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Muscle as a Secretory Organ

Bente K. Pedersen

10.1002/cphy.c120033

Source: Volume 3, Issue 3, July 2013

Published online: July 2013

Full Article on Wiley Online Library



Abstract

Skeletal muscle is the largest organ in the body. Skeletal muscles are primarily characterized by their 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. Recent evidence has identified skeletal muscle as a secretory organ. We have suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert either autocrine, paracrine, or endocrine effects should be classified as “myokines.” The muscle secretome consists of several hundred secreted peptides. This finding 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. In addition, several myokines exert their effects within the muscle itself. Many proteins produced by skeletal muscle are dependent upon contraction. Therefore, it is likely that myokines may contribute in the mediation of the health benefits of exercise. © 2013 American Physiological Society. Compr Physiol 3:1337‐1362, 2013.

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Figure 1. Figure 1.

Skeletal muscle is a secretory organ. Leukemia inhibitory factor (LIF), interleukin (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. Brain‐derived neurotropic factor (BDNF) and IL‐6 are involved in AMP‐activated protein kinase (AMPK)‐mediated fat oxidation and IL‐6 enhances insulin‐stimulated glucose uptake. IL‐6 appears to have systemic effects on the liver and adipose tissue and increases insulin secretion via upregulation of GLP‐1. Insulin‐like growth factor‐1 (IGF‐1) and FGF‐2 are involved in bone formation, and follistatin‐related protein 1 improves endothelial function and revascularization of ischemic vessels. Irisin has a role in “browning” of white adipose tissue. Adapted, with permission, from (172).
Figure 2. Figure 2.

The interplay between adipokines and myokines represents a Yin‐Yang balance. Especially under conditions of obesity, adipose tissue secretes adipokines that contribute to establish a chronic inflammatory environment, promoting pathological processes such as atherosclerosis and insulin resistance. Skeletal muscles are capable of producing myokines that confer some of the health benefits of exercise. Such myokines might counteract the harmful effects of proinflammatory adipokines. Adapted, with permission, from (172).
Figure 3. Figure 3.

Comparison of sepsis‐induced verses exercise‐induced increases in circulating cytokines. During sepsis, there is a marked and rapid increase in circulating tumor necrosis factor‐alpha (TNF‐α), which is followed by an increase in interleukin‐6 (IL‐6). In contrast, during exercise, the marked increase in IL‐6 is not preceded by elevated TNF‐α. Adapted, with permission, from (175).
Figure 4. Figure 4.

Different modes of exercise and the corresponding increase in plasma interleukin‐6 (IL‐6) levels. Graph is based on 73 exercise trials and represents ∼800 subjects. Each dot indicates one exercise trial; the corresponding bars represent geometric means with 95% confidence intervals. Although different modes of exercise are associated with different levels of muscle damage, the increase in plasma IL‐6 levels postexercise is a consistent finding. Modified, with permission, from (58,173).
Figure 5. Figure 5.

The overall log10‐log10 linear relation (straight solid line) between exercise duration and increase in plasma interleukin‐6 (IL‐6) (fold change from preexercise level) indicates that 51% of the variation in fold plasma IL‐6 increase may be explained by the duration of exercise. Modified, with permission, from (58).
Figure 6. Figure 6.

The figure presents a model on how interleukin‐6 (IL‐6) is regulated in response to training adaptation. Regular exercise leads to an enhancement of glycogen synthase and a trained muscle will consequently store more muscle glycogen. During acute exercise, the untrained muscle is highly dependent on glycogen as substrate, whereas training leads to an enhancement of beta‐oxidating enzymes and an enhanced capability to oxidize fat and hence to use fat as substrate during exercise. This means that the trained muscle uses less glycogen during work. The activation of muscle‐IL‐6 is glycogen dependent. At conditions with low muscle glycogen, the transcription rate of IL‐6 is faster and relatively more IL‐6 is produced at the same relative work compared to conditions with high muscle glycogen. Thus, the acute plasma IL‐6 response is lower in a trained versus an untrained subject. The mechanisms whereby basal plasma‐IL‐6 is decreased by training and whereby the muscular expression of IL‐6 receptors (IL‐6R) is enhanced are not fully understood. However, it appears that a trained muscle may be more sensitive to IL‐6. Adapted, with permission, from (175).
Figure 7. Figure 7.

Biological role of contraction‐induced interleukin‐6 (IL‐6). Skeletal muscle expresses and releases myokines into the circulation. In response to muscle contractions, both type I and type II muscle fibers express the myokine IL‐6, which subsequently exerts its effects both locally within the muscle (e.g., through activation of AMPK) and—when released into the circulation—peripherally in several organs in a hormone‐like fashion. Specifically in skeletal muscle, IL‐6 acts in an autocrine or paracrine manner to signal through a gp130Rβ/IL‐6Rα homodimer resulting in activation of AMP‐kinase and/or PI3‐kinase to increase glucose uptake and fat oxidation. IL‐6 is also known to increase hepatic glucose production during exercise or lipolysis in adipose tissue. Modified, with permission, from (173).
Figure 8. Figure 8.

Exercise increases the intramuscular expression of peroxisome proliferator activated receptor γ coactivator 1α (PGC‐1α). Boström and colleagues recently reported that PGC‐1α, a transcriptional coactivator, stimulates the expression of the membrane protein fibronectin type III domain containing 5 (FNDC5), which is proteolytically cleaved to form irisin, a myokine. Irisin drives the transformation of white fat cells into brite cells—white fat cells with a phenotype similar to that of brown fat cells, as indicated by a marked increase in the expression of uncoupling protein 1 (UCP1) in white adipose tissue. The investigators also showed that an elevated level of plasma irisin, achieved through gene replacement, is followed by a reduction in body weight and an improvement in metabolic homeostasis in obese mice. Adapted, with permission, from (168).
Figure 9. Figure 9.

Type 2 diabetes, cardiovascular diseases, colon cancer, postmenopausal breast cancer, dementia, and depression constitute a cluster of diseases, which can be identified as “the diseasome of physical inactivity”. Adapted, with permission, from (165).
Figure 10. Figure 10.

Hypothesis: physical inactivity leads to accumulation of visceral fat and consequently to the activation of a network of inflammatory pathways, which promotes development of insulin resistance, atherosclerosis, neurodegeneration, and tumor growth, leading to the development of “the diseasome of physical inactivity.” Adapted, with permission, from (165).
Figure 11. Figure 11.

MR‐scanning demonstrating visceral fat mass before and after 14 days of reduced daily stepping as described in (155).
Figure 12. Figure 12.

The proposed cytokine signaling pathways for macrophages and contracting skeletal muscle. While it is well known that transcription of interleukin‐6 (IL‐6) and other proinflammatory cytokines such as tumor necrosis factor‐alpha (TNF‐α) and IL‐β is principally regulated by the Toll like receptor (##TLR) receptor signaling cascade that results in nuclear translocation and activation of NFκB, evidence in contracting skeletal muscle suggests that contraction leads to increased cytosolic Ca2+ and activation of p38 MAPK and/or calcineurin, which leads to activation of transcription factors depending upon these upstream events. Adapted, with permission, from (175).
Figure 13. Figure 13.

The finding that muscle produces and releases myokines provides a conceptual basis for understanding some of the molecular mechanisms that link physical activity to protection against premature mortality (172).


Figure 1.

Skeletal muscle is a secretory organ. Leukemia inhibitory factor (LIF), interleukin (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. Brain‐derived neurotropic factor (BDNF) and IL‐6 are involved in AMP‐activated protein kinase (AMPK)‐mediated fat oxidation and IL‐6 enhances insulin‐stimulated glucose uptake. IL‐6 appears to have systemic effects on the liver and adipose tissue and increases insulin secretion via upregulation of GLP‐1. Insulin‐like growth factor‐1 (IGF‐1) and FGF‐2 are involved in bone formation, and follistatin‐related protein 1 improves endothelial function and revascularization of ischemic vessels. Irisin has a role in “browning” of white adipose tissue. Adapted, with permission, from (172).



