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Exercise and inflammation
by TA Lakka - Cited by 1 - Related articles
Timo A. Lakka
Institute of Biomedicine, Unit of Physiology, University of Kuopio, POB 1627, Kuopio 70210, Finland, Tel: +358 40 5776914, Fax: +358 17 163112, E-mail address:
Hanna-Maaria Lakka
Institute of Biomedicine, Unit of Physiology, University of Kuopio, POB 1627, Kuopio 70210, Finland, Tel: +358 40 5776914, Fax: +358 17 163112, E-mail address:
Tuomo Rankinen, Institute of Biomedicine
Claude Bouchard, Institute of Biomedicine
Our recent report from the HERITAGE Family Study showed that moderate to high-intensity exercise training reduced plasma levels of C-reactive protein, an important pro-inflammatory biomarker, in sedentary healthy adults with initial C-reactive protein levels >3.0 mg/L.1 This finding is potentially important from both a public health and a clinical point of view, because individuals with C-reactive protein >3.0 mg/L represent about one-fourth of all adults and are thought to have a markedly increased risk of cardiovascular disease and type-2 diabetes. A number of studies with different designs support the view that regular physical activity suppresses the inflammatory process,2,3 an observation that could partly explain the effectiveness of regular exercise in the prevention and treatment of cardiovascular disease and type-2 diabetes.
Dr Das discussed some of the evidence that exercise reduces the levels of pro-inflammatory cytokines but increases the levels of anti-inflammatory cytokines, which in turn suppress the production of pro-inflammatory cytokines. He suggested that the exercise-induced increase in the production of pro-inflammatory cytokines augments the production of free radicals, which increases the activity of the endogenous antioxidant, manganese superoxide dismutase, ultimately responsible for the cardioprotective effect of exercise. He concluded that regular exercise ensures adequate expression of anti-inflammatory cytokines and endogenous antioxidants for the prevention of coronary heart disease.
Indeed, there is evidence for the inflammation-suppressing effects of exercise. A recent review concluded that a single bout of strenuous exercise produces a short-term, transient increase in plasma levels of C-reactive protein. The C-reactive protein increase is due to an exercise-induced acute phase response, mediated by the cytokine system and mainly IL-6.2 In contrast, exercise training may blunt the acute pro-inflammatory response, and even suppress the inflammatory process, thereby contributing to the beneficial effects of habitual physical activity.2 There also appears to be an acute homeostatic anti-inflammatory response after a bout of strenuous exercise that counteracts the pro-inflammatory response.2
A Danish research group has suggested that the inflammation-suppressing effect of exercise training is explained by the anti-inflammatory response elicited by a bout of exercise, which is partly mediated by an increase in IL-6 in skeletal muscle.3 They have shown that physiological increases in plasma levels of IL-6, produced by the contraction of skeletal muscles during exercise, stimulate the production of anti-inflammatory cytokines IL-1ra and IL-10 but inhibit the production of a pro-inflammatory cytokine TNF-α. Thus, the inflammation-suppressing effect of exercise training may protect against TNF-α-induced insulin resistance, one of the important pathophysiological mechanisms of type-2 diabetes.
More research is needed to better understand the molecular mechanisms by which physical activity suppresses inflammation. Randomized controlled trials are warranted to investigate the dose of regular physical activity needed for an inflammation-suppressing effect, whether moderate intensity physical activity, as currently recommended, is sufficient for the effect, and whether there are dose and intensity thresholds above which no further benefits are gained or even harmful effects occur.
1. Effect of exercise training on serum levels of C-reactive protein in healthy individuals: the HERITAGE Family Study. Eur Heart J 2005;26:2018-2025.
