Edward F.

Adolph Distinguished Lecture: Muscle as an endocrine organ: IL-6 and other myokines
Bente K. Pedersen
J Appl Physiol 107:1006-1014, 2009. First published 20 August 2009; doi: 10.1152/japplphysiol.00734.2009 You might find this additional info useful... This article cites 121 articles, 65 of which you can access for free at: http://jap.physiology.org/content/107/4/1006.full#ref-list-1 This article has been cited by 23 other HighWire-hosted articles: http://jap.physiology.org/content/107/4/1006#cited-by Updated information and services including high resolution figures, can be found at: http://jap.physiology.org/content/107/4/1006.full Additional material and information about Journal of Applied Physiology can be found at: http://www.the-aps.org/publications/jappl This information is current as of July 25, 2013.

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Journal of Applied Physiology publishes original papers that deal with diverse area of research in applied physiology, especially those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2009 the American Physiological Society. ISSN: 8750-7587, ESSN: 1522-1601. Visit our website at http://www.the-aps.org/.

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J Appl Physiol 107: 10061014, 2009. First published August 20, 2009; doi:10.1152/japplphysiol.00734.2009.

Edward F. Adolph Distinguished Lecture: Muscle as an endocrine organ: IL-6 and other myokines
Bente K. Pedersen
The Centre of Inammation and Metabolism at the Department of Infectious Diseases, and Copenhagen Muscle Research Centre, Rigshospitalet, the Faculty of Health Sciences, University of Copenhagen, Denmark
Submitted 8 July 2009; accepted in nal form 17 August 2009

Pedersen BK. Edward F. Adolph Distinguished Lecture: Muscle as an endocrine organ: IL-6 and other myokines. J Appl Physiol 107: 1006 1014, 2009. First published August 20, 2009; doi:10.1152/japplphysiol.00734.2009.Skeletal muscle is an endocrine organ that produces and releases myokines in response to contraction. Some myokines are likely to work in a hormone-like fashion, exerting specic endocrine effects on other organs such as the liver, the brain, and the fat. Other myokines will work locally via paracrine mechanisms, exerting, e.g., angiogenetic effects, whereas yet other myokines work via autocrine mechanisms and inuence signaling pathways involved in fat oxidation and glucose uptake. The nding that muscles produce and release myokines creates a paradigm shift and opens new scientic, technological, and scholarly horizons. This nding represents a breakthrough within integrative physiology and contributes to our understanding of why regular exercise protects against a wide range of chronic diseases. Thus the myokine eld provides a conceptual basis for the molecular mechanisms underlying, e.g., muscle-fat, muscle-liver, muscle-pancreas, and muscle-brain cross talk. adipose tissue; cytokines; insulin resistance; skeletal muscle

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ONE DECADE AGO we identied a humoral factor (a cytokine) that was produced and released from contracting muscle cells and appeared to have major metabolic effects. Given that skeletal muscle is the largest organ in the human body, our discovery of contracting muscle as a cytokine-producing organ opened a whole new paradigm: Skeletal muscle is an endocrine organ, which by secretion of hormone-like factors may inuence metabolism in tissues and organs. In continuation, we suggested that cytokines and other peptides that are produced, expressed, and released by muscle bers and exert either autocrine, paracrine, or endocrine effects should be classied as myokines (86). Adipose tissues have been regarded as the major sources of cytokines (adipokines); however, the nding that muscles produce and release cytokines (myokines) suggests that working skeletal muscle in addition to adipose tissue may be a major source of secreted molecules. Myokines provide a conceptual basis to explain how muscles communicate to other organs. Thus our overall idea is that contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specic endocrine effects on other organs or which work locally via paracrine mechanisms.

STATE OF THE ART

For half a century, researchers sought a link between muscle contraction and changes in peripheral organs in the form of an exercise factor, which could be released from skeletal muscle during contraction and mediate some of the exerciseAddress for reprint requests and other correspondence: B. K. Pedersen, Centre of Inammation and Metabolism, Rigshospitalet, Section 7641, Blegdamsvej 9, DK-2100, Copenhagen, Denmark (e-mail: bkp@rh.dk). 1006

induced metabolic changes in other organs such as the liver and the adipose tissue. The idea that signaling pathways from contracting muscles to other organs were not solely mediated via the nervous system was supported by the ndings from electrical stimulation of paralyzed muscles in patients with spinal cord injuries (45). It was obvious that one or more muscle-derived humoral factors existed. For lack of more exact knowledge, these humoral factors were called the work stimulus or the work factor. In this context, our identication of muscle as a cytokine-producing organ was kind of a breakthrough. In year 2000, it became clear that contracting human skeletal muscle releases signicant amounts of interleukin (IL)-6 into the circulation during prolonged single-limb exercise (108). Research during the subsequent years highlighted the fact that muscle-derived IL-6 is an important player in metabolism (86). Today, it appears that skeletal muscle has the capacity to express several myokines. The list includes IL-6, IL-8, IL-15, brain-derived neurotrophic factor (BDNF), and leukemia inhibitory factor (LIF) (86). Through other strategies, Kenneth Walsh and colleagues (Boston, MA) identied the myokines broblast growth factor 21 (FGF21) and follistatin-like-1 (35, 77). Thus, although the idea of an exercise factor can be traced back many years, our identication of muscle as a myokine-producing organ opens for a whole new eld of research.
IL-6: THE MYOKINE PROTOTYPE

The fact that the plasma concentration of IL-6 increases during exercise has been a consistent nding (86). The increase in IL-6 is followed by the appearance of IL-1 receptor antagonist (IL-1ra) and the anti-inammatory cytokine IL-10. Conhttp://www. jap.org

