammation in apolipoprotein E(-/-) mice with 5/6 nephrectomy as a model of combined cardiovascular and kidney disease. METHODS: Nephrectomized mice were assigned to a normal chow diet group (normal chow), a group receiving 1000 mg/kg diet of α-tocopherol supplementation or a group receiving 1000 mg/kg diet mixed-tocopherol (60% γ-tocopherol). RESULTS: Following 12 weeks, in vitro aortic endothelial-independent relaxation was enhanced with both α-tocopherol and mixed-tocopherol (P < 0.05), while mixed-tocopherol enhanced aortic contraction at noradrenaline concentrations of 3 × 10(-7) M to 3 × 10(-5) M (P < 0.05), when compared to normal chow. Supplementation with α- and mixed-tocopherol reduced systemic concentrations of IL-6 (P < 0.001 and P < 0.001, respectively) and IL-10 (P < 0.05 and P < 0.001, respectively), while α-tocopherol also reduced MCP-1 (P < 0.05) and tumor necrosis factor (TNF)-α (P < 0.05). Aortic sinus plaque area was significantly reduced with α-tocopherol supplementation when compared to normal chow (P < 0.01). CONCLUSION: Tocopherol supplementation favorably influenced vascular function and cytokine profile, while it was also effective in reducing atherosclerosis in the apolipoprotein E(-/-) mouse with CKD.

Metabolic and hormonal responses to isoenergetic high-intensity interval exercise and continuous moderate-intensity exercise.

This study investigated the effects of high-intensity interval training (HIIT) vs. work-matched moderate-intensity continuous exercise (MOD) on metabolism and counterregulatory stress hormones. In a randomized and counterbalanced order, 10 well-trained male cyclists and triathletes completed a HIIT session [81.6 ± 3.7% maximum oxygen consumption (V̇o2 max); 72.0 ± 3.2% peak power output; 792 ± 95 kJ] and a MOD session (66.7 ± 3.5% V̇o2 max; 48.5 ± 3.1% peak power output; 797 ± 95 kJ). Blood samples were collected before, immediately after, and 1 and 2 h postexercise. Carbohydrate oxidation was higher (P = 0.037; 20%), whereas fat oxidation was lower (P = 0.037; -47%) during HIIT vs. MOD. Immediately after exercise, plasma glucose (P = 0.024; 20%) and lactate (P < 0.01; 5.4×) were higher in HIIT vs. MOD, whereas total serum free fatty acid concentration was not significantly different (P = 0.33). Targeted gas chromatography-mass spectromtery metabolomics analysis identified and quantified 49 metabolites in plasma, among which 11 changed after both HIIT and MOD, 13 changed only after HIIT, and 5 changed only after MOD. Notable changes included substantial increases in tricarboxylic acid intermediates and monounsaturated fatty acids after HIIT and marked decreases in amino acids during recovery from both trials. Plasma adrenocorticotrophic hormone (P = 0.019), cortisol (P < 0.01), and growth hormone (P < 0.01) were all higher immediately after HIIT. Plasma norepinephrine (P = 0.11) and interleukin-6 (P = 0.20) immediately after exercise were not significantly different between trials. Plasma insulin decreased during recovery from both HIIT and MOD (P < 0.01). These data indicate distinct differences in specific metabolites and counterregulatory hormones following HIIT vs. MOD and highlight the value of targeted metabolomic analysis to provide more detailed insights into the metabolic demands of exercise.

Cold water immersion enhances recovery of submaximal muscle function after resistance exercise.