Abstract/FREE Full Text 2. The effects of physical activity on serum C-reactive protein and inflammatory markers. A systematic review. J Am Coll Cardiol 2005;45:1563-1569. Abstract/FREE Full Text
3. The anti-inflammatory effect of exercise. J Appl Physiol 2005;98:1154-1162. Abstract/FREE Full Text
Exercise and inflammation
THE PURPOSE OF THIS REVIEW series is to highlight the tremendous advancement in knowledge that has taken place over the last five to ten years regarding the interaction between physical exercise and inflammation. Many years ago, it was recognized that regular, moderate exercise reduced the risk of infection compared with a sedentary lifestyle, whereas prolonged, heavy intensity exercise increased infection risk; the so called "J-shaped model" (16). However, the precise nexus between physical activity, inflammation, and immunity has, until recently, been unknown, as studies in this area, and the conclusions they made, were largely based on descriptive data analysis. Indeed, in a comprehensive review on exercise and immune function, published at the turn of the millennium, Pedersen and Hoffman Goetz (18) recognized this and commented, "The focus of future work in exercise immunology should move beyond descriptive, phenomenological studies to studies of underlying neural, hormonal, cytokine, and biochemical mechanisms for the observed effects." It must be said that researchers in the field have heeded this message, and this can be clearly observed from the present review series.
In the first of the series, Gleeson (7) reviews the literature relating to immune function in sport and exercise. One new and exciting development in this field, from work conducted in Dr. Gleeson's laboratory, is the role that Toll-like receptors (TLRs) play in the immune response in humans during exercise. TLR's are an evolutionary, conserved family of pattern recognition receptors known to play an essential role in detecting infection in both Drosophila and mammals (9). In a paper by Lancaster et al. (13), the authors demonstrated that physical activity decreased the expression of TLR1, TLR2, and TLR4 and concluded that TLR function is subject to modulation under physiological conditions in vivo. Intriguingly, physical exercise is known to increase circulating heat shock proteins (23), which are known to activate TLR2 and TLR4 (1), highlighting the complexity of the immune system in response to physical exercise. The theme of exercise and immune function is continued in the review by Cooper (4), who proposes the theory that exercise elicits an immunological danger type of stress that, on occasions, becomes dysregulated and detrimental to well-being. This view is consistent with that of Matzinger (14), who was the first to challenge the "self versus non-self" theory of immune function, a proposed model of immunity based on the idea that the immune system is more concerned with molecules that do damage rather than those that are foreign. In his review, Dr. Cooper provides various instances of the "danger theory" in the context of strenuous exercise. For example, he points out that food-sensitizing immune cells are relatively innocuous in homeostasis. However, in cases of exercise anaphylaxis, these cells are redistributed from depots such as the spleen into the central circulation where they are no longer harmless. The other reviews in this series center on the role of the contracting skeletal muscle in the interaction between exercise and inflammation. It is in this area that a tremendous amount of knowledge has been obtained in recent years, and the muscle can no longer be regarded as the organ whose role is purely to allow for locomotion. In their review, Pedersen and colleagues (17) suggest that, like the adipose tissue that produces adipokines that circulate and affect metabolic processes (20), skeletal muscle produces "myokines" that also affect metabolism. This work was largely based on important findings that skeletal muscle is the site for production of the cytokine interleukin-6 (IL-6; Ref. 88), contracting muscle releases this cytokine into the circulation (21), and during exercise the release of this cytokine is one of the so-called "work factors" that modulates hepatic glucose production during physical exercise (5). On the basis of the papers by Pedersen and her coworkers, the authors argue that the skeletal muscle can now be viewed as an endocrine organ. The authors provide a review of recent papers from both their group and others that show that other interleukins, namely IL-8 and IL-15, are also produced by skeletal muscle.
What leads to cytokine production in skeletal muscle with the onset of contraction? In the next review article (11), Kramer and Goodyear (11) present an informative review that suggests that two major signal transduction pathways, namely the mitogen-activated protein kinases (MAPK) and nuclear factor-κB (NF-κB), are upregulated by muscle contraction. In their review the authors suggest that during low-intensity exercise, contraction activates the extracellular signal-regulated kinases (ERK1/2), which enhance fat metabolism, possibly via the recruitment of the putative fatty acid transporter CD36 (22). In contrast, during heavy activity, p38 MAPK is activated and leads to the upregulation of various metabolic genes via activation of key transcription factors myocyte enhancing factor (MEF)-2 and activating transcription factor (ATF)-2. Next, the authors review the literature relating to NF-κB, which is known as the master controller of inflammation and critical to the life and/or death of a cell (10). Drs. Kramer and Goodyear point out that activation of NF-κB can be paradoxical, resulting in health benefits in some circumstances and disease in others. In doing so, this review highlights some important questions that suggest that NF-κB in skeletal muscle may indeed be unique when compared with other tissues or organs or cells. Why, for example does chronic activation of the upstream kinase, I Kappa kinase (IKK), result in profound insulin resistance and production of IL-6 in liver (3), whereas no such effects are seen in skeletal muscle (2)? It may well be because skeletal muscle is dynamic and undergoes rapid homeostatic alterations during contraction, and, as such, evolution has allowed for it to be protected against such disruption to homeostasis.