Figure 2.

The interplay between adipokines and myokines represents a Yin‐Yang balance. Especially under conditions of obesity, adipose tissue secretes adipokines that contribute to establish a chronic inflammatory environment, promoting pathological processes such as atherosclerosis and insulin resistance. Skeletal muscles are capable of producing myokines that confer some of the health benefits of exercise. Such myokines might counteract the harmful effects of proinflammatory adipokines. Adapted, with permission, from (172).



Figure 3.

Comparison of sepsis‐induced verses exercise‐induced increases in circulating cytokines. During sepsis, there is a marked and rapid increase in circulating tumor necrosis factor‐alpha (TNF‐α), which is followed by an increase in interleukin‐6 (IL‐6). In contrast, during exercise, the marked increase in IL‐6 is not preceded by elevated TNF‐α. Adapted, with permission, from (175).



Figure 4.

Different modes of exercise and the corresponding increase in plasma interleukin‐6 (IL‐6) levels. Graph is based on 73 exercise trials and represents ∼800 subjects. Each dot indicates one exercise trial; the corresponding bars represent geometric means with 95% confidence intervals. Although different modes of exercise are associated with different levels of muscle damage, the increase in plasma IL‐6 levels postexercise is a consistent finding. Modified, with permission, from (58,173).



Figure 5.

The overall log10‐log10 linear relation (straight solid line) between exercise duration and increase in plasma interleukin‐6 (IL‐6) (fold change from preexercise level) indicates that 51% of the variation in fold plasma IL‐6 increase may be explained by the duration of exercise. Modified, with permission, from (58).



Figure 6.

The figure presents a model on how interleukin‐6 (IL‐6) is regulated in response to training adaptation. Regular exercise leads to an enhancement of glycogen synthase and a trained muscle will consequently store more muscle glycogen. During acute exercise, the untrained muscle is highly dependent on glycogen as substrate, whereas training leads to an enhancement of beta‐oxidating enzymes and an enhanced capability to oxidize fat and hence to use fat as substrate during exercise. This means that the trained muscle uses less glycogen during work. The activation of muscle‐IL‐6 is glycogen dependent. At conditions with low muscle glycogen, the transcription rate of IL‐6 is faster and relatively more IL‐6 is produced at the same relative work compared to conditions with high muscle glycogen. Thus, the acute plasma IL‐6 response is lower in a trained versus an untrained subject. The mechanisms whereby basal plasma‐IL‐6 is decreased by training and whereby the muscular expression of IL‐6 receptors (IL‐6R) is enhanced are not fully understood. However, it appears that a trained muscle may be more sensitive to IL‐6. Adapted, with permission, from (175).



Figure 7.

Biological role of contraction‐induced interleukin‐6 (IL‐6). Skeletal muscle expresses and releases myokines into the circulation. In response to muscle contractions, both type I and type II muscle fibers express the myokine IL‐6, which subsequently exerts its effects both locally within the muscle (e.g., through activation of AMPK) and—when released into the circulation—peripherally in several organs in a hormone‐like fashion. Specifically in skeletal muscle, IL‐6 acts in an autocrine or paracrine manner to signal through a gp130Rβ/IL‐6Rα homodimer resulting in activation of AMP‐kinase and/or PI3‐kinase to increase glucose uptake and fat oxidation. IL‐6 is also known to increase hepatic glucose production during exercise or lipolysis in adipose tissue. Modified, with permission, from (173).



Figure 8.

Exercise increases the intramuscular expression of peroxisome proliferator activated receptor γ coactivator 1α (PGC‐1α). Boström and colleagues recently reported that PGC‐1α, a transcriptional coactivator, stimulates the expression of the membrane protein fibronectin type III domain containing 5 (FNDC5), which is proteolytically cleaved to form irisin, a myokine. Irisin drives the transformation of white fat cells into brite cells—white fat cells with a phenotype similar to that of brown fat cells, as indicated by a marked increase in the expression of uncoupling protein 1 (UCP1) in white adipose tissue. The investigators also showed that an elevated level of plasma irisin, achieved through gene replacement, is followed by a reduction in body weight and an improvement in metabolic homeostasis in obese mice. Adapted, with permission, from (168).



Figure 9.

Type 2 diabetes, cardiovascular diseases, colon cancer, postmenopausal breast cancer, dementia, and depression constitute a cluster of diseases, which can be identified as “the diseasome of physical inactivity”. Adapted, with permission, from (165).



Figure 10.

Hypothesis: physical inactivity leads to accumulation of visceral fat and consequently to the activation of a network of inflammatory pathways, which promotes development of insulin resistance, atherosclerosis, neurodegeneration, and tumor growth, leading to the development of “the diseasome of physical inactivity.” Adapted, with permission, from (165).



Figure 11.

MR‐scanning demonstrating visceral fat mass before and after 14 days of reduced daily stepping as described in (155).



Figure 12.

The proposed cytokine signaling pathways for macrophages and contracting skeletal muscle. While it is well known that transcription of interleukin‐6 (IL‐6) and other proinflammatory cytokines such as tumor necrosis factor‐alpha (TNF‐α) and IL‐β is principally regulated by the Toll like receptor (##TLR) receptor signaling cascade that results in nuclear translocation and activation of NFκB, evidence in contracting skeletal muscle suggests that contraction leads to increased cytosolic Ca2+ and activation of p38 MAPK and/or calcineurin, which leads to activation of transcription factors depending upon these upstream events. Adapted, with permission, from (175).



Figure 13.

The finding that muscle produces and releases myokines provides a conceptual basis for understanding some of the molecular mechanisms that link physical activity to protection against premature mortality (172).