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centrations of the chemokines IL-8, macrophage inammatory protein- (MIP-1), and MIP-1 are elevated after strenuous exercise. Of note, the cytokine response to exercise and sepsis differs with regard to TNF-. Thus the cytokine response to exercise is not preceded by an increase in plasma-TNF-. Although there may be a moderate increase in the systemic concentration of these cytokines, the underlying fact is that the appearance of IL-6 in the circulation is by far the most marked and that its appearance precedes that of the other cytokines (86). Exercise-induced plasma IL-6 concentrations increase in an almost exponential manner. The peak IL-6 level is reached at the end of the exercise or shortly thereafter, followed by a rapid decrease toward preexercise levels. The basal plasma IL-6 concentration may increase up to 100-fold after exercise (83). Because IL-6 is a classical inammatory cytokine, it was rst thought that the IL-6 response was related to muscle damage. However, it has become evident that muscle damage is not required to increase plasma IL-6 during exercise. Rather, eccentric exercise may result in a delayed peak and a slower decrease of plasma IL-6 during recovery (86). Sources of contraction-induced IL-6. As with many paradigm-shifting studies, our initial ndings that led to the identication of IL-6 as a myokine were somewhat serendipitous. A decade before, we had initiated the very rst studies using exercise as a tool to study the immune system (85). This research soon opened a new research eld called exercise immunology, leading in 1993 to the foundation of the International Society of Exercise and Immunology (84). It was while looking for a mechanistic explanation to exercise-induced immune changes that we came across IL-6, which we later identied as the rst exercise factor. With this in mind, it was obvious that we rst focused on immune cells as the source of IL-6 (72). However, it soon became clear that the contracting skeletal muscle per se is the main source of the IL-6 in the circulation in response to exercise. In resting human skeletal muscle, the IL-6 mRNA content is very low, although small amounts of IL-6 protein predominantly in type I bers may be detected using sensitive immunohistochemical methods (93). In response to exercise, an increase of the IL-6 mRNA content in the contracting skeletal muscle is detectable after 30 min of exercise, and up to 100-fold increases of the IL-6 mRNA content may be present at the end of the exercise bout (42, 107). By obtaining arterial-femoral venous differences over an exercising leg, we found that exercising limbs released IL-6. In an attempt to determine which cells produce the IL-6, Keller et al. (42) isolated nuclei from muscle biopsies obtained before, during, and after exercise. Using RT-PCR, it was demonstrated that the nuclear transcription rate for IL-6 increases rapidly and markedly after the onset of exercise (42). This suggested that a factor associated with contraction increases IL-6 transcriptional rate, probably in the nuclei from myocytes, given the observation that IL-6 protein is expressed within muscle bers (63). Further evidence that contracting muscle bers themselves are a source of IL-6 mRNA and protein has been achieved by analysis of biopsies from the human vastus lateralis using in situ hybridization and immunohistochemistry (33, 88). Contracting skeletal muscles may account for most of the IL-6 found in the circulation; however, other studies have demonstrated that skeletal muscle is not the sole source of
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exercise-induced IL-6. Fischer et al. found that the IL-6 net release from the exercising legs was almost completely blocked when subjects were pretreated with vitamins C and E for 4 wk, yet the systemic increase of plasma IL-6 was only reduced by 50% (24). Other sources of IL-6 include connective tissue (57), the brain (74), and adipose tissue (40, 62). Muscle-derived IL-6, muscle glycogen, and carbohydrate ingestion. By manipulating muscle-glycogen content, both intramuscular IL-6 mRNA expression (42) and protein release (105) were exacerbated when intramuscular glycogen was compromised, suggesting that IL-6 worked as an energy sensor. In addition, a number of studies show that glucose ingestion during exercise attenuates the exercise-induced increase in plasma IL-6 (86) and totally inhibits the IL-6 release from contracting skeletal muscle in humans (21). IL-6 upstream signaling in skeletal muscle. Skeletal muscle cells are capable of producing IL-6 in response to various stimuli such as lipopolysaccharide, reactive oxygen species (ROS), and inammatory cytokines as well as during contraction (86). The neuronal nitric oxide (NO) synthase isoform is abundantly expressed in human skeletal muscle (26), and a number of observations provide evidence that NO production is signicantly increased within contracting skeletal muscle (3, 31, 59, 60, 98, 103). In vitro studies suggest that NO (6) may alter signaling networks by redox-sensitive modication, by nitrosation of proteins within the cytoplasm or nucleus (32), or it may exert effects on transcription via an increase in cGMP (92). A human exercise study convincingly demonstrated that NO production within contracting skeletal muscles is a key regulator of pretranslational signaling events leading to muscle IL-6 production. Pharmacological inhibition of NO production during exercise attenuated the increase in IL-6 mRNA levels in human skeletal muscle and intra-arterial infusion of an NO donor was accompanied by increases in IL-6 mRNA content in resting skeletal muscle. Moreover, the drug-induced changes of IL-6 mRNA expression were accompanied by similar alterations in IL-6 protein release supporting the functional significance of the IL-6 mRNA change (109). In cultured skeletal muscle cells, inammatory stimuli may elicit the production of IL-6 via signaling pathways that involve c-Jun NH2-terminal kinase (27) and the transcription factor NF-B (52). NF-B represents a major pathway by which IL-6 is transcribed in immune cells, and this pathway may potentially play a role in exercise-induced IL-6 production. Increased ROS formation in skeletal muscle after exercise has been demonstrated directly in animals (18, 36) and indirectly in humans (2). NF-B is a redox-sensitive transcription factor (100) that may be activated by ROS. Murine skeletal myotubes release IL-6 when exposed to oxidative stress in an NF-B-dependent way (52). In addition, supplementation with different antioxidants attenuates the systemic increase of IL-6 in response to exercise (24, 112, 116). The observation that nonsteroidal anti-inammatory drugs, which inhibit NF-B activity, reduce the exercise-induced increase of IL-6 further supports the idea that NF-B represents a link between contractile activity and IL-6 synthesis (51, 97). On the other hand, a number of stimuli, including oxidative stress, low glucose availability, low glycogen content, catecholamines, and hyperthermia, which are all features of exercise, are capable of
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inducing heat shock proteins (5, 15, 22, 78, 117, 122), which may in turn activate IL-6 synthesis (95). However, the importance of the NF-B signaling pathway in contraction-induced activation of muscle-derived IL-6 is yet not understood as this pathway is activated by contraction in rodent skeletal muscle (34, 37) but not in humans (16, 109). Moreover, the IB kinase- does not increase the transcription of IL-6 (13), suggesting that it is less likely that IL-6 gene transcription in skeletal muscle is dependent on activation of the IB kinase-/NF-B signaling pathway. Membrane depolarization activates voltage-dependent Ca2 channels and induces Ca2 release, which is obligatory for skeletal muscle contraction. A low sustained intracellular concentration of Ca2 has been shown to activate nuclear factor of activated T cell (NFAT) through the action of calcineurin and IL-6 gene expression in cultured human muscle cells. Thus, whereas the Ca2/NFAT pathway represents one arm of the IL-6 gene regulation, intramuscular glycogen content has also been shown to play an inuential role in this process. It appears that, unlike IL-6 signaling in macrophages, which seems entirely dependent on activation of the NF- signaling pathway, intramuscular IL-6 expression is regulated by a network of signaling cascades that among other pathways are likely to involve cross talk between the Ca2/NFAT and glycogen/p38 MAPK pathways (reviewed in Ref. 86). IL-6 and AMP-activated protein kinase. Skeletal muscle displays a high degree of metabolic exibility, which allows the myobers to adapt to various physiological demands by shifting energy substrate utilization. Transcriptional events play a pivotal role in the metabolic adaptations of skeletal muscle. The expression of genes essential for skeletal muscle glucose and lipid metabolism is tightly coordinated in support of a shift in substrate utilization. AMP-activated protein kinase (AMPK) regulates skeletal muscle metabolic gene expression programs in response to changes in the energy status (61). Although AMPK may inuence the transcription of metabolic genes, AMPK exerts most of its effects via its role as a protein kinase that regulates the activity of key metabolic enzymes by phosphorylation. AMPK exerts an acute regulatory role on numerous metabolic processes, including fatty acid oxidation (68). It does so because activation of AMPK phosphorylates acetyl CoA carboxylase (ACC), resulting in inhibition of ACC activity, which in turn leads to a decrease in malonyl CoA content, relieving inhibition of carnitine palmitoyl transferase 1 and increasing fatty acid oxidation (38). Acute treatment of muscle cells with IL-6 increased both basal glucose uptake and translocation of the glucose transporter GLUT4 from intracellular compartments to the plasma membrane (14). Moreover, IL-6 increased insulin-stimulated glucose uptake in vitro, whereas infusion of recombinant human IL-6 into healthy humans during a hyperinsulinemic, euglycemic clamp increased glucose infusion rate without affecting the total suppression of endogenous glucose production (14). The effects of IL-6 on glucose uptake in vitro appeared to be mediated by activation of AMPK, since the results were abolished in cells infected with an AMPK dominant-negative adenovirus (14). Apart from the effects of IL-6 on glucose metabolism, several studies have reported that IL-6 may increase intramyocellular (8, 14, 91) or whole body (115) fatty acid oxidation. This effect is also mediated by AMPK (14, 38). A recent study suggests that IL-6
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activates AMPK in skeletal muscle by increasing the concentration of cAMP and secondarily the AMP-to-ATP ratio (43). Work from several groups (69, 110, 120) has demonstrated that leptin, signaling through the leptin receptor (LRb), may activate AMPK in peripheral tissues such as skeletal muscle. Thus it appears that IL-6 acutely mediates signaling through the gp130 receptor and exhibits many leptin-like actions such as activating AMPK and insulin signaling (111). Although most studies point to an effect of IL-6 on AMPK, Glund et al. (30) provided evidence that AMPK-dependent pathways regulate IL-6 release from isolated oxidative skeletal muscle. A number of studies both in vitro (56, 99, 101, 102) and in rodents in vivo (44, 46, 47) demonstrate that IL-6 is capable of inducing insulin resistance. In the latter studies, IL-6 appears to induce insulin resistance via adverse effects on the liver. The IL-6-induced insulin resistance appears due to increased suppressor of cytokine signaling-3 (SOCS-3) expression (102), since SOCS-3 may directly inhibit the insulin receptor (114). However, it is quite clear that in healthy skeletal muscle, not least in humans, the IL-6-induced activation of AMPK overrides the IL-6-induced activation of SOCS-3. Of note, IL-6 knockout mice develop mature onset obesity and glucose intolerance (118), supporting the notion that IL-6 may exert benecial effects on metabolism; however, even this observation is unclear (19). The anti-inammatory effects of exercise and IL-6. Systemic low-level inammation is dened as two- to fourfold elevations in circulating levels of proinammatory and anti-inammatory cytokines, naturally occurring cytokine antagonists, and acute-phase proteins, as well as minor increases in counts of neutrophils and natural killer cells (10 12). A recent number of papers have documented that self-reported physical activity or physical performance is correlated inversely with systemic low-level inammation, suggesting that the antiinammatory activity induced by regular exercise may exert some of the benecial health effects of exercise in patients with chronic diseases [reviewed previously (64, 79, 89, 90, 123)]. As said, IL-6 is the rst cytokine present in the circulation during exercise; the appearance of IL-6 in the circulation is by far the most marked, and its appearance precedes that of the other cytokines. The fact that the classical proinammatory cytokines, TNF- and IL-1, in general do not increase with exercise, whereas exercise provokes an increase in circulating levels of well-known anti-inammatory cytokines and cytokine inhibitors such as IL-1ra, IL-10, and soluble TNF receptor (sTNF-R) (75, 76), suggests that exercise provokes an environment of anti-inammatory cytokines. Importantly, we showed that rhIL-6 infusion as well as exercise inhibited the endotoxin-induced increase in circulating levels of TNF- in healthy humans (104). The anti-inammatory effects of IL-6 are also demonstrated by IL-6 stimulating the production of the classical anti-inammatory cytokines IL-1ra and IL-10 (106). The role of training adaptation. Several epidemiological studies have reported a negative association between the amount of regular physical activity and the basal plasma IL-6 levels: the more physically active, the lower the basal plasma IL-6 (83). Although plasma IL-6 appears to be downregulated by training, the muscular expression of the IL-6 receptor appears to be upregulated (41). Accordingly, it is possible that the downregulation of IL-6 is partially counteracted by an enhanced expression of IL-6R, whereby the sensitivity to IL-6
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is increased. This nding has made us speculate that IL-6 resistance exists as a biological phenomenon. If the amount of IL-6 receptor on the surface of muscle bers reects enhanced IL-6 signaling, it appears that healthy, well-trained humans are more sensitive to IL-6, whereas untrained people have impaired IL-6 signaling and compensatory high circulating IL-6 levels. The latter would be in line with what is known for leptin resistance and insulin resistance. IL-6: a true myokine with endocrine and paracrine effects. From a rather unexciting existence as a player in the textbook version of the inammatory response, IL-6 has recently been taken to center stage in the search for culprits underlying the inammatory component of the metabolic syndrome (55). The ndings suggesting that IL-6 is yet another proinammatory cytokine are in contrast to the numerous studies showing that IL-6 has benecial effects on muscle metabolism [reviewed previously (29, 80, 86)]. Chronically elevated IL-6 levels lead to inappropriate hyperinsulinemia, reduced body weight, and impaired insulinstimulated glucose uptake by the skeletal muscles (25). In contrast, IL-6 knockout mice develop obesity and insulin resistance, providing evidence against a causative effect of IL-6 in insulin resistance (118). Numerous explanations for the two divergent opinions have been put forward, including differences in model systems, chronic vs. pulsatile exposure, and in vitro vs. in vivo effects (29, 82). Of note, in resting healthy humans, plasma IL-6 is normally about 12 pg/ml or less (49). Although exercise itself leads to an acute increase in IL-6 production and release by the working muscle, exercise training leads to reduced circulating IL-6 levels (23) and, according to changes in levels of IL-6 receptor expression, to an increased IL-6 sensitivity in skeletal muscle (41). In patients with type 2 diabetes or in elderly people (9, 87), circulating levels of IL-6 are about two- to threefold higher than those measured in healthy individuals. This represents a low, but chronic IL-6

