[MUSIC] My name is Bente Klarlund Pedersen, I'm a medical doctor specialized in infectious diseases. And a Professor of Integrative Medicine at the University of Copenhagen. I'm also the Director of the Center for Physical Activity Research. In this lecture, I gave you a new perspective on the muscle, the largest organ in the body. Skeletal muscles are primarily identified by the mechanical activity required for posture, movement, and breathing. Which depends on muscle fiber contractions. However, skeletal muscle is not just a component in our locomotor system. It's also important for our glucose and fat regulation, and thereby of importance for both obesity and diabetes. The discovery that contracting skeletal muscle secretes proteins, so-called myokines, sets a novel paradigm. Skeletal muscle is a secretary organ producing and releasing myokines in response to contraction. Which can influence metabolism and function of both muscle tissue and other tissues and organs. For nearly half a century, researchers hypothesized that skeletal muscle cells posses a humoral factor that was released in response to increased glucose demand during contraction. Due to lack of more precise knowledge, the unidentified contraction induced factor was named the work stimulus, the work factor, or the exercise factor. It was known that electrical stimulation of paralyzed muscle in spinal cord injured patients with no afferent or efferent impulses, induces many of the same physiological changes as in intact human beings. Therefore, it was clear the contracting skeletal muscles were able to communicate to other organs via humoral factors. Which are released into the circulation during physical activity. Such factors might directly or indirectly influence the functions of other organs. Such as the adipose tissue, the liver, the cardiovascular system, and the brain. In more recent time, it has been suggested that skeletal muscle might secrete proteins that could counteract the harmful effects of the proinflammatory adipokines secreted by adipose tissue in the obese state in a yin-yang fashion. During the past 20 to 30 years it has become evident that exercise induces considerable changes in the immune system. Especially with regard to the innate immune system, also known as the non-specific immune system and first line of defense. The so-called natural killer cells are part of the innate immune system. And they are very sensitive to stress, including an exercise stimulus. It was while looking for a mechanism to explain exercise-induced changes in the distribution and concentration of lymphocyte subpopulations that we came across IL-6. IL-6 increases in an exponential fashion proportional to the length of exercise and the amount of muscle mass engaged in the exercise. Thus, plasma IL-6 may increase up to 100 fold, although less dramatic increases are more frequent. Of note, the increase of IL-6 in the circulation occurs during exercise without any sign of muscle damage. The IL-6 increase is followed by the appearance of the anti-inflammatory cytokines IL-1ra and IL-10. Importantly, the cytokine response to exercise differs from sepsis with regard to TNF. Thus, the cytokine response to exercise is not preceded by an increase in plasma TNF. Until the beginning of this millennium, it was thought that the increase in IL-6 during the exercise was a consequence of an immune response due to local damage in the working muscle. And it was hypothesized that macrophages were responsible for this increase. However, it soon became clear that immune cells do not contribute to produce IL-6 in relation to exercise. By inserting catheters into the femoral vein and artery, we could measure AV differences over both an exercising leg and a resting leg. It appeared that exercising muscle was responsible for the production and release of IL-6 during exercise. Measurement of AV IL-6 concentrations and blood flow across the leg has demonstrated that IL-6 is released in relatively high quantities into the circulation from the exercising leg. This finding soon led to a discovery that muscle-derived cytokines may play a role in mediating some of the exercise-associated metabolic changes. IL-6 works as an energy sensor. Exercise is an IL-6 trigger, but low muscle glycogen is also a trigger for the production and release of high concentrations of IL-6. It soon became clear that muscle-derived IL-6 has major impact on metabolism. Muscle-derived IL-6 has many biological effects, just to mention some. It is is involved in mediating increased hepatic glucose production during exercise. IL-6 has also a strong impact on lipid metabolism. It enhances both lipolysis and fat oxidation. And IL-6 is involved in mediating