From the discovery of myokines to exercise as medicine
Key messages from the paper
Early in my career, we studied the effect of exercise on the immune system. The main finding was that immune cells such as natural killer (NK) cells and T cells were mobilised to the blood during a bout of ergometer cycling exercise. While searching for a mechanism to explain these exercise-induced immune changes, we came across interleukin (IL)-6 and found that, in relation to an acute bout of aerobic exercise, contracting muscles released IL-6 into the blood whereby systemic levels of IL-6 increased exponentially. This unexpected and serendipitous finding contributed to identify skeletal muscle as an endocrine organ, which together with subsequent findings, e.g., that exercise-induced IL-6 has multiple metabolic and anti-inflammatory effects, further contributed to laying the groundwork for the discipline “exercise as medicine”.
THE MYOKINE CONCEPT
Within the society of human integrative physiology, the search for an exercise factor capable of mediating exercise-induced changes in other organs such as liver and adipose tissue dates back more than 60 years . It became clear that signalling pathways from exercising skeletal muscle to other organs were not solely mediated via the nervous system . In 2000, we discovered that contracting skeletal muscle produces and releases IL-6 into the circulation . This finding together with research during the subsequent years demonstrating that IL-6 has multiple metabolic effects in other parts of the body contributed to identify IL-6 as an exercise factor .
Given the manifold physiological, metabolic and immunological effects of exercise, it was obvious to us that more than one exercise factor likely existed. In 2003, we introduced the term “myokines”  and proposed that “cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines” [5, 6].
Following the identification of muscle-derived IL-6 as the first myokine, it soon became clear that muscles were able to secrete more than 650 different myokines . The identification of the myokinome has provided a new paradigm and a conceptual basis for understanding by which mechanisms muscles communicate with other organs. It has been proposed that the total sum of all exercise-induced factors released from muscle and other organs into the blood should be named “exerkines” [8, 9]. Exerkines may be released within extracellular vesicles known as exosomes , which may contain nucleic acids, peptides, mRNA, miRNA and mtDNA.
The role of myokines has previously been reviewed [6, 11-15]. Myokines are also involved in muscle proliferation, differentiation and regeneration independently of exercise [16, 17, 18]. During exercise, myokines signal within the muscle and mediate muscle-organ crosstalk to the brain, adipose tissue, bone, liver, gut, pancreas, vascular bed and skin [6, 13, 14] (Figure 1). In addition, myokines with anti-cancer effects have been recognised [19, 20]. The aim of the present narrative review is to provide an update on our recent advances within the myokine field, focussing on IL-6 and linking this research to clinical medicine.
INTERLEUKIN-6 – ENERGY SENSOR AND ENERGY ALLOCATOR
Muscle contractions as such stimulate the production of muscle-derived IL-6. However, low muscular glycogen further stimulates the production and release of IL-6 into the circulation, which classifies muscle-derived IL-6 as an energy sensor . Inspired by Professor Daniel Lieberman, the well-known evolutionary biologist, and his PhD student Tim Kistner, we proposed that IL-6 has a role in short-term energy allocation, especially during sustained, strenuous endurance physical activity . In humans, the half-life of IL-6 appears to be context dependent. The myokine IL-6 production during aerobic exercise is dependent on metabolic stress within the muscle. Furthermore, IL-6 mobilises stored energy from adipose and skeletal muscle, primarily by promoting lipolysis. Lastly, myokine IL-6 promotes differential uptake of liberated energy in myocytes by increasing muscular insulin sensitivity and transiently downregulating inflammation .
INTERLEUKIN-6 CAN WORK AS AN ANTI-INFLAMMATORY CYTOKINE
Lack of exercise is associated with low-grade chronic inflammation, not least when a physically inactive lifestyle is associated with obesity. Chronic inflammation is associated with most chronic diseases, and more than 50% of all deaths worldwide are attributed to chronic inflammatory diseases, including cancer, cardiovascular disease, dementia, stroke and diabetes .
Aerobic exercise induces anti-inflammatory effects with each bout of exercise and via long-term training adaptation .
The exercise-induced acute increase in IL‐6 promotes the production of the two anti-inflammatory cytokines IL‐1 receptor antagonist and IL‐10 . Moreover, in healthy humans, we showed that a bout of exercise or an IL-6 infusion prior to endotoxin infusion totally blunted the increase in circulating levels of tumour necrosis factor (TNF)‐α that was observed during a resting situation . Thus, an acute bout of exercise induces anti‐inflammatory effects that may in part be mediated by IL‐6, not excluding the contribution of other anti-inflammatory factors such as epinephrine and cortisol .