exposure, contrasting the situation in exercise, where IL-6 levels increase acutely up 100-fold. As recently pointed out by Anna Krook (55), the IL-6 levels achieved after electrotransfer by Franckhauser et al. (25) was 800 pg/ml, corresponding to many 100-fold above both normal and diabetic values and 5-fold higher than those seen after strenuous exercise. In fact, concentrations are equivalent to those noted in the context of severe infections. Therefore, caution should be taken before extrapolating these ndings to what is seen in patients with chronic disorders or in normal physiology, such as exercise. Although the effects of IL-6 is highly dependent on the tissue and although both dose and time appear to be determining factors for the biological role of exercise, the role of IL-6 in contracting muscle is, as a matter of fact, very clear. In response to muscle contractions, both type I and type II muscle bers express the myokine IL-6, which subsequently exerts its effects locally within the muscle (e.g., through activation of AMPK). In skeletal muscle, IL-6 acts in an autocrine or paracrine manner to signal through a gp130R/IL-6R homodimer, resulting in activation of AMPK and/or phosphatidylinositol 3-kinase to increase glucose uptake and fat oxidation (14). IL-6 is also known to increase hepatic glucose production during exercise (20) and induces whole body lipolysis in humans (115) (Fig. 1).
IL-15: A ROLE IN MUSCLE-FAT CROSS TALK