References
 1. Addison CL, Daniel TO, Burdick MD, Liu H, Ehlert JE, Xue YY, Buechi L, Walz A, Richmond A, Strieter RM. The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine‐induced angiogenic activity. J Immunol 165: 5269‐5277, 2000.
 2. Allen DL, Cleary AS, Speaker KJ, Lindsay SF, Uyenishi J, Reed JM, Madden MC, Mehan RS. Myostatin, activin receptor IIb, and follistatin‐like‐3 gene expression are altered in adipose tissue and skeletal muscle of obese mice. Am J Physiol Endocrinol Metab 294: E918‐E927, 2008.
 3. Allen DL, Hittel DS, McPherron AC. Expression and function of myostatin in obesity, diabetes, and exercise adaptation. Med Sci Sports Exerc 43: 1828‐1835, 2011.
 4. Alter J, Rozentzweig D, Bengal E. Inhibition of myoblast differentiation by tumor necrosis factor alpha is mediated by c‐Jun N‐terminal kinase 1 and leukemia inhibitory factor. J Biol Chem 283: 23224‐23234, 2008.
 5. Alvarez B, Carbo N, Lopez‐Soriano J, Drivdahl RH, Busquets S, Lopez‐Soriano FJ, Argiles JM, Quinn LS. Effects of interleukin‐15 (IL‐15) on adipose tissue mass in rodent obesity models: Evidence for direct IL‐15 action on adipose tissue. Biochim Biophys Acta 1570: 33‐37, 2002.
 6. Argiles JM, Lopez‐Soriano J, Almendro V, Busquets S, Lopez‐Soriano FJ. Cross‐talk between skeletal muscle and adipose tissue: A link with obesity? Med Res Rev 25: 49‐65, 2005.
 7. Asmussen E. Ventilation at transition from rest to exercise. Acta Physiol Scand 89: 68‐78, 1973.
 8. Astrom MB, Feigh M, Pedersen BK. Persistent low‐grade inflammation and regular exercise. Front Biosci (Schol Ed) 2: 96‐105, 2010.
 9. Austin L, Burgess AW. Stimulation of myoblast proliferation in culture by leukaemia inhibitory factor and other cytokines. J Neurol Sci 101: 193‐197, 1991.
 10. Baggiolini M. Chemokines in pathology and medicine. J Intern Med 250: 91‐104, 2001.
 11. Bamberger AM, Jenatschke S, Schulte HM, Ellebrecht I, Beil FU, Bamberger CM. Regulation of the human leukemia inhibitory factor gene by ETS transcription factors. Neuroimmunomodulation 11: 10‐19, 2004.
 12. Banzet S, Koulmann N, Simler N, Birot O, Sanchez H, Chapot R, Peinnequin A, Bigard X. Fibre‐type specificity of interleukin‐6 gene transcription during muscle contraction in rat: Association with calcineurin activity. J Physiol 566: 839‐847, 2005.
 13. Barabasi AL. Network medicine–from obesity to the “diseasome”. N Engl J Med 357: 404‐407, 2007.
 14. Barra NG, Reid S, MacKenzie R, Werstuck G, Trigatti BL, Richards C, Holloway AC, Ashkar AA. Interleukin‐15 contributes to the regulation of murine adipose tissue and human adipocytes. Obesity (Silver Spring) 18: 1601‐1607, 2010.
 15. Bartoccioni E, Michaelis D, Hohlfeld R. Constitutive and cytokine‐induced production of interleukin‐6 by human myoblasts. Immunol Lett 42: 135‐138, 1994.
 16. Bays HE. “ Sick fat,” metabolic disease, and atherosclerosis. Am J Med 122: S26‐S37, 2009.
 17. Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD, Strieter RM. CXC chemokines in angiogenesis. J Leukoc Biol 68: 1‐8, 2000.
 18. Bergfors M, Barnekow‐Bergkvist M, Kalezic N, Lyskov E, Eriksson JW. Short‐term effects of repetitive arm work and dynamic exercise on glucose metabolism and insulin sensitivity. Acta Physiol Scand 183: 345‐356, 2005.
 19. Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Comprehensive Physiology, 2(2): 1143‐1211, 2012.
 20. Bortoluzzi S, Scannapieco P, Cestaro A, Danieli GA, Schiaffino S. Computational reconstruction of the human skeletal muscle secretome. Proteins 62: 776‐792, 2006.
 21. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM. A PGC1‐alpha‐dependent myokine that drives brown‐fat‐like development of white fat and thermogenesis. Nature 481: 463‐468, 2012.
 22. Bouzakri K, Plomgaard P, Berney T, Donath MY, Pedersen BK, Halban PA. Bimodal effect on pancreatic â‐cells of secretory products from normal or insulin‐resistant human skeletal muscle. Diabetes 60: 1111‐1121, 2011.
 23. Brandt C, Nielsen AR, Fischer CP, Hansen J, Pedersen BK, Plomgaard P. Plasma and muscle myostatin in relation to type 2 diabetes. PLoS One 7: e37236, 2012.
 24. Brandt C, Pedersen BK. The role of exercise‐induced myokines in muscle homeostasis and the defense against chronic diseases. J Biomed Biotechnol 2010: 520258, 2010.
 25. Broholm C, Laye MJ, Brandt C, Vadalasetty R, Pilegaard H, Pedersen BK, Scheele C. LIF is a contraction‐induced myokine stimulating human myocyte proliferation. J Appl Physiol 111: 251‐259, 2011.
 26. 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: 2195‐2201, 2008.
 27. Broholm C, Pedersen BK. Leukaemia inhibitory factor–an exercise‐induced myokine. Exerc Immunol Rev 16: 77‐85, 2010.
 28. 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.
 29. Bruunsgaard H, Galbo H, Halkjaer‐Kristensen J, Johansen TL, MacLean DA, Pedersen BK. Exercise‐induced increase in interleukin‐6 is related to muscle damage. J Physiol Lond 499: 833‐841, 1997.
 30. Carbo N, Lopez‐Soriano J, Costelli P, Alvarez B, Busquets S, Baccino FM, Quinn LS, Lopez‐Soriano FJ, Argiles JM. Interleukin‐15 mediates reciprocal regulation of adipose and muscle mass: A potential role in body weight control. Biochim Biophys Acta 1526: 17‐24, 2001.
 31. Carbo N, Lopez‐Soriano J, Costelli P, Busquets S, Alvarez B, Baccino FM, Quinn LS, Lopez‐Soriano FJ, Argiles JM. Interleukin‐15 antagonizes muscle protein waste in tumour‐bearing rats. Br J Cancer 83: 526‐531, 2000.
 32. Carey AL, Febbraio MA. Interleukin‐6 and insulin sensitivity: Friend or foe? Diabetologia 47: 1135‐1142, 2004.
 33. 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.
 34. Caron‐Debarle M, Lagathu C, Boccara F, Vigouroux C, Capeau J. HIV‐associated lipodystrophy: From fat injury to premature aging. Trends Mol Med 16: 218‐229, 2010.
 35. Chomarat P, Banchereau J. An update on interleukin‐4 and its receptor. Eur Cytokine Netw 8: 333‐344, 1997.
 36. Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. N Engl J Med 357: 370‐379, 2007.
 37. Christiansen T, Paulsen SK, Bruun JM, Pedersen SB, Richelsen B. Exercise training versus diet‐induced weight‐loss on metabolic risk factors and inflammatory markers in obese subjects: A 12‐week randomized intervention study. Am J Physiol Endocrinol Metab 298: E824‐E831, 2010.
 38. Cook KS, Min HY, Johnson D, Chaplinsky RJ, Flier JS, Hunt CR, Spiegelman BM. Adipsin: A circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 237: 402‐405, 1987.
 39. Copray S, Liem R, Brouwer N, Greenhaff P, Habens F, Fernyhough P. Contraction‐induced muscle fiber damage is increased in soleus muscle of streptozotocin‐diabetic rats and is associated with elevated expression of brain‐derived neurotrophic factor mRNA in muscle fibers and activated satellite cells. Exp Neurol 161: 597‐608, 2000.
 40. Crofford LJ. The hypothalamic‐pituitary‐adrenal axis in the pathogenesis of rheumatic diseases. Endocrinol Metab Clin North Am 31: 1‐13, 2002.
