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EDITORIAL
HIGHLIGHTED TOPIC
Exercise and Inflammation
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-
B (NF-B), 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-B, 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-B 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-B 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)-1
. In skeletal muscle, PGC-1 inhibits the expression of atrogenes MuRF-1 and MAFbx (19), and it is known that PGC-1 expression is reduced in diseases such as Type 2 diabetes (15). During exercise, PGC-1 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-1. Could it be that much of the beneficial health effects of exercise are due to the upregulation of PGC-1 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.
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: mark.febbraio{at}baker.edu.au)
FOOTNOTES
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: mark.febbraio{at}baker.edu.au)
REFERENCES
B signaling in skeletal muscle. J Appl Physiol. In press; doi:10.1152/japplphysiol.00085-2007. responsive genes involved in oxidative phosphorylation are co-ordinately downregulated in human diabetes. Nat Genet 34: 267–273, 2003.[CrossRef][Web of Science][Medline]
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