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IL-15 is expressed in human skeletal muscle (81). It possesses anabolic effects on skeletal muscle in vitro and in vivo and may also take part in reducing adipose tissue mass (81). Therefore, IL-15 has been suggested to be involved in musclefat cross talk. Recently, we demonstrated that IL-15 mRNA levels were upregulated in human skeletal muscle after a bout of strength training (71), suggesting that IL-15 may accumulate within the muscle as a consequence of regular training.

Fig. 1. Biological role of contraction-induced interleukin (IL)-6. Skeletal muscle expresses and releases myokines into the circulation. In response to muscle contractions, both type I and type II muscle bers express the myokine IL-6, which subsequently exerts its effects both locally within the muscle [e.g., through activation of AMP-activated protein kinase (AMPK)] and, when released into the circulation, peripherally in several organs in a hormone-like fashion. Specically, in skeletal muscle, IL-6 acts in an autocrine or paracrine manner to signal through a gp130R/IL-6R homodimer, resulting in activation of AMP kinase and/or phosphatidylinositol 3-kinase to increase glucose uptake and fat oxidation. IL-6 is also known to increase hepatic glucose production during exercise or lipolysis in adipose tissues. Previously published in Pedersen and Febbraio (86).

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MUSCLE AND IL-6 BDNF: A ROLE IN NEUROBIOLOGY AND METABOLISM

We further demonstrated a negative association between plasma IL-15 concentration and trunk fat mass, but not limb fat mass, in humans. In support of this nding, we demonstrated a decrease in visceral fat mass, but not subcutaneous fat mass, when IL-15 was overexpressed in murine muscle (70). Quinn et al. (96) found that elevated circulating levels of IL-15 in mice resulted in signicant reductions in body fat and increased bone mineral content, without appreciably affecting lean body mass or levels of other cytokines. Although the latter model represented an articial system, the ndings lend some support to the idea that IL-15 secretion from muscle tissue may modulate visceral fat mass specically via an endocrine mechanism.
IL-8: A ROLE IN EXERCISE-INDUCED ANGIOGENESIS?

IL-8 is a known chemokine that attracts primarily neutrophils. In addition to its chemokine properties, IL-8 acts as an angiogenic factor. The plasma concentration of IL-8 increases in response to exhaustive exercise such as running, which involves eccentric muscle contractions, whereas we and others found no increase in plasma-IL-8 in relation to concentric exercise (86). However, when measuring the arteriovenous concentration difference across a concentrically exercising limb, our group (1) detected a small and transient net release of IL-8, which did not result in an increase in the systemic IL-8 plasma concentration. The fact that a high local IL-8 expression takes place in contracting muscle with only a small and transient net release may indicate that muscle-derived IL-8 acts locally and exerts its effect in an autocrine or paracrine fashion (1). It is not likely that muscle-derived IL-8 would work as a chemoattractant of neutrophils and macrophages when, in fact, in concentric exercise there is little or no accumulation of neutrophils or macrophages in skeletal muscle. However, a more likely function of musclederived IL-8 is to stimulate angiogenesis. It induces its chemotactic effects via CXCR1, whereas CXCR2, which is expressed by human microvascular endothelial cells, is the receptor responsible for IL-8-induced angiogenesis (4, 48, 73). The expression of the IL-8 receptor CXCR2 is enhanced in human skeletal muscle biopsies after concentric exercise, and the increase in CXCR2 protein is seen not only in the muscle bers but to a greater extent in the vascular endothelium, suggesting that it may play a role in angiogenesis (28). IL-8 signaling promotes angiogenic responses in endothelial cells, increases proliferation and survival of endothelial and cancer cells, and potentiates the migration of cancer cells, endothelial cells, and inltrating neutrophils at the tumor site. Accordingly, IL-8 expression correlates with the angiogenesis, tumorigenicity, and metastasis of tumors in numerous xenograft and orthotopic in vivo models (121). The nding that a high local IL-8 expression takes place in contracting muscle with only a small and transient release that does not contribute to the plasma levels of IL-8 underscores the fact that muscle-produced IL-8 has no systemic effects. However, it is likely that IL-8 produced by contracting myobers exerts its effect locally and plays a role in exercise-induced angiogenesis.
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BDNF is a member of the neurotrophic factor family, which plays a key role in regulating survival, growth, and maintenance of neurons (67), and BDNF plays a role in learning and memory (113). Hippocampal samples from donors with Alzheimer disease show decreased BDNF expression (17), and individuals with Alzheimer disease have low plasma levels of BDNF (58). Also, patients with major depression have lower levels of serum BDNF than normal control subjects (39). Other studies suggest that plasma BDNF is a biomarker of impaired memory and general cognitive function in aging women (50), and a low circulating BDNF level was recently shown to be an independent and robust biomarker of mortality risk in elderly women (53). Interestingly, low levels of circulating BDNF are also found in individuals with obesity and Type 2 diabetes (54). In addition, we demonstrated that there is a cerebral output of BDNF and that this is inhibited during hyperglycemic clamp conditions in humans. The latter nding may explain the concomitant nding of low circulating levels of BDNF in individuals with Type 2 diabetes and the association between low plasma BDNF and the severity of insulin resistance (54). BDNF appears to play a role in both neurobiology and metabolism. Studies have demonstrated that physical exercise may increase circulating BDNF levels in humans (65). We studied whether skeletal muscle would produce BDNF in response to exercise (66). It was found that BDNF mRNA and protein