 41. De Rossi M, Bernasconi P, Baggi F, de Waal MR, Mantegazza R. Cytokines and chemokines are both expressed by human myoblasts: Possible relevance for the immune pathogenesis of muscle inflammation. Int Immunol 12: 1329‐1335, 2000.
 42. Dhawan J, Rando TA. Stem cells in postnatal myogenesis: Molecular mechanisms of satellite cell quiescence, activation and replenishment. Trends Cell Biol 15: 666‐673, 2005.
 43. Diamant M, Tushuizen ME. The metabolic syndrome and endothelial dysfunction: Common highway to type 2 diabetes and CVD. Curr Diab Rep 6: 279‐286, 2006.
 44. Diao Y, Wang X, Wu Z. SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by inhibiting the leukemia inhibitory factor‐induced JAK1/STAT1/STAT3 pathway. Mol Cell Biol 29: 5084‐5093, 2009.
 45. Dinarello CA, Mier JW. Interleukins. Annu Rev Med 37: 173‐178, 1986.
 46. Domouzoglou EM, Maratos‐Flier E. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr 93: 901S‐905, 2011.
 47. Ellingsgaard H, Ehses JA, Hammar EB, Van LL, Quintens R, Martens G, Kerr‐Conte J, Pattou F, Berney T, Pipeleers D, Halban PA, Schuit FC, Donath MY. Interleukin‐6 regulates pancreatic alpha‐cell mass expansion. Proc Natl Acad Sci U S A 105: 13163‐13168, 2008.
 48. Ellingsgaard H, Hauselmann I, Schuler B, Eppler E, Meier D, Bouzakri K, Wueest S, Muller Y, Reinecke M, Konrad D, Gassmann M, Halban P, Gromada J, Ehses J, Donath M. Interleukin‐6 enhances insulin secretion by increasing glucagon‐like peptide‐1 secretion from L cells and alpha cells. Nat Med 17: 1481‐1489, 2011.
 49. Febbraio MA. Signaling pathways for IL‐6 within skeletal muscle. Exerc Immunol Rev 9: 34‐9, 2003.
 50. 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: 1643‐1648, 2004.
 51. Febbraio MA, Ott P, Nielsen HB, Steensberg A, Keller C, Krustrup P, Secher NH, Pedersen BK. Hepatosplanchnic clearance of interleukin‐6 in humans during exercise. Am J Physiol Endocrinol Metab 285: E397‐E402, 2003.
 52. Febbraio MA, Pedersen BK. Muscle‐derived interleukin‐6: Mechanisms for activation and possible biological roles. FASEB J 16: 1335‐1347, 2002.
 53. Febbraio MA, Pedersen BK. Contraction‐induced myokine production and release: Is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 33: 114‐119, 2005.
 54. 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 (London) 549: 607‐612, 2003.
 55. Feldman BJ, Streeper RS, Farese RV, Jr., Yamamoto KR. Myostatin modulates adipogenesis to generate adipocytes with favorable metabolic effects. Proc Natl Acad Sci U S A 103: 15675‐15680, 2006.
 56. Festa A, D'Agostino R, Jr., Tracy RP, Haffner SM. Elevated levels of acute‐phase proteins and plasminogen activator inhibitor‐1 predict the development of type 2 diabetes: The insulin resistance atherosclerosis study. Diabetes 51: 1131‐1137, 2002.
 57. Figueras M, Busquets S, Carbo N, Barreiro E, Almendro V, Argiles JM, Lopez‐Soriano FJ. Interleukin‐15 is able to suppress the increased DNA fragmentation associated with muscle wasting in tumour‐bearing rats. FEBS Lett 569: 201‐206, 2004.
 58. Fischer CP. Interleukin‐6 in acute exercise and training: What is the biological relevance? Exerc Immunol Rev 12: 6‐33, 2006.
 59. Fischer CP, Hiscock N, Basu S, Vessby B, Kallner A, Sjöberg 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.
 60. Fischer CP, Plomgaard P, Hansen AK, Pilegaard H, Saltin B, Pedersen BK. Endurance training reduces the contraction‐induced interleukin‐6 mRNA expression in human skeletal muscle. Am J Physiol Endocrinol Metab 287: E1189‐E1194, 2004.
 61. Furmanczyk PS, Quinn LS. Interleukin‐15 increases myosin accretion in human skeletal myogenic cultures. Cell Biol Int 27: 845‐851, 2003.
 62. Fuster G, Almendro V, Fontes‐Oliveira CC, Toledo M, Costelli P, Busquets S, Lopez‐Soriano FJ, Argiles JM. Interleukin‐15 affects differentiation and apoptosis in adipocytes: Implications in obesity. Lipids 46: 1033‐1042, 2011.
 63. Gala RR. Prolactin and growth hormone in the regulation of the immune system. Proc Soc Exp Biol Med 198: 513‐527, 1991.
 64. Giese B, Roderburg C, Sommerauer M, Wortmann SB, Metz S, Heinrich PC, Muller‐Newen G. Dimerization of the cytokine receptors gp130 and LIFR analysed in single cells. J Cell Sci 118: 5129‐5140, 2005.
 65. Giovannucci E. Metabolic syndrome, hyperinsulinemia, and colon cancer: A review. Am J Clin Nutr 86: s836‐s842, 2007.
 66. Gleeson M. Interleukins and exercise. J Physiol 529: 1, 2000.
 67. Gleeson M. Immune function in sport and exercise. J Appl Physiol 103: 693‐699, 2007.
 68. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti‐inflammatory effects of exercise: Mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 11: 607‐615, 2011.
 69. Goldstein MS. Humoral nature of the hypoglycemic factor of muscular work. Diabetes 10: 232‐234, 1961.
 70. Gomez‐Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF‐mediated mechanism that promotes neuroplasticity. J Neurophysiol 88: 2187‐2195, 2002.
 71. Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin‐2 receptor. Science 264: 965‐968, 1994.
 72. Green CJ, Pedersen M, Pedersen BK, Scheele C. Elevated NF‐{kappa}B activation is conserved in human myocytes cultured from obese type 2 diabetic patients and attenuated by AMP‐activated protein kinase. Diabetes 60: 2810‐2819, 2011.
 73. Gregorevic P, Williams DA, Lynch GS. Effects of leukemia inhibitory factor on rat skeletal muscles are modulated by clenbuterol. Muscle Nerve 25: 194‐201, 2002.
 74. Guo T, Jou W, Chanturiya T, Portas J, Gavrilova O, McPherron AC. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity. PLoS One 4: e4937, 2009.
 75. Haffner SM. Abdominal adiposity and cardiometabolic risk: Do we have all the answers? Am J Med 120: S10‐S16, 2007.
 76. Hamrick MW. A role for myokines in muscle‐bone interactions. Exerc Sport Sci Rev 39: 43‐47, 2011.
 77. Handschin C, Spiegelman BM. The role of exercise and PGC1[alpha] in inflammation and chronic disease. Nature 454: 463‐469, 2008.
 78. Hansen J, Brandt C, Nielsen AR, Hojman P, Whitham M, Febbraio MA, Pedersen BK, Plomgaard P. Exercise induces a marked increase in plasma follistatin: Evidence that follistatin is a contraction‐induced hepatokine. Endocrinology 152: 164‐171, 2011.
 79. Haugen F, Norheim F, Lian H, Wensaas AJ, Dueland S, Berg O, Funderud A, Skalhegg BS, Raastad T, Drevon CA. IL‐7 is expressed and secreted by human skeletal muscle cells. Am J Physiol Cell Physiol 298: C807‐C816, 2010.
 80. Heinrich PC, Behrmann I, Muller‐Newen G, Schaper F, Graeve L. Interleukin‐6‐type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334: 297‐314, 1998.
 81. Hellsten Y, Frandsen U, Orthenblad N, Sjodin N, Richter EA. Xanthine oxidase in human skeletal muscle following eccentric exercise: A role of inflammation. J Physiol (London) 498: 239‐248, 1997.