We investigated the effect of cold water immersion (CWI) on the recovery of muscle function and physiological responses after high-intensity resistance exercise. Using a randomized, cross-over design, 10 physically active men performed high-intensity resistance exercise followed by one of two recovery interventions: 1) 10 min of CWI at 10°C or 2) 10 min of active recovery (low-intensity cycling). After the recovery interventions, maximal muscle function was assessed after 2 and 4 h by measuring jump height and isometric squat strength. Submaximal muscle function was assessed after 6 h by measuring the average load lifted during 6 sets of 10 squats at 80% of 1 repetition maximum. Intramuscular temperature (1 cm) was also recorded, and venous blood samples were analyzed for markers of metabolism, vasoconstriction, and muscle damage. CWI did not enhance recovery of maximal muscle function. However, during the final three sets of the submaximal muscle function test, participants lifted a greater load (P < 0.05, Cohen's effect size: 1.3, 38%) after CWI compared with active recovery. During CWI, muscle temperature decreased ∼7°C below postexercise values and remained below preexercise values for another 35 min. Venous blood O2 saturation decreased below preexercise values for 1.5 h after CWI. Serum endothelin-1 concentration did not change after CWI, whereas it decreased after active recovery. Plasma myoglobin concentration was lower, whereas plasma IL-6 concentration was higher after CWI compared with active recovery. These results suggest that CWI after resistance exercise allows athletes to complete more work during subsequent training sessions, which could enhance long-term training adaptations.

Acute resistance exercise increases the expression of chemotactic factors within skeletal muscle.

INTRODUCTION: Intense resistance exercise causes mechanical loading of skeletal muscle, followed by muscle adaptation. Chemotactic factors likely play an important role in these processes. PURPOSE: We investigated the time course of changes in the expression and tissue localization of several key chemotactic factors in skeletal muscle during the early phase of recovery following resistance exercise. METHODS: Muscle biopsy samples were obtained from vastus lateralis of eight untrained men (22 ± 0.5 years) before and 2, 4 and 24 h after three sets of leg press, squat and leg extension at 80 % 1-RM. RESULTS: Monocyte chemotactic protein-1 (95×), interleukin-8 (2,300×), IL-6 (317×), urokinase-type plasminogen activator (15×), vascular endothelial growth factor (2×) and fractalkine (2.5×) mRNA was significantly elevated 2 h post-exercise. Interleukin-8 (38×) and interleukin-6 (58×) protein was also significantly elevated 2 h post-exercise, while monocyte chemotactic protein-1 protein was significantly elevated at 2 h (22×) and 4 h (21×) post-exercise. Monocyte chemotactic protein-1 and interleukin-8 were expressed by cells residing in the interstitial space between muscle fibers and, in some cases, were co-localized with CD68 + macrophages, PAX7 + satellite cells and blood vessels. However, the patterns of staining were inconclusive and not consistent. CONCLUSION: In conclusion, resistance exercise stimulated a marked increase in the mRNA and protein expression of various chemotactic factors in skeletal muscle. Myofibers were not the dominant source of these factors. These findings suggest that chemotactic factors regulate remodeling/adaptation of skeletal muscle during the early phase of recovery following resistance exercise.

The effects of sports drink osmolality on fluid intake and immunoendocrine responses to cycling in hot conditions.

We investigated the effects of two carbohydrate-based sports drinks on fluid intake and immunoendocrine responses to cycling. Six well-trained male cyclists completed trials on three separate days that involved cycling at 60% VO(2peak) for 90 min in hot conditions (28.1 ± 1.5ºC and 52.6 ± 3.1% relative humidity). During each trial, the subjects consumed ad libitum (1) an isotonic sports drink (osmolality 317 mOsm/kg), (2) a hypotonic sports drink (osmolality 193 mOsm/kg) or (3) plain water. The cyclists consumed significantly (p<0.05) more of the isotonic drink (1.23 ± 0.35 L) and hypotonic drink (1.44 ± 0.55 L) compared with water (0.73 ± 0.26 L). Compared with water (-0.96 ± 0.26 kg), body mass decreased significantly less after consuming the hypotonic drink (-0.50 ± 0.38 kg) but not the isotonic drink (-0.51 ± 0.41 kg). Blood glucose concentration was significantly higher at the end of the isotonic and hypotonic drink trials compared with the water trial. Neutrophil count and the plasma concentrations of catecholamines, interleukin 6 (IL-6), myeloperoxidase, calprotectin and myoglobin increased significantly during all three trials. IL-6 and calprotectin were significantly lower following the hypotonic drink trial compared with the water trial. In conclusion, hypotonic sports drinks are appealing for athletes to drink during exercise, and may help to offset fluid losses and attenuate some inflammatory responses to exercise.

Transcriptome analysis of neutrophils after endurance exercise reveals novel signaling mechanisms in the immune response to physiological stress.