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Fig. 2. Biological role of contraction-induced brain-derived neurotropic factor (BDNF). In response to muscle contractions, BDNF mRNA and protein expression are markedly increased in human skeletal muscle after exercise; however, muscle-derived BDNF appears not to be released into the circulation. BDNF mRNA and protein expression were increased in muscle cells that were electrically stimulated. Interestingly, BDNF increased phosphorylation (p) of AMPK and acetyl CoA carboxylase (ACC) and enhanced fat oxidation both in vitro and ex vivo. Thus BDNF has been identied as a novel contractioninduced muscle cell-derived protein that exerts its effect either via autocrine or paracrine effects, whereby it increases fat oxidation in skeletal muscle in an AMPK-dependent fashion. www.jap.org

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expression were increased in human skeletal muscle after exercise; however, muscle-derived BDNF appeared not to be released into the circulation. BDNF mRNA and protein expression were increased in muscle cells that were electrically stimulated. Interestingly, BDNF increased phosphorylation of AMPK and ACC and enhanced fat oxidation both in vitro and ex vivo. Thus we have been able to identify BDNF as a novel contraction-induced muscle cell-derived protein that may increase fat oxidation in skeletal muscle in an AMPK-dependent fashion (Fig. 2). The possibility exists that BDNF may be classied as a myokine, which works in an autocrine or paracrine fashion.
OTHER MYOKINES

the discovery of adipose tissue as a secretory organ in the mid-1990s was a dominating research area in the past decade, giving rise to the identication of new regulatory peptides (e.g., leptin and adiponectin) and their receptors.
ACKNOWLEDGMENTS I gratefully acknowledge my collaborators, not least Mark Febbraio, professor of Cell Biology at the Cellular and Molecular Metabolism Laboratory, Division of Metabolism & Obesity, Baker IDI Heart & Diabetes Institute, Melbourne, Australia, and postdoctoral fellows, students, and technicians who have contributed much of the work reported in this review. GRANTS The Centre of Inammation and Metabolism is supported by a grant from the Danish National Research Foundation (DG 02-512-555). In addition, support was obtained from the Danish Medical Research Council and the Commission of the European Communities (contract no. LSHM-CT-2004005272 EXGENESIS). The Capital Region of Copenhagen and the Copenhagen University support the Copenhagen Muscle Research Centre. REFERENCES 1. Akerstrom TC, Steensberg A, Keller P, Keller C, Penkowa M, Pedersen BK. Exercise induces interleukin-8 expression in human skeletal muscle. J Physiol 563: 507516, 2005. 2. Bailey DM, Young IS, McEneny J, Lawrenson L, Kim J, Barden J, Richardson RS. Regulation of free radical outow from an isolated muscle bed in exercising humans. Am J Physiol Heart Circ Physiol 287: H1689 H1699, 2004. 3. Balon TW, Nadler JL. Nitric oxide release is present from incubated skeletal muscle preparations. J Appl Physiol 77: 2519 2521, 1994. 4. Bek EL, McMillen MA, Scott P, Angus LD, Shaftan GW. The effect of diabetes on endothelin, interleukin-8 and vascular endothelial growth factor-mediated angiogenesis in rats. Clin Sci (Lond) 103, Suppl 48: 424S 429S, 2002. 5. Bergstedt K, Hu BR, Wieloch T. Initiation of protein synthesis and heat-shock protein-72 expression in the rat brain following severe insulin-induced hypoglycemia. Acta Neuropathol (Berl) 86: 145153, 1993. 6. Bogdan C. Nitric oxide and the regulation of gene expression. Trends Cell Biol 11: 66 75, 2001. 7. Broholm C, Mortensen OH, Nielsen S, Akerstrom T, Zankari A, Dahl B, Pedersen BK. Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle. J Physiol 586: 21952201, 2008. 8. Bruce CR, Dyck DJ. Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-alpha. Am J Physiol Endocrinol Metab 287: E616 E621, 2004. 9. Bruunsgaard H, Andersen-Ranberg K, Hjelmborg JB, Pedersen BK, Jeune B. Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med 115: 278 283, 2003. 10. Bruunsgaard H, Ladelund S, Pedersen AN, Schroll M, Jorgensen T, Pedersen BK. Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people. Clin Exp Immunol 132: 24 31, 2003. 11. Bruunsgaard H, Pedersen AN, Schroll M, Skinhoj P, Pedersen BK. Impaired production of proinammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans. Clin Exp Immunol 118: 235241, 1999. 12. Bruunsgaard H, Pedersen BK. Age-related inammatory cytokines and disease. Immunol Allergy Clin North Am 23: 1539, 2003. 13. Cai D, Frantz JD, Tawa NE Jr, Melendez PA, Oh BC, Lidov HG, Hasselgren PO, Frontera WR, Lee J, Glass DJ, Shoelson SE. IKK/ NF-B activation causes severe muscle wasting in mice. Cell 119: 285298, 2004. 14. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Pedersen BK, Febbraio MA. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55: 2688 2697, 2006. 15. Cavaliere F, DAmbrosi N, Sancesario G, Bernardi G, Volonte C. Hypoglycaemia-induced cell death: features of neuroprotection by the P2 receptor antagonist basilen blue. Neurochem Int 38: 199 207, 2001. 16. Chan MH, McGee SL, Watt MJ, Hargreaves M, Febbraio MA. Altering dietary nutrient intake that reduces glycogen content leads to www.jap.org

Through other strategies, Kenneth Walsh (Boston, MA) (119) discovered other new myokines. He developed the socalled myomouse. The myomouse demonstrates that substantial increases in muscle ber hypertrophy, weight, and strength occur on induction of Akt signaling in skeletal muscle. The increase in muscle mass caused by myogenic Akt induction results in diminished fat deposition and improvements in whole body metabolism. Based on these ndings, Walsh devised a protocol to identify novel muscle-secreted proteins (myokines) that confer the phenotypic changes brought on by myogenic Akt induction. One of these newly discovered factors, referred to as follistatin-like 1, functions to promote endothelial cell function and stimulates revascularization in response to ischemic insult through its ability to activate Akt-endothelial nitric oxide synthase signaling (77). Using the myomouse model, Walsh and colleagues (35) further identied FGF21 to be produced by skeletal muscle. FGF21 has been known to be a hormone that is induced in liver by fasting. A recent study demonstrated that FGF21 induces hepatic expression of peroxisome proliferator-activated receptor gamma coactivator protein-1 (PGC-1), a key transcriptional regulator of energy homeostasis, and causes corresponding increases in fatty acid oxidation, tricarboxylic acid cycle ux, and gluconeogenesis without increasing glycogenolysis. Mice lacking FGF21 fail to fully induce PGC-1 expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis (94). The latter results reveal an unexpected relationship between FGF21 and PGC-1. However, the precise biological function of muscle-derived FGF21 is not known. LIF belongs to the IL-6 cytokine superfamily and is constitutively expressed in skeletal muscle. We have demonstrated that endurance exercise in humans increases the expression of LIF in skeletal muscle (7). Ongoing research in our group suggests that also LIF may be classied as a true myokine (7).
NEW HORIZONS