 82. Henningsen J, Rigbolt KT, Blagoev B, Pedersen BK, Kratchmarova I. Dynamics of the skeletal muscle secretome during myoblast differentiation. Mol Cell Proteomics 9: 2482‐96, 2010.
 83. Henson DA, Nieman DC, Nehlsen‐Cannarella SL, Fagoaga OR, Shannon M, Bolton MR, Davis JM, Gaffney CT, Kelln WJ, Austin MD, Hjertman JM, Schilling BK. Influence of carbohydrate on cytokine and phagocytic responses to 2 h of rowing. Med Sci Sports Exerc 32: 1384‐1389, 2000.
 84. Hilton DJ, Nicola NA, Metcalf D. Purification of a murine leukemia inhibitory factor from Krebs ascites cells. Anal Biochem 173: 359‐367, 1988.
 85. Hinds MG, Maurer T, Zhang JG, Nicola NA, Norton RS. Resonance assignments, secondary structure and topology of leukaemia inhibitory factor in solution. J Biomol NMR 9: 113‐126, 1997.
 86. Hirose L, Nosaka K, Newton M, Laveder A, Kano M, Peake J, Suzuki K. Changes in inflammatory mediators following eccentric exercise of the elbow flexors. Exerc Immunol Rev 10: 75‐90.: 75‐90, 2004.
 87. 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 fiber type specificity. FASEB J 18: 992‐994, 2004.
 88. Hittel DS, Berggren JR, Shearer J, Boyle K, Houmard JA. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 58: 30‐38, 2009.
 89. Hoene M, Weigert C. The role of interleukin‐6 in insulin resistance, body fat distribution and energy balance. Obes Rev 9: 20‐29, 2008.
 90. Hojman P, Brolin C, Gissel H, Brandt C, Zerahn B, Pedersen BK, Gehl J. Erythropoietin over‐expression protects against diet‐induced obesity in mice through increased fat oxidation in muscles. PLoS One 4: e5894, 2009.
 91. Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L, Pedersen BK. Exercise‐induced muscle‐derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab 301: E504‐E510, 2011.
 92. Hojman P, Pedersen M, Nielsen AR, Krogh‐Madsen R, Yfanti C, Akerstrom T, Nielsen S, Pedersen BK. Fibroblast growth factor‐21 is induced in human skeletal muscles by hyperinsulinemia. Diabetes 58: 2797‐2801, 2009.
 93. Holmes AG, Watt MJ, Carey AL, Febbraio MA. Ionomycin, but not physiologic doses of epinephrine, stimulates skeletal muscle interleukin‐6 mRNA expression and protein release. Metabolism 53: 1492‐1495, 2004.
 94. Horsley V, Jansen KM, Mills ST, Pavlath GK. IL‐4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113: 483‐494, 2003.
 95. Horsley V, Pavlath GK. Forming a multinucleated cell: Molecules that regulate myoblast fusion. Cells Tissues Organs 176: 67‐78, 2004.
 96. Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 27(Suppl 3): S53‐S55, 2003.
 97. Huang EJ, Reichardt LF. Neurotrophins: Roles in neuronal development and function. Annu Rev Neurosci 24: 677‐736, 2001.
 98. Izumiya Y, Hopkins T, Morris C, Sato K, Zeng L, Viereck J, Hamilton JA, Ouchi N, LeBrasseur NK, Walsh K. Fast/Glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab 7: 159‐172, 2008.
 99. Johnson HM, Smith EM, Torres BA, Blalock JE. Regulation of the in vitro antibody response by neuroendocrine hormones. Proc Natl Acad Sci U S A 79: 4171‐4174, 1982.
 100. Jonsdottir IH, Schjerling P, Ostrowski K, Asp S, Richter EA, Pedersen BK. Muscle contractions induce interleukin‐6 mRNA production in rat skeletal muscles. J Physiol (London) 528: 157‐163, 2000.
 101. 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: 15‐25, 2005.
 102. Kami K, Senba E. Localization of leukemia inhibitory factor and interleukin‐6 messenger ribonucleic acids in regenerating rat skeletal muscle. Muscle Nerve 21: 819‐822, 1998.
 103. Keane MP, Arenberg DA, Lynch JP, III, Whyte RI, Iannettoni MD, Burdick MD, Wilke CA, Morris SB, Glass MC, DiGiovine B, Kunkel SL, Strieter RM. The CXC chemokines, IL‐8 and IP‐10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol 159: 1437‐1443, 1997.
 104. Keller C, Hellsten Y, Steensberg A, Pedersen BK. Differential regulation of IL‐6 and TNF‐alpha via calcineurin in human skeletal muscle cells. Cytokine 36: 141‐147, 2006.
 105. 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: 2075‐2079, 2005.
 106. 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: Influence of muscle glycogen content. FASEB J 15: 2748‐2750, 2001.
 107. 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 58: 1953‐1960, 2009.
 108. Kim GY, Lee JW, Ryu HC, Wei JD, Seong CM, Kim JH. Proinflammatory cytokine IL‐1beta stimulates IL‐8 synthesis in mast cells via a leukotriene B4 receptor 2‐linked pathway, contributing to angiogenesis. J Immunol 184: 3946‐3954, 2010.
 109. Kishimoto T. Signal transduction through homo‐ or heterodimers of gp130. Stem Cells Dayt 12(Suppl 1): 37‐44, 1994.
 110. Kjaer M, Secher NH, Bangsbo J, Perko G, Horn A, Mohr T, Galbo H. Hormonal and metabolic responses to electrically induced cycling during epidural anesthesia in humans. J Appl Physiol 80: 2156‐2162, 1996.
 111. 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 DR's EXTRA Study. Neurobiol Learn Mem 90: 596‐603, 2008.
 112. Kurek JB, Bower J, Romanella M, Austin L. Leukaemia inhibitory factor treatment stimulates muscle regeneration in the mdx mouse. Neurosci Lett 212: 167‐170, 1996.
 113. Lafreniere JF, Mills P, Bouchentouf M, Tremblay JP. Interleukin‐4 improves the migration of human myogenic precursor cells in vitro and in vivo. Exp Cell Res 312: 1127‐1141, 2006.
 114. Lancaster GI, Jentjens RL, Moseley L, Jeukendrup AE, Gleeson M. Effect of pre‐exercise carbohydrate ingestion on plasma cytokine, stress hormone, and neutrophil degranulation responses to continuous, high‐intensity exercise. Int J Sport Nutr Exerc Metab 13: 436‐453, 2003.
 115. Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL‐8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170: 3369‐3376, 2003.
 116. Li TL, Gleeson M. The effect of single and repeated bouts of prolonged cycling on leukocyte redistribution, neutrophil degranulation, IL‐6, and plasma stress hormone responses. Int J Sport Nutr Exerc Metab 14: 501‐516, 2004.
 117. Li TL, Gleeson M. The effects of carbohydrate supplementation during the second of two prolonged cycling bouts on immunoendocrine responses. Eur J Appl Physiol 95: 391‐399, 2005.
 118. Li TL, Wu CL, Gleeson M, Williams C. The effects of pre‐exercise high carbohydrate meals with different glycemic indices on blood leukocyte redistribution, IL‐6, and hormonal responses during a subsequent prolonged exercise. Int J Sport Nutr Exerc Metab 14: 647‐656, 2004.
 119. Lin J, Arnold HB, la‐Fera MA, Azain MJ, Hartzell DL, Baile CA. Myostatin knockout in mice increases myogenesis and decreases adipogenesis. Biochem Biophys Res Commun 291: 701‐706, 2002.
 120. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC‐1 family of transcription coactivators. Cell Metabolism 1: 361‐370, 2005.
 121. Lin WW, Karin M. A cytokine‐mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117: 1175‐1183, 2007.