Neutrophils serve as an intriguing model for the study of innate immune cellular activity induced by physiological stress. We measured changes in the transcriptome of circulating neutrophils following an experimental exercise trial (EXTRI) consisting of 1 h of intense cycling immediately followed by 1 h of intense running. Blood samples were taken at baseline, 3 h, 48 h, and 96 h post-EXTRI from eight healthy, endurance-trained, male subjects. RNA was extracted from isolated neutrophils. Differential gene expression was evaluated using Illumina microarrays and validated with quantitative PCR. Gene set enrichment analysis identified enriched molecular signatures chosen from the Molecular Signatures Database. Blood concentrations of muscle damage indexes, neutrophils, interleukin (IL)-6 and IL-10 were increased (P < 0.05) 3 h post-EXTRI. Upregulated groups of functionally related genes 3 h post-EXTRI included gene sets associated with the recognition of tissue damage, the IL-1 receptor, and Toll-like receptor (TLR) pathways (familywise error rate, P value < 0.05). The core enrichment for these pathways included TLRs, low-affinity immunoglobulin receptors, S100 calcium binding protein A12, and negative regulators of innate immunity, e.g., IL-1 receptor antagonist, and IL-1 receptor associated kinase-3. Plasma myoglobin changes correlated with neutrophil TLR4 gene expression (r = 0.74; P < 0.05). Neutrophils had returned to their nonactivated state 48 h post-EXTRI, indicating that their initial proinflammatory response was transient and rapidly counterregulated. This study provides novel insight into the signaling mechanisms underlying the neutrophil responses to endurance exercise, suggesting that their transcriptional activity was particularly induced by damage-associated molecule patterns, hypothetically originating from the leakage of muscle components into the circulation.

Early inflammatory and myogenic responses to resistance exercise in the elderly.

INTRODUCTION AND METHODS: This study compared changes in myokine and myogenic genes following resistance exercise (3 sets of 12 repetitions of maximal unilateral knee extension) in 20 elderly men (67.8 ± 1.0 years) and 15 elderly women (67.2 ± 1.5 years). RESULTS: Monocyte chemotactic protein (MCP)-1, macrophage inhibitory protein (MIP)-1ß, interleukin (IL)-6 and MyoD mRNA increased significantly (P < 0.05), whereas myogenin and myostatin mRNA decreased significantly after exercise in both groups. Macrophage-1 (Mac-1) and MCP-3 mRNA did not change significantly after exercise in either group. MIP-1ß, Mac-1 and myostatin mRNA were significantly higher before and after exercise in men compared with women. In contrast, MCP-3 and myogenin mRNA were significantly higher before and after exercise in the women compared with the men. CONCLUSIONS: In elderly individuals, gender influences the mRNA expression of certain myokines and growth factors, both at rest and after resistance exercise. These differences may influence muscle regeneration following muscle injury.

Leucocytes, cytokines and satellite cells: what role do they play in muscle damage and regeneration following eccentric exercise?

Exercise-induced muscle damage is an important topic in exercise physiology. However several aspects of our understanding of how muscles respond to highly stressful exercise remain unclear In the first section of this review we address the evidence that exercise can cause muscle damage and inflammation in otherwise healthy human skeletal muscles. We approach this concept by comparing changes in muscle function (i.e., the force-generating capacity) with the degree of leucocyte accumulation in muscle following exercise. In the second section, we explore the cytokine response to 'muscle-damaging exercise', primarily eccentric exercise. We review the evidence for the notion that the degree of muscle damage is related to the magnitude of the cytokine response. In the third and final section, we look at the satellite cell response to a single bout of eccentric exercise, as well as the role of the cyclooxygenase enzymes (COX1 and 2). In summary, we propose that muscle damage as evaluated by changes in muscle function is related to leucocyte accumulation in the exercised muscles. 'Extreme' exercise protocols, encompassing unaccustomed maximal eccentric exercise across a large range of motion, generally inflict severe muscle damage, inflammation and prolonged recovery (> 1 week). By contrast, exercise resembling regular athletic training (resistance exercise and downhill running) typically causes mild muscle damage (myofibrillar disruptions) and full recovery normally occurs within a few days. Large variation in individual responses to a given exercise should, however be expected. The link between cytokine and satellite cell responses and exercise-induced muscle damage is not so clear The systemic cytokine response may be linked more closely to the metabolic demands of exercise rather than muscle damage. With the exception of IL-6, the sources of systemic cytokines following exercise remain unclear The satellite cell response to severe muscle damage is related to regeneration, whereas the biological significance of satellite cell proliferation after mild damage or non-damaging exercise remains uncertain. The COX enzymes regulate satellite cell activity, as demonstrated in animal models; however the roles of the COX enzymes in human skeletal muscle need further investigation. We suggest using the term 'muscle damage' with care. Comparisons between studies and individuals must consider changes in and recovery of muscle force-generating capacity.