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Skeletal muscle has the capacity to produce and express cytokines belonging to distinctly different families. To date, the list includes IL-6, IL-8, IL-15, LIF, BDNF, follistatin-like 1, and FGF21 and contractile activity plays a role in regulating the expression of these cytokines in skeletal muscle. The nding that muscles produce myokines creates a paradigm shift and opens new scientic, technological, and scholarly horizons. We are convinced that the characterization of the biological effects of known and unknown peptides, constituting the muscle secretome, will dominate the coming decade, just as
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MUSCLE AND IL-6 38. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1: 1525, 2005. 39. Karege F, Perret G, Bondol G, Schwald M, Bertschy G, Aubry JM. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109: 143148, 2002. 40. Keller C, Keller P, Marshall-Gradisnik SM, Pedersen BK. IL-6 gene expression in human adipose tissue in response to exercise - effect of carbohydrate ingestion. J Physiol 550: 927931, 2003. 41. Keller C, Steensberg A, Hansen AK, Fischer CP, Plomgaard P, Pedersen BK. The effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle. J Appl Physiol 99: 20752079, 2005. 42. Keller C, Steensberg A, Pilegaard H, Osada T, Saltin B, Pedersen BK, Neufer PD. Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: inuence of muscle glycogen content. FASEB J 15: 2748 2750, 2001. 43. Kelly M, Gauthier MS, Saha AK, Ruderman NB. Activation of AMP-activated protein kinase (AMPK) by Interleukin-6 in rat skeletal muscle: association with changes in cAMP, energy state, and endogenous fuel mobilization. Diabetes In press. 44. Kim HJ, Higashimori T, Park SY, Choi H, Dong J, Kim YJ, Noh HL, Cho YR, Cline G, Kim YB, Kim JK. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 53: 1060 1067, 2004. 45. Kjaer M, Pollack SF, Mohr T, Weiss H, Gleim GW, Bach FW, Nicolaisen T, Galbo H, Ragnarsson KT. Regulation of glucose turnover and hormonal responses during electrical cycling in tetraplegic humans. Am J Physiol Regul Integr Comp Physiol 271: R191R199, 1996. 46. Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology 146: 34173427, 2005. 47. Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52: 2784 2789, 2003. 48. Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258: 1798 1801, 1992. 49. Kolb H, Mandrup-Poulsen T. An immune origin of type 2 diabetes? Diabetologia 48: 1038 1050, 2005. 50. Komulainen P, Pedersen M, Hanninen T, Bruunsgaard H, Lakka TA, Kivipelto M, Hassinen M, Rauramaa TH, Pedersen BK, Rauramaa R. BDNF is a novel marker of cognitive function in ageing women: The DRs EXTRA Study. Neurobiol Learn Mem 90: 596 603, 2008. 51. Kopp E, Ghosh S. Inhibition of NF-B by sodium salicylate and aspirin. Science 265: 956 959, 1994. 52. Kosmidou I, Vassilakopoulos T, Xagorari A, Zakynthinos S, Papapetropoulos A, Roussos C. Production of interleukin-6 by skeletal myotubes: role of reactive oxygen species. Am J Respir Cell Mol Biol 26: 587593, 2002. 53. Krabbe KS, Mortensen EL, Avlund K, Pedersen AN, Pedersen BK, Jorgensen T, Bruunsgaard H. Brain-derived neurotrophic factor predicts mortality risk in older women. J Am Geriatr Soc 57: 14471452, 2009. 54. Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C, Fischer CP, Lindegaard B, Petersen AM, Taudorf S, Secher NH, Pilegaard H, Bruunsgaard H, Pedersen BK. Brainderived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 50: 431 438, 2007. 55. Krook A. IL-6 and metabolism-new evidence and new questions. Diabetologia 51: 10971099, 2008. 56. Lagathu C, Bastard JP, Auclair M, Maachi M, Capeau J, Caron M. Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. Biochem Biophys Res Commun 311: 372379, 2003. 57. Langberg H, Olesen JL, Gemmer C, Kjaer M. Substantial elevation of interleukin-6 concentration in peritendinous tissue, in contrast to muscle, following prolonged exercise in humans. J Physiol 542: 985990, 2002. 58. Laske C, Stransky E, Leyhe T, Eschweiler GW, Wittorf A, Richartz E, Bartels M, Buchkremer G, Schott K. Stage-dependent BDNF serum concentrations in Alzheimers disease. J Neural Transm 113: 12171224, 2005. www.jap.org

17. 18. 19.

20. 21.

22.

23. 24.

25.

26. 27.

28. 29. 30.

31. 32. 33.

34.

35. 36. 37.