 122. Lira SA, Zalamea P, Heinrich JN, Fuentes ME, Carrasco D, Lewin AC, Barton DS, Durham S, Bravo R. Expression of the chemokine N51/KC in the thymus and epidermis of transgenic mice results in marked infiltration of a single class of inflammatory cells. J Exp Med 180: 2039‐2048, 1994.
 123. Lyngso D, Simonsen L, Bulow J. Interleukin‐6 production in human subcutaneous abdominal adipose tissue: The effect of exercise. J Physiol 543: 373‐378, 2002.
 124. Ma Q. Beneficial effects of moderate voluntary physical exercise and its biological mechanisms on brain health. Neurosci Bull 24: 265‐270, 2008.
 125. MacIntyre DL, Sorichter S, Mair J, Berg A, McKenzie DC. Markers of inflammation and myofibrillar proteins following eccentric exercise in humans. Eur J Appl Physiol 84: 180‐186, 2001.
 126. Mathur N, Pedersen BK. Exercise as a mean to control low‐grade systemic inflammation. Mediators Inflamm 2008: 109502, 2008.
 127. Matter CM, Handschin C. RANTES (regulated on activation, normal T cell expressed and secreted), inflammation, obesity, and the metabolic syndrome. Circulation 115: 946‐948, 2007.
 128. Matthews VB, Astrom MB, Chan MH, Bruce CR, Krabbe KS, Prelovsek O, Akerstrom T, Yfanti C, Broholm C, Mortensen OH, Penkowa M, Hojman P, Zankari A, Watt MJ, Bruunsgaard H, Pedersen BK, Febbraio MA. Brain‐derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP‐activated protein kinase. Diabetologia 52: 1409‐1418, 2009.
 129. McFarlane C, Hui GZ, Amanda WZ, Lau HY, Lokireddy S, Xiaojia G, Mouly V, Butler‐Browne G, Gluckman PD, Sharma M, Kambadur R. Human myostatin negatively regulates human myoblast growth and differentiation. Am J Physiol Cell Physiol 301: C195‐C203, 2011.
 130. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF‐beta superfamily member. Nature 387: 83‐90, 1997.
 131. McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin‐deficient mice. J Clin Invest 109: 595‐601, 2002.
 132. Metcalf D. The unsolved enigmas of leukemia inhibitory factor. Stem Cells 21: 5‐14, 2003.
 133. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty‐acid oxidation by activating AMP‐activated protein kinase. Nature 415: 339‐343, 2002.
 134. Miura P, Amirouche A, Clow C, Belanger G, Jasmin BJ. Brain‐derived neurotrophic factor expression is repressed during myogenic differentiation by miR‐206. J Neurochem 120: 230‐238, 2012.
 135. Mizuhara H, O'Neill E, Seki N, Ogawa T, Kusunoki C, Otsuka K, Satoh S, Niwa M, Senoh H, Fujiwara H. T cell activation‐associated hepatic injury: Mediation by tumor necrosis factors and protection by interleukin 6. J Exp Med 179: 1529‐1537, 1994.
 136. Mohr T, Andersen JL, Biering‐Sorensen F, Galbo H, Bangsbo J, Wagner A, Kjaer M. Long‐term adaptation to electrically induced cycle training in severe spinal cord injured individuals. Spinal Cord 35: 1‐16, 1997.
 137. Monninkhof EM, Elias SG, Vlems FA, van dT, I, Schuit AJ, Voskuil DW, van Leeuwen FE. Physical activity and breast cancer: A systematic review. Epidemiology 18: 137‐157, 2007.
 138. Mousavi K, Jasmin BJ. BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation. J Neurosci 26: 5739‐5749, 2006.
 139. Mucci P, Durand F, Lebel B, Bousquet J, Prefaut C. Interleukins 1‐beta, ‐8, and histamine increases in highly trained, exercising athletes. Med Sci Sports Exerc 32: 1094‐1100, 2000.
 140. Nehlsen Cannarella SL, Fagoaga OR, Nieman DC, Henson DA, Butterworth DE, Schmitt RL, Bailey EM, Warren BJ, Utter A, Davis JM. Carbohydrate and the cytokine response to 2.5 h of running. J Appl Physiol 82: 1662‐1667, 1997.
 141. 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.
 142. 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 fibre type composition. J Physiol 584: 305‐312, 2007.
 143. Nielsen AR, Pedersen BK. The biological roles of exercise‐induced cytokines: IL‐6, IL‐8, and IL‐15. Appl Physiol Nutr Metab 32: 833‐839, 2007.
 144. Nielsen S, Pedersen BK. Skeletal muscle as an immunogenic organ. Curr Opin Pharmacol 8: 346‐351, 2008.
 145. Nieman DC. Current perspective on exercise immunology. Curr Sports Med Rep 2: 239‐242, 2003.
 146. Nieman DC, Davis JM, Brown VA, Henson DA, Dumke CL, Utter AC, Vinci DM, Downs MF, Smith JC, Carson J, Brown A, McAnulty SR, McAnulty LS. Influence of carbohydrate ingestion on immune changes after 2 h of intensive resistance training. J Appl Physiol 96: 1292‐1298, 2004.
 147. Nieman DC, Davis JM, Henson DA, Gross SJ, Dumke CL, Utter AC, Vinci DM, Carson JA, Brown A, McAnulty SR, McAnulty LS, Triplett NT. Muscle cytokine mRNA changes after 2.5 h of cycling: Influence of carbohydrate. Med Sci Sports Exerc 37: 1283‐1290, 2005.
 148. Nieman DC, Davis JM, Henson DA, Walberg‐Rankin J, Shute M, Dumke CL, Utter AC, Vinci DM, Carson JA, Brown A, Lee WJ, McAnulty SR, McAnulty LS. Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plasma cytokine levels after a 3‐h run. J Appl Physiol 94: 1917‐1925, 2003.
 149. Nieman DC, Henson DA, McAnulty SR, McAnulty L, Swick NS, Utter AC, Vinci DM, Opiela SJ, Morrow JD. Influence of vitamin C supplementation on oxidative and immune changes after an ultramarathon. J Appl Physiol 92: 1970‐1977, 2002.
 150. Nieman DC, Henson DA, Smith LL, Utter AC, Vinci DM, Davis JM, Kaminsky DE, Shute M. Cytokine changes after a marathon race. J Appl Physiol 91: 109‐114, 2001.
 151. Nieman DC, Nehlsen‐Canarella SL, Fagoaga OR, Henson DA, Utter A, Davis JM, Williams F, Butterworth DE. Influence of mode and carbohydrate on the cytokine response to heavy exertion. Med Sci Sports Exerc 30: 671‐678, 1998.
 152. Nocon M, Hiemann T, Muller‐Riemenschneider F, Thalau F, Roll S, Willich SN. Association of physical activity with all‐cause and cardiovascular mortality: A systematic review and meta‐analysis. Eur J Cardiovasc Prev Rehabil 15: 239‐246, 2008.
 153. Norheim F, Raastad T, Thiede B, Rustan AC, Drevon CA, Haugen F. Proteomic identification of secreted proteins from human skeletal muscle cells and expression in response to strength training. Am J Physiol Endocrinol Metab 301: E1013‐E1021, 2011.
 154. Nosaka K, Clarkson PM. Changes in indicators of inflammation after eccentric exercise of the elbow flexors. Med Sci Sports Exerc 28: 953‐961, 1996.
 155. Olsen RH, Krogh‐Madsen R, Thomsen C, Booth FW, Pedersen BK. Metabolic responses to reduced daily steps in healthy nonexercising men. JAMA 299: 1261‐1263, 2008.
 156. Oshima Y, Ouchi N, Sato K, Izumiya Y, Pimentel DR, Walsh K. Follistatin‐like 1 is an Akt‐regulated cardioprotective factor that is secreted by the heart. Circulation 117: 3099‐3108, 2008.
 157. Ostrowski K, Hermann C, Bangash A, Schjerling P, Nielsen JN, Pedersen BK. A trauma‐like elevation of plasma cytokines in humans in response to treadmill running. J Physiol 513: 889‐894, 1998.
 158. Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK. Chemokines are elevated in plasma after strenuous exercise in humans. Eur J Appl Physiol 84: 244‐245, 2001.
 159. 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.