Inflammatory cytokine responses to progressive resistance training and supplementation with fortified milk in men aged 50+ years: an 18-month randomized controlled trial.

We examined the effects of progressive resistance training (PRT) and supplementation with calcium-vitamin D(3) fortified milk on markers of systemic inflammation, and the relationship between inflammation and changes in muscle mass, size and strength. Healthy men aged 50-79 years (n = 180) participated in this 18-month randomized controlled trial that comprised a factorial 2 × 2 design. Participants were randomized to (1) PRT + fortified milk supplement, (2) PRT, (3) fortified milk supplement, or (4) a control group. Participants assigned to PRT trained 3 days per week, while those in the supplement groups consumed 400 ml day(-1) of milk containing 1,000 mg calcium plus 800 IU vitamin D(3). We collected venous blood samples at baseline, 12 and 18 months to measure the serum concentrations of IL-6, TNF-α and hs-CRP. There were no exercise × supplement interactions, but serum IL-6 was 29% lower (95% CI, -62, 0) in the PRT group compared with the control group after 12 months. Conversely, IL-6 was 31% higher (95% CI, -2, 65) in the supplement group compared with the non-supplemented groups after 12 and 18 months. These between-group differences did not persist after adjusting for changes in fat mass. In the PRT group, mid-tibia muscle cross-sectional area increased less in men with higher pre-training inflammation compared with those men with lower inflammation (net difference ~2.5%, p < 0.05). In conclusion, serum IL-6 concentration decreased following PRT, whereas it increased after supplementation with fortified milk concomitant with changes in fat mass. Furthermore, low-grade inflammation at baseline restricted muscle hypertrophy following PRT.

The effects of dietary fish oil on inflammation, fibrosis and oxidative stress associated with obstructive renal injury in rats.

SCOPE: We examined whether dietary supplementation with fish oil modulates inflammation, fibrosis and oxidative stress following obstructive renal injury. METHODS AND RESULTS: Three groups of Sprague-Dawley rats (n=16 per group) were fed for 4 wk on normal rat chow (oleic acid), chow containing fish oil (33 g eicosapentaenoic acid and 26 g docosahexaenoic acid per kg diet), or chow containing safflower oil (60 g linoleic acid per kg diet). All diets contained 7% fat. After 4 wk, the rats were further subdivided into four smaller groups (n=4 per group). Unilateral ureteral obstruction was induced in three groups (for 4, 7 and 14 days). The fourth group for each diet did not undergo surgery, and was sacrificed as controls at 14 days. When rats were sacrificed, plasma and portions of the kidneys were removed and frozen; other portions of kidney tissue were fixed and prepared for histology. Compared with normal chow and safflower oil, fish oil attenuated collagen deposition, macrophage infiltration, TGF-ß expression, apoptosis, and tissue levels of arachidonic acid, MIP-1α, IL-1ß, MCP-1 and leukotriene B(4). Compared with normal chow, fish oil increased the expression of HO-1 protein in kidney tissue. CONCLUSIONS: Fish oil intake reduced inflammation, fibrosis and oxidative stress following obstructive renal injury.

Bovine colostrum modulates cytokine production in human peripheral blood mononuclear cells stimulated with lipopolysaccharide and phytohemagglutinin.