Exercise also induces anti-inflammatory effects via an exercise-mediated reduction in abdominal fat . When visceral fat is accumulated, it represents an important place of origin of chronic systemic inflammation, as it was shown to be more inflamed than subcutaneous fat, constituting an important source of inflammatory markers . Lack of exercise provokes accumulation of visceral fat and thereby enhances inflammation and hence a network of chronic diseases, whereby a vicious circle of chronic inflammation is established . Recent evidence substantiates that exercise training decreases the amount of visceral and cardiac fat mass [30-32] via a mechanism that involves an exercise-induced increase in IL-6 . A human study from our group  found that IL-6 delays the rate of gastric emptying, which is the most significant regulator of postprandial glucose. As hyperglycaemia causes inflammation, lowering postprandial glucose levels further contributes to lowering chronic inflammation.
Epidemiological studies suggest that physical activity in leisure time reduces the risk of at least 13 cancer types [19, 20, 34, 35]. People who are physically active after a diagnosis of prostate cancer, colorectal cancer and breast cancer have a higher survival rate than physically inactive people suffering from the same cancer types .
Pernille Hojman and her team explored the effects of wheel-running on tumour growth in preclinical models . They first established a B16F10 melanoma model and randomised tumour-bearing mice to voluntary wheel running or control. Running mice demonstrated a marked reduction in tumour volume and incidence across six tumour models. The inhibitory effects of exercise on tumour growth were mediated via a direct regulation of NK cells, where these cells were mobilised to the circulation and redistributed to the tumour tissue by a mechanism involving both epinephrine and IL-6. Blocking IL-6 signalling during exercise abolished the exercise-induced inhibition of tumour growth. These findings in mice indicate that IL-6 may have a role in mediating anti-cancer effects [19, 37-40]. Indeed, a recent pilot study in humans suggests that supervised high-intensity interval exercise training prior to surgery may have the potential to increase tumour NK-cell infiltration in men with localised prostate cancer .
Exercise-induced IL-6 has major effects on fat metabolism [36, 42]. Cell culture studies and studies in rodents show that IL-6 may enhance lipolysis and fat oxidation via a mechanism that involves AMP-activated protein kinase activation . Moreover, in vivo studies show that infusion of recombinant human IL-6 enhances lipolysis and fat oxidation in healthy humans [43, 44].
To further explore the role of IL-6, abdominally obese humans were randomised to tocilizumab (IL-6 receptor antibody) or placebo during a 12-week intervention with either aerobic exercise training or no exercise [30, 45]. As expected, exercise training produced a reduction in visceral adipose tissue mass. However, this effect was abolished by IL-6 receptor blockade . Moreover, IL-6 receptor blockade abolished the exercise-induced loss of cardiac fat . In another placebo-controlled, non-randomised participant-blinded crossover study , we used tocilizumab to further investigate the role of endogenous IL-6 in regulating systemic energy metabolism at rest and during exercise and recovery in lean and obese men using tracer dilution methodology. We found that blocking endogenous IL-6 signalling with tocilizumab impairs fat mobilisation, which may contribute to expansion of adipose tissue mass and thus affect the health of individuals undergoing anti-IL-6 therapy.
EXERCISE AS MEDICINE
Today, noncommunicable diseases (NCDs), such as diabetes, cardiovascular diseases, cancer, chronic respiratory diseases and mental disorders, are responsible for more than 68% of deaths worldwide and 75% of deaths in low- and middle-income countries . Two millennia ago, Hippocrates observed that “walking is man's best medicine”. Already then, the benefits of physical activity to health were recognised. Since then, the benefits of physical activity in lowering the risk of death from any cause and improving longevity have been well documented, and today exercise is prescribed as medicine for many chronic diseases .
The finding that exercise-induced myokines may mediate communication from muscle to distant organs contributes to providing a conceptual basis for prescribing exercise training as medicine for NCDs such as type 2 diabetes, cardiovascular disease, pulmonary diseases and cancer.
Here, I will mention just one example of an “Exercise-as-medicine” project. To test the effects of an intensive lifestyle intervention, we conducted a randomised study in 98 adult participants with type 2 diabetes who had been diagnosed for less than ten years. Participants were randomly assigned to the lifestyle group (n = 64) or to the standard care group (n = 34). All participants received standard care with individual counselling and standardised, blinded, target-driven medical therapy. Additionally, the lifestyle intervention included 5-6 weekly partly supervised aerobic training sessions (duration 30-60 minutes) of which 2-3 sessions were combined with resistance training. Participants were followed for 12 months. Reduction in glucose-lowering medications occurred in 73.5% of the participants in the lifestyle group and in 26.4% in the standard care group. After 12 months, 56% of the patients in the lifestyle group were without glucose-lowering medication . Evidence exists that exercise has the potential to improve beta cell function and that this is associated with a decrease in low-grade inflammation [50, 51].