 160. Paffenbarger RS, Jr., Hyde RT, Wing AL, Hsieh CC. Physical activity, all‐cause mortality, and longevity of college alumni. N Engl J Med 314: 605‐613, 1986.
 161. Paffenbarger RS, Jr., Lee IM, Leung R. Physical activity and personal characteristics associated with depression and suicide in American college men. Acta Psychiatr Scand Suppl 377: 16‐22, 1994.
 162. Pedersen BK. Special feature for the Olympics: Effects of exercise on the immune system: Exercise and cytokines. Immunol Cell Biol 78: 532‐535, 2000.
 163. Pedersen BK. The anti‐inflammatory effect of exercise: Its role in diabetes and cardiovascular disease control. Essays Biochem 42: 105‐117, 2006.
 164. Pedersen BK. IL‐6 signalling in exercise and disease. Biochem Soc Trans 35: 1295‐1297, 2007.
 165. Pedersen BK. The diseasome of physical inactivity and the role of myokines in muscle‐fat cross talk. J Physiol 587: 5559‐5568, 2009.
 166. Pedersen BK. Exercise‐induced myokines and their role in chronic diseases. Brain Behav Immun 25: 811‐816, 2011.
 167. Pedersen BK. Muscles and their myokines. J Exp Biol 214: 337‐346, 2011.
 168. Pedersen BK. A muscular twist on the fate of fat. N Engl J Med 366: 1544‐1545, 2012.
 169. Pedersen BK. Muscular IL‐6 and Its Role as an Energy Sensor. Med Sci Sports Exerc 44: 392‐396, 2012.
 170. Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol 103(3): 1093‐1090, 2007.
 171. Pedersen BK, Febbraio M. Muscle‐derived interleukin‐6: A possible link between skeletal muscle, adipose tissue, liver, and brain. Brain Behav Immun 19: 371‐376, 2005.
 172. Pedersen BK, Febbraio MA. Muscle, exercise and obesity: Skeletal muscle as a secretory organ. Nature Reviews Endocrinology 3: 457‐465, 2012.
 173. Pedersen BK, Fischer CP. Beneficial health effects of exercise—the role of IL‐6 as a myokine. Trends Pharmacol Sci 28: 152‐156, 2007.
 174. Pedersen BK, Fischer CP. Physiological roles of muscle‐derived interleukin‐6 in response to exercise. Curr Opin Clin Nutr Metab Care 10: 265‐271, 2007.
 175. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: Focus on muscle‐derived interleukin‐6. Physiol Rev 88: 1379‐1406, 2008.
 176. Pedersen BK, Hoffman‐Goetz L. Exercise and the immune system: Regulation, integration and adaptation. Physiol Rev 80: 1055‐1081, 2000.
 177. Pedersen BK, Pedersen M, Krabbe KS, Bruunsgaard H, Matthews VB, Febbraio MA. Role of exercise‐induced brain‐derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Exp Physiol 94: 1153‐60, 2009.
 178. Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Febbraio M, Saltin B. Searching for the exercise factor: Is IL‐6 a candidate? J Muscle Res Cell Motil 24: 113‐119, 2003.
 179. Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Wolsk‐Petersen E, Febbraio M. The metabolic role of IL‐6 produced during exercise: Is IL‐6 an exercise factor? Proc Nutr Soc 63: 263‐267, 2004.
 180. Pedersen BK, Steensberg A, Keller P, Keller C, Fischer C, Hiscock N, Hall Gv, Plomgaard P, Febbraio MA. Muscle‐derived interleukin‐6: Lipolytic, anti‐inflammatory and immune regulatory effects. Pflugers Arch 446: 9‐16, 2003.
 181. Pedersen BK, Steensberg A, Schjerling P. Exercise and interleukin‐6. Curr Opin Hematol 8: 137‐141, 2001.
 182. Pedersen BK, Steensberg A, Schjerling P. Muscle‐derived interleukin‐6: Possible biological effects. J Physiol (London) 536: 329‐337, 2001.
 183. Pedersen BK, Tvede N, Hansen FR, Andersen V, Bendix T, Bendixen G, Bendtzen K, Galbo H, Haahr PM, Klarlund K and et al. Modulation of natural killer cell activity in peripheral blood by physical exercise. Scand J Immunol 27: 673‐678, 1988.
 184. Pedersen BK, Febbraio MA, Mooney RA. Interleukin‐6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis. J Appl Physiol 102: 814‐816, 2007.
 185. Pedersen L, Pilegaard H, Hansen J, Brandt C, Adser H, Hidalgo J, Olesen J, Pedersen BK, Hojman P. Exercise‐induced liver CXCL‐1 expression is linked to muscle derived IL‐6 expression. J Physiol 589: 1409‐1420, 2011.
 186. Pelletier M, Montplaisir S, Dardenne M, Bach JF. Thymic hormone activity and spontaneous autoimmunity in dwarf mice and their littermates. Immunology 30: 783‐788, 1976.
 187. Petersen AM, Pedersen BK. The anti‐inflammatory effect of exercise. J Appl Physiol 98: 1154‐1162, 2005.
 188. Petersen AM, Pedersen BK. The role of IL‐6 in mediating the anti‐inflammatory effects of exercise. J Physiol Pharmacol 57(Suppl 10): 43‐51, 2006.
 189. Petersen EW, Carey AL, Sacchetti M., Steinberg GR, Macaulay SL, Febbraio M.A., 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 288: E155‐E162, 2005.
 190. Phillips SM, Green HJ, Tarnopolsky MA, Heigenhauser GF, Hill RE, Grant SM. Effects of training duration on substrate turnover and oxidation during exercise. J Appl Physiol 81: 2182‐2191, 1996.
 191. Pischon T, Boeing H, Hoffmann K, Bergmann M, Schulze MB, Overvad K, van der Schouw YT, Spencer E, Moons KGM, Tjonneland A, Halkjaer J, Jensen MK, Stegger J, Clavel‐Chapelon F, Boutron‐Ruault MC, Chajes V, Linseisen J, Kaaks R, Trichopoulou A, Trichopoulos D, Bamia C, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Peeters PHM, May AM, Bueno‐De‐Mesquita HB, van Duijnhoven FJB, Hallmans G, Weinehall L, Manjer J, Hedblad B, Lund E, Agudo A, Arriola L, Barricarte A, Navarro C, Martinez C, Quiros JR, Key T, Bingham S, Khaw KT, Boffetta P, Jenab M, Ferrari P, Riboli E. General and abdominal adiposity and risk of death in Europe. New Engl J Med 359: 2105‐2120, 2008.
 192. Plomgaard P, Fischer CP, Ibfelt T, Pedersen BK, van HG. TNF‐alpha modulates human in vivo lipolysis. J Clin Endocrinol Metab 93: 543‐9, 2007.
 193. Plomgaard P, Keller P, Keller C, Pedersen BK. TNF‐alpha, but not IL‐6, stimulates plasminogen activator inhibitor‐1 expression in human subcutaneous adipose tissue. J Appl Physiol 98: 2019‐2023, 2005.
 194. 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‐1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci U S A 106: 10853‐10858, 2009.
 195. Quinn LS, Anderson BG. Interleukin‐15, IL‐15 receptor‐alpha, and obesity: Concordance of laboratory animal and human genetic studies. J Obes 2011: 456347, 2011.
 196. Quinn LS, Anderson BG, Drivdahl RH, Alvarez B, Argiles JM. Overexpression of interleukin‐15 induces skeletal muscle hypertrophy in vitro: Implications for treatment of muscle wasting disorders. Exp Cell Res 280: 55‐63, 2002.
 197. 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: E191‐E202, 2009.
 198. Quinn LS, Haugk KL, Damon SE. Interleukin‐15 stimulates C2 skeletal myoblast differentiation. Biochem Biophys Res Commun 239: 6‐10, 1997.
 199. Quinn LS, Strait‐Bodey L, Anderson BG, Argiles JM, Havel PJ. Interleukin‐15 stimulates adiponectin secretion by 3T3‐L1 adipocytes: Evidence for a skeletal muscle‐to‐fat signaling pathway. Cell Biol Int 29: 449‐457, 2005.
 200. Richardson LC, Pollack LA. Therapy insight: Influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat Clin Pract Oncol 2: 48‐53, 2005.