Finally, Frost and Lang (6) review the literature with respect to the role of acute transforming retrovirus thymoma (Akt), also known as protein kinase B (PKB). This is indeed an heroic task as there are three isoforms of this kinase (Akt1-3); multiple inputs into activation, including growth factor receptors, nutrients, and muscle contraction per se; and several downstream targets associated with anabolism and nutrient delivery to the cell. One section of their review that is both thought provoking and important is the role of Akt in the regulation of the important transcriptional coactivator, peroxisome proliforator-activated receptor gamma coactivator (PGC)-1α. In skeletal muscle, PGC-1α inhibits the expression of atrogenes MuRF-1 and MAFbx (19), and it is known that PGC-1α expression is reduced in diseases such as Type 2 diabetes (15). During exercise, PGC-1α expression is increased (24), and, importantly, in a recent study, treatment of mice with resveratrol, a polyphenol found in red wine and known to extend life span in Drosophila and Caenorhabdtis elegans (25), protected mice against diet-induced obesity and insulin resistance (12). Importantly, in this recent study (12), the authors were able to show that the effects of resveratrol were largely mediated by increased activation of PGC-1α. Could it be that much of the beneficial health effects of exercise are due to the upregulation of PGC-1α in muscle by contraction? These questions and many others are raised by this comprehensive series of reviews published in this Highlighted Topic series in the Journal of Applied Physiology.
Mark A. Febbraio
Cellular and Molecular Metabolism Laboratory Diabetes and Metabolism Division Baker Heart Research Institute Victoria, Australia Address for reprint requests and other correspondence: M. A. Febbraio, Cellular & Molecular Metabolism Laboratory, Diabetes & Metabolism Division, Baker Heart Research Institute, PO Box 6492 St Kilda Road Central VIC, 8008, Australia (e-mail:
Address for reprint requests and other correspondence: M. A. Febbraio, Cellular & Molecular Metabolism Laboratory, Diabetes & Metabolism Division, Baker Heart Research Institute, PO Box 6492 St Kilda Road Central VIC, 8008, Australia (e-mail:
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Arch Intern Med. 2002 Jun 10;162(11):1286-92.
Relationship between physical activity and inflammation among apparently healthy middle-aged and older US adults.
Abramson JL, Vaccarino V.
Department of Medicine (Cardiology), Emory University School of Medicine, 1256 Briarcliff Rd NE, Suite 1 North, Atlanta, GA 30306, USA.
Physical activity has been associated with a reduced risk of coronary heart disease, but the mechanism underlying this association is unclear. Because coronary heart disease is increasingly seen as an inflammatory process, it might be reasonable to hypothesize that physical activity reduces risk of coronary heart disease by reducing or preventing inflammation.
METHODS: The study examined the relationship between physical activity and elevated inflammation as indicated by a high C-reactive protein level, white blood cell count, or fibrinogen level. Study subjects were 3638 apparently healthy US men and women 40 years and older who participated in the Third National Health and Nutrition Examination Survey.
RESULTS: More frequent physical activity was independently associated with a lower odds of having an elevated C-reactive protein level. Compared with those engaging in physical activity 0 to 3 times per month, the odds of having an elevated C-reactive protein level was reduced among those engaging in physical activity 4 to 21 times per month (odds ratio, 0.77; 95% confidence interval, 0.58-1.02) and 22 or more times per month (odds ratio, 0.63; 95% confidence interval, 0.43-0.93) (P for trend,.02). Similar associations were seen for white blood cell count and fibrinogen levels.