MAKING MORE PEOPLE MOVE
The physiology and molecular biology of exercise suggests that exercise activates multiple signalling pathways of major health importance. However, a need exists to close the gap between knowledge and practice and to translate basic research both into clinical practice and into political statements. In other terms: How do we make more people move?
History clearly demonstrates that structural changes in a society have more impact on health than any group interventions or sophisticated discovery strategies . Therefore, structural changes that make a healthy lifestyle more accessible to these communities will reduce health disparities .
Such physical activity interventions should include promoting walking and cycling as means of transportation. In addition, urban planners, schools and workplace designers should prioritise physical activity in their plans [54, 55]. We move more when the environment is interesting, aesthetic, green or with shops and restaurants nearby [54, 55]. We do not move simply because we are told to do so. We move to get forward!! We move when the context compels us to do so.
A translational research perspective on skeletal muscle as an endocrine organ and its relevance for exercise as medicine includes a bi-directional continuum from molecular events to sub-cellular, cellular, tissue and organ function, at the organism level using preclinical models, in human small-group studies and in human populations with direct implications for clinical practice and public health (Figure 2).
Correspondence Bente Klarlund Pedersen. E-mail: firstname.lastname@example.org
Accepted 2 June 2023
Conflicts of interest none. Disclosure forms provided by the authors are available with the article at ugeskriftet.dk/dmj
Acknowledgement The Centre for Physical Activity Research is supported by TrygFonden (grants ID 101390, ID 20045 and ID 125132).
Cite this as Dan Med J 2023;70(9):A12220766
- Goldstein M. Humoral nature of hypoglycemia in muscular activity. Am J Physiol. 1961;200:67-70.
- Kjaer M, Pollack SF, Mohr T et al. Regulation of glucose turnover and hormonal responses during electrical cycling in tetraplegic humans. Am J Physiol. 1996;271(1 pt 2):R191-R199.
- Steensberg A, van Hall G, Osada T, Sacchetti M et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol. 2000;529(pt 1):237-42.
- Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88(4):1379-406.
- Pedersen BK, Steensberg A, Fischer C et al. Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil. 2003;24(2-3):113-9.
- Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8(8):457-65.
- Khan SU, Ghafoor S. Myokines: discovery challenges and therapeutic impediments. J Pak Med Assoc. 2019;69(7):1014-7.
- Safdar A, Tarnopolsky MA. Exosomes as mediators of the systemic adaptations to endurance exercise. Cold Spring Harb Perspect Med. 2018;8(3):a029827.
- Safdar A, Saleem A, Tarnopolsky MA. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat Rev Endocrinol. 2016;12(9):504-17.
- Whitham M, Parker BL, Friedrichsen M et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 2018;27(1):237-251.e4.
- Pedersen BK. Exercise-induced myokines and their role in chronic diseases. Brain Behav Immun. 2011;25(5):811-6.
- Pedersen BK. The diseasome of physical inactivity - and the role of myokines in muscle-fat cross talk. J Physiol. 2009;587(pt 23):5559-68.
- Benatti FB, Pedersen BK. Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation. Nat Rev Rheumatol. 2015;11(2):86-97.
- Pedersen BK. Physical activity and muscle-brain crosstalk. Nat RevEndocrinol. 2019;15(7):383-92.
- Chow LS, Gerszten RE, Taylor JM et al. Exerkines in health, resilience and disease. Nat Rev Endocrinol. 2022;18(5):273-89.
- Henningsen J, Pedersen BK, Kratchmarova I. Quantitative analysis of the secretion of the MCP family of chemokines by muscle cells. Mol Biosyst. 2011;7(2):311-21.
- Henningsen J, Rigbolt KTG, Blagoev B et al. Dynamics of the skeletal muscle secretome during myoblast differentiation. Mol Cell Proteomics. 2010;9(11):2482-96.
- Severinsen MCK, Pedersen BK. Muscle-organ crosstalk: the emerging roles of myokines. Endocr Rev. 2020;41(4):594-609.
- Hojman P, Gehl J, Christensen JF, Pedersen BK. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab. 2018;27(1):10-21.
- Pedersen L, Idorn M, Olofsson GH et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 2016;23(3):554-62.
- Steensberg A, Febbraio MA, Osada T et al. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol. 2001;537(pt 2):633-9.
- Kistner TM, Pedersen BK, Lieberman DE. Interleukin 6 as an energy allocator in muscle tissue. Nat Metab. 2022;4(2):170-9.
- Furman D, Campisi J, Verdin E et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822-32.
- Bay ML, Pedersen BK. Muscle-organ crosstalk: focus on immunometabolism. Front Physiol. 2020;11:567881.