Bovine colostrum has been shown to influence the cytokine production of bovine leukocytes. However, it remains unknown whether processed bovine colostrum, a supplement popular among athletes to enhance immune function, is able to modulate cytokine secretion of human lymphocytes and monocytes. The aim of this investigation was to determine the influence of a commercially available bovine colostrum protein concentrate (CPC) to stimulate cytokine production by human peripheral blood mononuclear cells (PBMCs). Blood was sampled from four healthy male endurance athletes who had abstained from exercise for 48 h. PBMCs were separated and cultured with bovine CPC concentrations of 0 (control), 1.25, 2.5, and 5% with and without lipopolysaccharide (LPS) (3 microg/mL) and phytohemagglutinin (PHA) (2.5 microg/mL). Cell supernatants were collected at 6 and 24 h of culture for the determination of tumor necrosis factor (TNF), interferon (IFN)-gamma, interleukin (IL)-10, IL-6, IL-4, and IL-2 concentrations. Bovine CPC significantly stimulated the release of IFN-gamma, IL-10, and IL-2 (p < 0.03). The addition of LPS to PBMCs cocultured with bovine CPC significantly stimulated the release of IL-2 and inhibited the early release of TNF, IL-6, and IL-4 (p < 0.02). Phytohemagglutinin stimulation in combination with bovine CPC significantly increased the secretion of IL-10 and IL-2 at 6 h of culture and inhibited IFN-gamma and TNF (p < 0.05). This data show that a commercial bovine CPC is able to modulate in vitro cytokine production of human PBMCs. Alterations in cytokine secretion may be a potential mechanism for reported benefits associated with supplementation.

The influence of antioxidant supplementation on markers of inflammation and the relationship to oxidative stress after exercise.

Interest in the relationship between inflammation and oxidative stress has increased dramatically in recent years, not only within the clinical setting but also in the fields of exercise biochemistry and immunology. Inflammation and oxidative stress share a common role in the etiology of a variety of chronic diseases. During exercise, inflammation and oxidative stress are linked via muscle metabolism and muscle damage. Because oxidative stress and inflammation have traditionally been associated with fatigue and impaired recovery from exercise, research has focused on nutritional strategies aimed at reducing these effects. In this review, we have evaluated the findings of studies involving antioxidant supplementation on alterations in markers of inflammation (e.g., cytokines, C-reactive protein and cortisol). This review focuses predominantly on the role of reactive oxygen and nitrogen species generated from muscle metabolism and muscle damage during exercise and on the modulatory effects of antioxidant supplements. Furthermore, we have analyzed the influence of factors such as the dose, timing, supplementation period and bioavailability of antioxidant nutrients.

Systemic inflammatory responses to maximal versus submaximal lengthening contractions of the elbow flexors.

We compared changes in markers of muscle damage and systemic inflammation after submaximal and maximal lengthening muscle contractions of the elbow flexors. Using a cross-over design, 10 healthy young men not involved in resistance training completed a submaximal trial (10 sets of 60 lengthening contractions at 10% maximum isometric strength, 1 min rest between sets), followed by a maximal trial (10 sets of three lengthening contractions at 100% maximum isometric strength, 3 min rest between sets). Lengthening contractions were performed on an isokinetic dynamometer. Opposite arms were used for the submaximal and maximal trials, and the trials were separated by a minimum of two weeks. Blood was sampled before, immediately after, 1 h, 3 h, and 1-4 d after each trial. Total leukocyte and neutrophil numbers, and the serum concentration of soluble tumor necrosis factor-alpha receptor 1 were elevated after both trials (P < 0.01), but there were no differences between the trials. Serum IL-6 concentration was elevated 3 h after the submaximal contractions (P < 0.01). The concentrations of serum tumor necrosis factor-alpha, IL-1 receptor antagonist, IL-10, granulocyte-colony stimulating factor and plasma C-reactive protein remained unchanged following both trials. Maximum isometric strength and range of motion decreased significantly (P < 0.001) after both trials, and were lower from 1-4 days after the maximal contractions compared to the submaximal contractions. Plasma myoglobin concentration and creatine kinase activity, muscle soreness and upper arm circumference all increased after both trials (P < 0.01), but were not significantly different between the trials. Therefore, there were no differences in markers of systemic inflammation, despite evidence of greater muscle damage following maximal versus submaximal lengthening contractions of the elbow flexors.