CONCLUSIONS: More frequent physical activity is independently associated with a lower odds of having elevated inflammation levels among apparently healthy US adults 40 years and older, independent of several confounding factors. The results suggest that the association between physical activity and reduced coronary heart disease risk may be mediated by anti-inflammatory effects of regular physical activity.
Epidemiology. 2002 Sep;13(5):561-8.
Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults.
Ford ES.
Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
Physical activity may lower the risk for coronary heart disease by mitigating inflammation, which plays a key role in the pathophysiology of atherosclerosis. The purpose of this study was to examine the association between physical activity and C-reactive protein concentration in a national sample of the U.S. population.
METHODS: The analytic sample included 13,748 participants >or=20 years of age in the National Health and Nutrition Examination Survey III (1988-1994) with complete data for the main study variables.
RESULTS: After adjusting for age, sex, ethnicity, education, work status, smoking status, cotinine concentration, hypertension, body mass index, waist-to-hip ratio, high-density lipoprotein cholesterol concentration, and aspirin use, the odds ratios for elevated C-reactive protein concentration (dichotomized at the >or=85th percentile of the sex-specific distribution) were 0.98 (95% confidence interval = 0.78-1.23), 0.85 (0.70-1.02), and 0.53 (0.40-0.71) for participants who engaged in light, moderate, and vigorous physical activity, respectively, during the previous month compared with participants who did not engage in any leisure-time physical activity. In addition, leisure-time physical activity was positively associated with serum albumin concentration and inversely associated with both log-transformed plasma fibrinogen concentration and log-transformed white blood cell count.
CONCLUSIONS: These results add to mounting evidence that physical activity may reduce inflammation, which is a critical process in the pathogenesis of cardiovascular disease.
Atherosclerosis. 2004 Oct;176(2):303-10.
Association between leisure time physical activity and markers of chronic inflammation related to coronary heart disease.
Verdaet D, Dendale P, De Bacquer D, Delanghe J, Block P, De Backer G.
Department of Cardiology, Hospital of the Free University of Brussels (AZ-VUB), Cardiac Rehabilitation, Laarbeeklaan 101, 1090 Brussels, Belgium.
BACKGROUND: Some markers of chronic inflammation have been recognized as predictors of cardiovascular risk in apparently healthy subjects and in patients with coronary heart disease (CHD). High sensitivity C-reactive protein (CRP) appears to be the most useful marker in clinical settings. Several studies reported associations between inflammatory markers and other cardiovascular risk factors, such as age, obesity, cholesterol levels, the presence of diabetes mellitus, physical activity, social level and smoking habits. We focussed on the association between C-reactive protein, serum amyloid A (SAA), fibrinogen and leisure time physical activity (LTPA).
METHODS: This report deals with the results observed in a sub-sample of the BELSTRESS study. 892 male subjects, free from clinical CHD and major ECG abnormalities, working in the same environment, aged 35-59 years, were selected. A questionnaire was used to estimate the level of leisure time physical activity. Associations between CRP, SAA, fibrinogen and leisure time physical activity were evaluated through univariate and multivariate methods. Subjects taking statins or other lipid lowering medication were excluded from the study.
RESULTS: Regular leisure time physical activity is associated with reductions of several cardiovascular risk factors, such as body mass index (BMI), waist hip ratio and the lipid profile. Smokers and low educated subjects had a lower physical activity status. Age adjustment did not alter the means of inflammatory parameters according to the levels of leisure time physical activity. After correction for personal characteristics (BMI, current smoking status, educational level, presence of diabetes and alcohol consumption) no significant relation was found between leisure time physical activity and levels of inflammatory markers. The differences of CRP and fibrinogen according to the level of physical activity, found in bivariate analysis, seem to be explained by linked differences in BMI, or related to current smoking habits. Leisure time physical activity, as reported in this study, is not significantly related to C-reactive protein, serum amyloid A or fibrinogen levels, after correction for other cardiovascular risk factors.
CONCLUSION: These data indicate that leisure time physical activity, as reported in our study, is not an independent predictor of C-reactive protein, serum amyloid A or fibrinogen levels. Possible interactions of physical activity and other cardiovascular risk factors might explain the (indirect) relation we found in the bivariate analysis.
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