phosphorylation of nuclear p38 MAP kinase in human skeletal muscle: association with IL-6 gene transcription during contraction. FASEB J 18: 17851787, 2004. Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M. Brain-derived neurotrophic factor is reduced in Alzheimers disease. Brain Res Mol Brain Res 49: 71 81, 1997. Davies KJ, Quintanilha AT, Brooks GA, Packer L. Free radicals and tissue damage produced by exercise. Biochem Biophys Res Commun 107: 1198 1205, 1982. Di Gregorio GB, Hensley L, Lu T, Ranganathan G, Kern PA. Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity. Am J Physiol Endocrinol Metab 287: E182E187, 2004. Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53: 16431648, 2004. Febbraio MA, Steensberg A, Keller C, Starkie RL, Krustrup P, Ott P, Secher NH, Pedersen BK. Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans. J Physiol 549: 607 612, 2003. Febbraio MA, Steensberg A, Walsh R, Koukoulas I, van Hall G, Saltin B, Pedersen BK. Reduced glycogen availability is associated with an elevation in HSP72 in contracting human skeletal muscle. J Physiol 538: 911917, 2002. Fischer CP, Berntsen A, Perstrup LB, Eskildsen P, Pedersen BK. Plasma levels of IL-6 and CRP are associated with physical inactivity independent of obesity. Scand J Med Sci Sports 17: 580 587, 2007. Fischer CP, Hiscock N, Basu S, Vessby B, Kallner A, Sjo berg LB, Febbraio MA, Pedersen BK. Supplementation with vitamins C and E inhibits the release of interleukin-6 from contracting human skeletal muscle. J Physiol 558: 633 645, 2004. Franckhauser S, Elias I, Rotter SV, Ferre T, Nagaev I, Andersson CX, Agudo J, Ruberte J, Bosch F, Smith U. Overexpression of Il6 leads to hyperinsulinaemia, liver inammation and reduced body weight in mice. Diabetologia 51: 1306 1316, 2008. Frandsen U, Lopez-Figueroa M, Hellsten Y. Localization of nitric oxide synthase in human skeletal muscle. Biochem Biophys Res Commun 227: 88 93, 1996. Frost RA, Nystrom GJ, Lang CH. Lipopolysaccharide and proinammatory cytokines stimulate interleukin-6 expression in C2C12 myoblasts: role of the Jun NH2-terminal kinase. Am J Physiol Regul Integr Comp Physiol 285: R1153R1164, 2003. Frydelund-Larsen L, Penkowa M, Akerstrom T, Zankari A, Nielsen S, Pedersen BK. Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle. Exp Physiol 92: 233240, 2007. Glund S, Krook A. Role of interleukin-6 signalling in glucose and lipid metabolism. Acta Physiol (Oxf) 192: 37 48, 2008. Glund S, Treebak JT, Long YC, Barres R, Viollet B, Wojtaszewski JF, Zierath JR. Role of adenosine 5-monophosphate-activated protein kinase in interleukin-6 release from isolated mouse skeletal muscle. Endocrinology 150: 600 606, 2009. Grange RW, Isotani E, Lau KS, Kamm KE, Huang PL, Stull JT. Nitric oxide contributes to vascular smooth muscle relaxation in contracting fast-twitch muscles. Physiol Genomics 5: 35 44, 2001. Hemish J, Nakaya N, Mittal V, Enikolopov G. Nitric oxide activates diverse signaling pathways to regulate gene expression. J Biol Chem 278: 42321 42329, 2003. Hiscock N, Chan MH, Bisucci T, Darby IA, Febbraio MA. Skeletal myocytes are a source of interleukin-6 mRNA expression and protein release during contraction: evidence of ber type specicity. FASEB J 18: 992994, 2004. Ho RC, Hirshman MF, Li Y, Cai D, Farmer JR, Aschenbach WG, Witczak CA, Shoelson SE, Goodyear LJ. Regulation of IB kinase and NF-B in contracting adult rat skeletal muscle. Am J Physiol Cell Physiol 289: C794 C801, 2005. Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt-regulated myokine. FEBS Lett 582: 38053810, 2008. Jackson MJ, Edwards RH, Symons MC. Electron spin resonance studies of intact mammalian skeletal muscle. Biochim Biophys Acta 847: 185190, 1985. Ji LL, Gomez-Cabrera MC, Steinhafel N, Vina J. Acute exercise activates nuclear factor (NF)-B signaling pathway in rat skeletal muscle. FASEB J 18: 1499 1506, 2004. J Appl Physiol VOL

Downloaded from http://jap.physiology.org/ by guest on July 25, 2013

107 OCTOBER 2009

Review
MUSCLE AND IL-6 59. Lau KS, Grange RW, Chang WJ, Kamm KE, Sarelius I, Stull JT. Skeletal muscle contractions stimulate cGMP formation and attenuate vascular smooth muscle myosin phosphorylation via nitric oxide. FEBS Lett 431: 7174, 1998. 60. Lau KS, Grange RW, Isotani E, Sarelius IH, Kamm KE, Huang PL, Stull JT. nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Physiol Genomics 2: 2127, 2000. 61. Long YC, Zierath JR. Inuence of AMP-activated protein kinase and calcineurin on metabolic networks in skeletal muscle. Am J Physiol Endocrinol Metab 295: E545E552, 2008. 62. Lyngso D, Simonsen L, Bulow J. Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect of exercise. J Physiol 543: 373378, 2002. 63. Malm C, Nyberg P, Engstrom M, Sjodin B, Lenkei R, Ekblom B, IL. Immunological changes in human skeletal muscle and blood after eccentric exercise and multiple biopsies. J Physiol 529: 243262, 2000. 64. Mathur N, Pedersen BK. Exercise as a mean to control low-grade systemic inammation. Mediators Inamm First published January 11, 2009; doi:10.1155/2008/109502. 65. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28: 412 419, 1985. stro 66. Matthews VB, A m MB, Chan MHS, Bruce CR, Prelovsek O, kerstro A m T, Yfanti C, Broholm C, Mortensen OH, Penkowa M, Hojman P, Zankari A, Watt MJ, Pedersen BK, Febbraio MA. Brain derived neutrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMPK. Diabetologia 52: 1409 1418, 2009. 67. Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27: 589 594, 2004. 68. Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol Endocrinol Metab 273: E1107 E1112, 1997. 69. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMPactivated protein kinase. Nature 415: 339 343, 2002. 70. Nielsen AR, Hojman P, Erikstrup C, Fischer CP, Plomgaard P, Mounier R, Mortensen OH, Broholm C, Taudorf S, Krogh-Madsen R, Lindegaard B, Petersen AM, Gehl J, Pedersen BK. Association between IL-15 and obesity: IL-15 as a potential regulator of fat mass. J Clin Endocrinol Metab 93: 4486 93, 2008. 71. Nielsen AR, Mounier R, Plomgaard P, Mortensen OH, Penkowa M, Speerschneider T, Pilegaard H, Pedersen BK. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle bre type composition. J Physiol 584: 305312, 2007. 72. Nieman DC, Nehlsen-Canarella SL, Fagoaga OR, Henson DA, Utter A, Davis JM, Williams F, Butterworth DE. Inuence of mode and carbohydrate on the cytokine response to heavy exertion. Med Sci Sports Exerc 30: 671 678, 1998. 73. Norrby K. Interleukin-8 and de novo mammalian angiogenesis. Cell Prolif 29: 315323, 1996. 74. Nybo L, Nielsen B, Pedersen BK, Moller K, Secher NH. Interleukin-6 release from the human brain during prolonged exercise. J Physiol 542: 991995, 2002. 75. Ostrowski K, Schjerling P, Pedersen BK. Physical activity and plasma interleukin-6 in humans effect of intensity of exercise. Eur J Appl Physiol 83: 512515, 2000. 76. Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK. Pro- and anti-inammatory cytokine balance in strenuous exercise in humans. J Physiol 515: 287291, 1999. 77. Ouchi N, Oshima Y, Ohashi K, Higuchi A, Ikegami C, Izumiya Y, Walsh K. Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J Biol Chem 283: 32802 32811, 2008. 78. Paroo Z, Noble EG. Isoproterenol potentiates exercise-induction of Hsp70 in cardiac and skeletal muscle. Cell Stress Chaperones 4: 199 204, 1999. J Appl Physiol VOL