- Steensberg A, Fischer CP, Keller C et al. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab. 2003;285(2):E433-E437.
- Starkie R, Ostrowski SR, Jauffred S et al. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003;17(8):884-6.
- Pedersen BK. Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease. Eur J Clin Invest. 2017;47(8):600-11.
- Rosenkilde M, Nordby P, Stallknecht B. Maintenance of improvements in fitness and fatness 1 year after a 3-month lifestyle intervention in overweight men. Eur J Clin Nutr. 2016;70(10):1212-4.
- Yudkin JS. Inflammation, obesity, and the metabolic syndrome. Horm Metab Res. 2007;39(10):707-9.
- Wedell-Neergaard AS, Lehrskov LL, Christensen RH et al. Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial. Cell Metab. 2019;29(4):844-855.e3.
- Christensen RH, Wedell-Neergaard AS, Lehrskov LL et al. Effect of aerobic and resistance exercise on cardiac adipose tissues: secondary analyses from a randomized clinical trial. JAMA Cardiol. 2019;4(8):778-87.
- Christensen RH, Lehrskov LL, Wedell-Neergaard AS et al. Aerobic exercise induces cardiac fat loss and alters cardiac muscle mass through an interleukin-6 receptor-dependent mechanism: cardiac analysis of a double-blind randomized controlled clinical trial in abdominally obese humans. Circulation. 2019;140(20):1684-6.
- Lehrskov LL, Lyngbaek MP, Soederlund L et al. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control. Cell Metab. 2018;27(6):1201-1211.e3.
- Moore SC, Lee IM, Weiderpass E et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern Med. 2016;176(6):816-25.
- Christensen JF, Simonsen C, Hojman P. Exercise training in cancer control and treatment. Compr Physiol. 2018;9(1):165-205.
- Pedersen BK. The physiology of optimizing health with a focus on exercise as medicine. Annu Rev Physiol. 2018;81:607-27.
- Hojman P, Dethlefsen C, Brandt C et al. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab. 2011;301(3):E504-E510.
- Aoi W, Naito Y, Takagi T et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut. 2013;62(6):882-9.
- Lucia A, Ramirez M. Muscling in on cancer. N Engl J Med. 2016;375(9):892-4.
- Hojman P, Stagaard R, Adachi-Fernandez E et al. Exercise suppresses tumor growth independent of high fat food intake and associated immune dysfunction. Sci Rep. 2022;12(1):5476.
- Djurhuus SS, Simonsen C, Toft BG et al. Exercise training to increase tumour natural killer-cell infiltration in men with localised prostate cancer: a randomised controlled trial. BJU Int. 2023;131(1):116-24.
- Pedersen BK. Muscle as a secretory organ. Compr Physiol. 2013;3(3):1337-62.
- Petersen EW, Carey AL, Sacchetti M et al. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Am J Physiol Endocrinol Metab. 2005;288(1):E155-E162.
- van Hall G, Steensberg A, Sacchetti M et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab. 2003;88(7):3005-10.
- Christensen RH, Wedell-Neergaard AS, Lehrskov LL et al. The role of exercise combined with tocilizumab in visceral and epicardial adipose tissue and gastric emptying rate in abdominally obese participants: protocol for a randomised controlled trial. Trials. 2018;19(1):266.
- Trinh B, Peletier M, Simonsen C et al. Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men. Cell Rep Med. 2021;2(9):100396.
- Centers for Disease Control and Prevention. Global noncommunicable diseases. www.cdc.gov/globalhealth/healthprotection/ncd/index.html (May 2023).
- Pedersen BK, Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015;25(suppl 3):1-72.
- Johansen MY, MacDonald CS, Hansen KB et al. Effect of an intensive lifestyle intervention on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017;318(7):637-46.
- Johansen MY, Karstoft K, MacDonald CS et al. Effects of an intensive lifestyle intervention on the underlying mechanisms of improved glycaemic control in individuals with type 2 diabetes: a secondary analysis of a randomised clinical trial. Diabetologia. 2020;63(11):2410-22.
- Legaard GE, Lyngbæk MPP, Almdal TP et al. Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial. Nat Metab. 2023;5(5):880-95.
- Joyner MJ, Pedersen BK. Ten questions about systems biology. J Physiol. 2011;589(pt 5):1017-30.
- Brook RH. Medical leadership in an increasingly complex world. JAMA. 2010;304(4):465-6.
- Celis-Morales CA, Lyall DM, Welsh P et al. Association between active commuting and incident cardiovascular disease, cancer, and mortality: prospective cohort study. BMJ. 2017;357:j1456.
- Sallis JF, Cerin E, Conway TL et al. Physical activity in relation to urban environments in 14 cities worldwide: a cross-sectional study. Lancet. 2016;387(10034):2207-17.