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Beneficial health effects of exercise – the role of IL-6 as a myokine

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It is not clear how contracting skeletal muscles mediate the numerous and diverse metabolic and physiological effects that are beneficial for health. Researchers have searched for a muscle-contraction-induced factor – an ‘exercise factor’ – that mediates some of the exercise effects in other tissues such as the liver and adipose tissue. In our search for such a factor, we encountered the cytokine interleukin (IL)-6, which is produced by contracting muscles and released into the blood. We propose that muscle-derived IL-6 meets the criteria of an exercise factor and that such classes of cytokine should be named ‘myokines’. The discovery of contracting muscle as a cytokine-producing organ creates a new paradigm: skeletal muscle as an endocrine organ. By contracting, it stimulates the production and release of myokines that can influence metabolism in tissue and organs. Newly identified myokines and their receptors could serve as targets in the treatment of metabolic disorders and other diseases.

Introduction

Chronic diseases are the major cause of death worldwide, led by cardiovascular disease (17 million deaths per year) and followed by cancer (7 million deaths per year), chronic lung diseases (4 million deaths per year) and diabetes mellitus (almost 1 million deaths per year) [1]. The rapid increase in the number of noncommunicable chronic diseases represents one of the major health challenges to global development this century. This growing challenge threatens economic and social development, in addition to the lives and health of millions of people. Based on current trends, these diseases are expected to account for 70% of deaths and 60% of disease burden by 2020 (http://www.who.int/healthinfo/bod/en/).

It is well known that regular exercise, independent of body mass index, offers protection against all-cause mortality, primarily by protecting against atherosclerosis, type 2 diabetes, colon cancer and breast cancer [2]. In addition, randomized intervention studies show that physical training is effective in the treatment of patients with ischemic heart disease, heart failure, type 2 diabetes and chronic obstructive pulmonary disease [3]. Moreover, recent observational studies indicate that exercise after the onset of breast cancer [4] or colorectal cancer [5] could reduce the risk of death from these diseases.

It is, however, unclear how contracting skeletal muscles mediate the numerous and diverse metabolic and physiological effects that are beneficial for health. For most of the twentieth century, researchers attempted to identify a muscle-contraction-induced factor that could mediate some of the exercise-induced changes in other organs such as the liver and adipose tissue.

In response to exercise, the markedly increased glucose uptake by the contracting skeletal muscle corresponds to an increased glucose production by the liver, whereby glucose homeostasis is maintained. How does contracting muscle modulate metabolism in the liver? In response to exercise, adipose tissue increases the release of free fatty acids into the circulation. How do contracting skeletal muscle and adipose tissue communicate? Furthermore, repeated bouts of exercise affect blood pressure, lipid profile and insulin sensitivity. Which mechanisms link contracting skeletal muscle to these diverse effects?

Section snippets

The idea of an ‘exercise factor’

It has long been known that the signaling pathways from contracting muscles to other organs are not mediated solely by the nervous system because the electrical stimulation of paralyzed muscles, with no afferent and efferent nerve impulses, in spinal-cord-injured patients induces many of the same physiological changes as in intact humans 6, 7. On this basis, it was clear that a humoral factor must exist. For the lack of more-precise knowledge, such a factor has been called the ‘work stimulus’

Muscle-derived IL-6: the first myokine

IL-6 is most often classified as a proinflammatory cytokine, although data also indicate that IL-6 and IL-6-regulated acute-phase proteins are anti-inflammatory and immunosuppressive and might negatively regulate the acute-phase response 9, 10. Growing evidence links type 2 diabetes and cardiovascular diseases to a state of low-grade chronic inflammation and it has been suggested that IL-6 promotes insulin resistance because of the observation that plasma levels of IL-6 are often elevated in

Other myokines

IL-6 might be one of several myokines. Recently, we suggested that IL-8 should be classified as a myokine 38, 39. IL-8 belongs to the CXC family of chemokines and associates with CXC receptor (CXCR)1 and CXCR2. It induces its chemotactic effects through CXCR1, whereas IL-8-induced angiogenesis is mediated by CXCR2, which is expressed by human microvascular endothelial cells. Locally produced IL-8 might elicit its response by interacting with CXCR2 receptors present in the capillary. In response

Concluding remarks

It is noteworthy that the cytokines IL-6 and IL-8 have proinflammatory properties, and it is suggested in some studies that these cytokines could have a role in the pathogenesis of several chronic diseases. By contrast, skeletal muscle expresses these cytokines acutely and muscle-derived IL-6 contributes to a marked increase in the systemic concentration of IL-6 in relation to exercise. Recent data indicate that the acute effects of IL-6 and IL-8 are not proinflammatory but that these cytokines

Acknowledgements

The Centre of Inflammation and Metabolism is supported by a grant from the Danish National Research Foundation (02–512–55). The study was further supported by the Danish Medical Research Council (22–01–009) and the Commission of the European Communities (contract LSHM-CT-2004–005272 EXGENESIS). The CMRC is supported by grants from The Copenhagen Hospital Corporation, The University of Copenhagen, The Faculty of Science and The Faculty of Health Sciences at this University.

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