1013

79. Pedersen BK. The anti-inammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays Biochem 42: 105 117, 2006. 80. Pedersen BK. IL-6 signalling in exercise and disease. Biochem Soc Trans 35: 12951297, 2007. 81. Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol 103: 10931090, 2007. 82. Pedersen BK, Febbraio MA. Point: Interleukin-6 does have a benecial role in insulin sensitivity and glucose homeostasis. J Appl Physiol 102: 814 816, 2007. 83. Pedersen BK, Fischer CP. Benecial health effects of exercise-the role of IL-6 as a myokine. Trends Pharmacol Sci 28: 152156, 2007. 84. Pedersen BK, Kappel M, Klokker M, Nielsen HB, Secher NH. The immune system during exposure to extreme physiologic conditions. Int J Sports Med 15: S116 S121, 1994. 85. Pedersen BK, Tvede N, Hansen FR, Andersen V, Bendix T, Bendixen G, Bendtzen K, Galbo H, Haahr PM, Klarlund K, et al. Modulation of natural killer cell activity in peripheral blood by physical exercise. Scand J Immunol 27: 673 678, 1988. 86. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 88: 1379 1406, 2008. 87. Pedersen M, Bruunsgaard H, Weis N, Hendel HW, Andreassen BU, Eldrup E, Dela F, Pedersen BK. Circulating levels of TNF- and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes. Mech Ageing Dev 124: 495502, 2003. 88. Penkowa M, Keller C, Keller P, Jauffred S, Pedersen BK. Immunohistochemical detection of interleukin-6 in human skeletal muscle bers following exercise. FASEB J 17: 2166 2168, 2003. 89. Petersen AM, Pedersen BK. The anti-inammatory effect of exercise. J Appl Physiol 98: 1154 1162, 2005. 90. Petersen AM, Pedersen BK. The role of IL-6 in mediating the antiinammatory effects of exercise. J Physiol Pharmacol 57, Suppl 10: 4351, 2006. 91. Petersen EW, Carey AL, Sacchetti M, Steinberg GR, Macaulay SL, Febbraio MA, Pedersen BK. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro: evidence that IL-6 acts independently of lipolytic hormones. Am J Physiol Endocrinol Metab 288: E155E162, 2005. 92. Pilz RB, Broderick KE. Role of cyclic GMP in gene regulation. Front Biosci 10: 1239 1268, 2005. 93. Plomgaard P, Penkowa M, Pedersen BK. Fiber type specic expression of TNF-, IL-6 and IL-18 in human skeletal muscles. Exerc Immunol Rev 11: 53 63, 2005. 94. Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA, Burgess SC. FGF21 induces PGC-1 and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA 106: 1085310858, 2009. 95. Pritts TA, Hungness ES, Hershko DD, Robb BW, Sun X, Luo GJ, Fischer JE, Wong HR, Hasselgren PO. Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells. Am J Physiol Regul Integr Comp Physiol 282: R1016 R1026, 2002. 96. Quinn LS, Anderson BG, Strait-Bodey L, Stroud AM, Argiles JM. Oversecretion of interleukin-15 from skeletal muscle reduces adiposity. Am J Physiol Endocrinol Metab 296: E191E202, 2009. 97. Rhind SG, Gannon GA, Shephard RJ, Shek PN. Indomethacin modulates circulating cytokine responses to strenuous exercise in humans. Cytokine 19: 153158, 2002. 98. Roberts CK, Barnard RJ, Jasman A, Balon TW. Acute exercise increases nitric oxide synthase activity in skeletal muscle. Am J Physiol Endocrinol Metab 277: E390 E394, 1999. 99. Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278: 45777 45784, 2003. 100. Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-B transcription factor and HIV-1. EMBO J 10: 22472258, 1991. 101. Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 51: 33913399, 2002. www.jap.org

Downloaded from http://jap.physiology.org/ by guest on July 25, 2013

107 OCTOBER 2009

Review 1014
MUSCLE AND IL-6 recovery from demanding exercise. Int J Sport Nutr Exerc Metab 11: 466 481, 2001. Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9: 224 237, 2002. Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24: 5434 5446, 2004. van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, Pedersen BK. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88: 30053010, 2003. Vassilakopoulos T, Karatza MH, Katsaounou P, Kollintza A, Zakynthinos S, Roussos C. Antioxidants attenuate the plasma cytokine response to exercise in humans. J Appl Physiol 94: 10251032, 2003. Wallen ES, Buettner GR, Moseley PL. Oxidants differentially regulate the heat shock response. Int J Hyperthermia 13: 517524, 1997. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO. Interleukin-6-decient mice develop mature-onset obesity. Nat Med 8: 7579, 2002. Walsh K. Adipokines, myokines and cardiovascular disease. Circ J 73: 1318, 2009. Watt MJ, Dzamko N, Thomas WG, Rose-John S, Ernst M, Carling D, Kemp BE, Febbraio MA, Steinberg GR. CNTF reverses obesityinduced insulin resistance by activating skeletal muscle AMPK. Nat Med 12: 541548, 2006. Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res 14: 6735 6741, 2008. Welch WJ, Garrels JI, Thomas GP, Lin JJ, Feramisco JR. Biochemical characterization of the mammalian stress proteins and identication of two stress proteins as glucose- and Ca2-ionophore-regulated proteins. J Biol Chem 258: 71027111, 1983. Wilund KR. Is the anti-inammatory effect of regular exercise responsible for reduced cardiovascular disease? Clin Sci (Lond) 112: 543555, 2007.

102. Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, Mooney RA. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 278: 13740 13746, 2003. 103. Silveira LR, Pereira-Da Silva L, Juel C, Hellsten Y. Formation of hydrogen peroxide and nitric oxide in rat skeletal muscle cells during contractions. Free Radic Biol Med 35: 455 464, 2003. 104. Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF- production in humans. FASEB J 17: 884 886, 2003. 105. Steensberg A, Febbraio MA, Osada T, Schjerling P, van HG, Saltin B, Pedersen BK. Interleukin-6 production in contracting human skeletal muscle is inuenced by pre-exercise muscle glycogen content. J Physiol 537: 633 639, 2001. 106. Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab 285: E433E437, 2003. 107. Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA, Pedersen BK. IL-6 and TNF- expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab 283: E1272 E1278, 2002. 108. Steensberg A, van HG, Osada T, Sacchetti M, Saltin B, Klarlund PB. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol 529: 237242, 2000. 109. Steensberg A, Keller C, Hillig T, Frosig C, Wojtaszewski JFP, Pedersen BK, Pilegaard H, Sander M. Nitric oxide production is a proximal signaling event controlling exercise-induced mRNA expression in human skeletal muscle. FASEB J 21: 26832694, 2007. 110. Steinberg GR, Rush JW, Dyck DJ. AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment. Am J Physiol Endocrinol Metab 284: E648 E654, 2003. 111. Steinberg GR, Watt MJ, Febbraio MA. Cytokine Regulation of AMPK signalling. Front Biosci 14: 19021916, 2009. 112. Thompson D, Williams C, McGregor SJ, Nicholas CW, McArdle F, Jackson MJ, Powell JR. Prolonged vitamin C supplementation and

113.

114.

115.

116. 117. 118. 119. 120.

Downloaded from http://jap.physiology.org/ by guest on July 25, 2013

121. 122.

123.

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