exercise-induced glucose uptake in healthy people. In continuation, we suggested that cytokines or other peptides that are produced, expressed, and released by muscle fibers. And exert either autocrine, paracrine or endocrine effects, should be classified as myokines. While the word adipokine refers to factors secreted from adipose tissue. The term myokine refers to a protein that is secreted from myocytes. It has been clearly demonstrated that both the upstream and downstream signalling pathways for IL-6 differ markedly between myocytes and macrophages. Unlike IL-6 signalling in macrophages, which is dependent upon NF-kB signalling. It appears that it's a muscular IL-6 expression. It's regulated by a network of signalling cascades that, among other pathways, is likely to involve a crosstalk between nFAT and MAP kinase pathways. Therefore, when IL-6 is signaling a myocyte or macrophages, it creates a pro-inflammatory response. Whereas IL-6 activation and signaling in muscle is totally independent of a preceding CNF response, or NF-kB. The muscle secretome has been identified using various forms of proteomic analysis. Today we know that there are several hundred myokines. However, so far, the biological effects have been mapped for only some of the identified myokines. Some myokines may be involved in communicating to other organs, such as adipose tissue, liver, pancreas, bones, and brain. However, some myokines exert their effects within the muscle itself. Thus, LIF, IL-4, IL-6, IL-7, and IL-15 promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy, and exercise provokes the release of a myostatin inhibitor, follistatin, from the liver. BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 stimulates lipolysis and IL-15 stimulates lipolysis, especially of visceral fat. IL-6 enhances insulin-stimulated glucose uptake and stimulates glucose output from the liver, but only during exercise. IL-6 also increases insulin secretion via up-regulation of GLP-1 in the L cells of the intestine. IL-6 has also anti-inflammatory effects, as it inhibits TNF production. But stimulate the occurrence of the anti-inflammatory cytokines IL-1Ra and IL-10. Furthermore, IL-6 stimulates cortisol production, and hence, neutrocytosis and lymphopenia. Other myokines, like IL-8 and CXCL-1, may promote angiogenesis. IGF-1, FGF-2, and TNF beta are involved in bone formation. And follistatin-related protein 1 improved endothelial function and revascularization of ischemic muscles. The myokine irisin has been shown to increase in plasma during exercise. Irisin is an interesting protein that has a role in browning of white adipose tissue. Also, the myokine meteorin-like, have a role in browning. The finding that the muscle secretome appears to consist of several hundred secreted peptides provides a conceptual basis. And a whole new paradigm for understanding how muscles communicate with other organs such as adipose tissue, liver, pancreas, bones and brain. The possibility exists that myokines are involved in mediating the preventive effects of exercise with regard to chronic diseases such as type 2 diabetes. Physical activity decreases the risk of a whole network of chronic diseases. People with diabetes have a two to three fold increased risk of diseases within this network. Recent research suggests that myokines may also be involved in mediating the protective effects of exercise on tumor growth. In a murine model of malignant melanoma, voluntary wheel running had a major impact on tumor growth. Here we see the malignant melanoma in murine lungs who did not have access to wheel running. And in mice who had access to wheel running, infiltration of natural killer cells was markedly increased in tumors from the running mice. A mechanistic analysis showed that NK cells were mobilized by epinephrine. And that the myokine IL-6 was involved in NK cell mobilization and weight distribution of these cells to the tumor site, thereby controlling tumor growth. Two millennia ago, Hippocrates observed that walking is man's best medicine. Already, then, the benefits of physical activity to health were recognized. Since then, the benefits of physical activity in lowering the risk of death from any cause, and improving longevity, have been well documented. In the past few years, exercise research has contributed tremendously to our understanding of the benefits of exercise on a molecular level. And recently also to the concept of considering skeletal muscle as a secretory organ. The identification of the muscle secretome provides a new platform for understanding how muscles communicate with other organs. And to explain how a healthy muscle tissue is developed and maintained. Thank you for your attention. [MUSIC]