 201. Riechman SE, Balasekaran G, Roth SM, Ferrell RE. Association of interleukin‐15 protein and interleukin‐15 receptor genetic variation with resistance exercise training responses. J Appl Physiol 97: 2214‐2219, 2004.
 202. Rodgers BD, Garikipati DK. Clinical, agricultural, and evolutionary biology of myostatin: A comparative review. Endocr Rev 29: 513‐534, 2008.
 203. Rosendal L, Sogaard K, Kjaer M, Sjogaard G, Langberg H, Kristiansen J. Increase in interstitial interleukin‐6 of human skeletal muscle with repetitive low‐force exercise. J Appl Physiol 98: 477‐481, 2005.
 204. Rovio S, Kareholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, Soininen H, Nissinen A, Kivipelto M. Leisure‐time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 4: 705‐711, 2005.
 205. Rubio N, Sanz‐Rodriguez F. Induction of the CXCL1 (KC) chemokine in mouse astrocytes by infection with the murine encephalomyelitis virus of Theiler. Virology 358: 98‐108, 2007.
 206. Ruderman NB, Keller C, Richard AM, Saha AK, Luo Z, Xiang X, Giralt M, Ritov VB, Menshikova EV, Kelley DE, Hidalgo J, Pedersen BK, Kelly M. Interleukin‐6 regulation of AMP‐activated protein kinase: Potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes 55(Suppl 2): S48‐S54, 2006.
 207. Rundqvist H, Rullman E, Sundberg CJ, Fischer H, Eisleitner K, Stahlberg M, Sundblad P, Jansson E, Gustafsson T. Activation of the erythropoietin receptor in human skeletal muscle. Eur J Endocrinol 161: 427‐434, 2009.
 208. Sakuma K, Watanabe K, Sano M, Uramoto I, Totsuka T. Differential adaptation of growth and differentiation factor 8/myostatin, fibroblast growth factor 6 and leukemia inhibitory factor in overloaded, regenerating and denervated rat muscles. Biochim Biophys Acta 1497: 77‐88, 2000.
 209. Sakuma K, Watanabe K, Sano M, Uramoto I, Totsuka T. Postnatal profiles of myogenic regulatory factors and the receptors of TGF‐beta 2, LIF and IGF‐I in the gastrocnemius and rectus femoris muscles of dy mouse. Acta Neuropathol 99: 169‐176, 2000.
 210. Sakuma K, Yamaguchi A. The recent understanding of the neurotrophin's role in skeletal muscle adaptation. J Biomed Biotechnol 2011: 201696, 2011.
 211. Scheele C, Nielsen S, Kelly M, Broholm C, Nielsen AR, Taudorf S, Pedersen M, Fischer CP, Pedersen BK. Satellite cells derived from obese humans with type 2 diabetes and differentiated into myocytes in vitro exhibit abnormal response to IL‐6. PLoS One 7: e39657, 2012.
 212. Scheele C, Nielsen S, Pedersen BK. ROS and myokines promote muscle adaptation to exercise. Trends Endocrinol Metab 20: 95‐99, 2009.
 213. Scherer PE. Adipose tissue: From lipid storage compartment to endocrine organ. Diabetes 55: 1537‐1545, 2006.
 214. Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA. Correlations and interactions in the production of interleukin‐6 (IL‐6), IL‐1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL‐6 suppresses IL‐1 and TNF. Blood 75: 40‐47, 1990.
 215. Schmelzer CH, Burton LE, Tamony CM. Purification and partial characterization of recombinant human differentiation‐stimulating factor. Protein Expr Purif 1: 54‐62, 1990.
 216. Seidl K, Erck C, Buchberger A. Evidence for the participation of nerve growth factor and its low‐affinity receptor (p75NTR) in the regulation of the myogenic program. J Cell Physiol 176: 10‐21, 1998.
 217. Serrano AL, Baeza‐Raja B, Perdiguero E, Jardi M, Munoz‐Canoves P. Interleukin‐6 is an essential regulator of satellite cell‐mediated skeletal muscle hypertrophy. Cell Metab 7: 33‐44, 2008.
 218. Shetty S, Kusminski CM, Scherer PE. Adiponectin in health and disease: Evaluation of adiponectin‐targeted drug development strategies. Trends Pharmacol Sci 30: 234‐239, 2009.
 219. Shimano M, Ouchi N, Nakamura K, van WB, Ohashi K, Asaumi Y, Higuchi A, Pimentel DR, Sam F, Murohara T, van den Hoff MJ, Walsh K. Cardiac myocyte follistatin‐like 1 functions to attenuate hypertrophy following pressure overload. Proc Natl Acad Sci U S A 108: E899‐E906, 2011.
 220. Smith PE. Effect of hypophysectomy on the involution of the thymus in the rat. Anat Rec 47: 119‐129, 1930.
 221. Spangelo BL, Gorospe WC. Role of the cytokines in the neuroendocrine‐immune system axis. Front Neuroendocrinol 16: 1‐22, 1995.
 222. Spangenburg EE, Booth FW. Multiple signaling pathways mediate LIF‐induced skeletal muscle satellite cell proliferation. Am J Physiol Cell Physiol 283: C204‐C211, 2002.
 223. Spangenburg EE, Booth FW. Leukemia inhibitory factor restores the hypertrophic response to increased loading in the LIF(‐/‐) mouse. Cytokine 34: 125‐130, 2006.
 224. Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL‐6 infusion inhibit endotoxin‐induced TNF‐alpha production in humans. FASEB J 17: 884‐886, 2003.
 225. Starkie RL, Angus DJ, Rolland J, Hargreaves M, Febbraio M. Effect of prolonged submaximal exercise and carbohydrate ingestion on monocyte intracellular cytokine production in humans. J Physiol (London) 528: 647‐655, 2000.
 226. Starkie RL, Arkinstall MJ, Koukoulas I, Hawley JA, Febbraio MA. Carbohydrate ingestion attenuates the increase in plasma interleukin‐6, but not skeletal muscle interleukin‐6 mRNA, during exercise in humans. J Physiol (London) 533: 585‐591, 2001.
 227. Starkie RL, Rolland J, Angus DJ, Anderson MJ, Febbraio MA. Circulating monocyes are not the source of elevations in plasma IL‐6 and TNF‐alpha levels after prolonged running. Am J Physiol Cell Physiol 280: C769‐C774, 2001.
 228. Steensberg A, Febbraio MA, Osada T, Schjerling P, van HG, Saltin B, Pedersen BK. Interleukin‐6 production in contracting human skeletal muscle is influenced by pre‐exercise muscle glycogen content. J Physiol 537: 633‐639, 2001.
 229. 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: E433‐E437, 2003.
 230. Steensberg A, Fischer CP, Sacchetti M, Keller C, Osada T, Schjerling P, van Hall G, Febbraio MA, Pedersen BK. Acute interleukin‐6 administration does not impair muscle glucose uptake or whole body glucose disposal in healthy humans. J Physiol 548: 631‐638, 2003.
 231. Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA, Pedersen BK. IL‐6 and TNF‐alpha expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab 283: E1272‐E1278, 2002.
 232. 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(Pt 1): 237‐242, 2000.
 233. 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.
 234. Steinberg GR, Watt MJ, Febbraio MA. Cytokine regulation of AMPK signalling. Front Biosci 14: 1902‐1916, 2009.
 235. Sun L, Ma K, Wang H, Xiao F, Gao Y, Zhang W, Wang K, Gao X, Ip N, Wu Z. JAK1‐STAT1‐STAT3, a key pathway promoting proliferation and preventing premature differentiation of myoblasts. J Cell Biol 179: 129‐138, 2007.
 236. Suzuki K, Nakaji S, Yamada M, Liu Q, Kurakake S, Okamura N, Kumae T, Umeda T, Sugawara K. Impact of a competitive marathon race on systemic cytokine and neutrophil responses. Med Sci Sports Exerc 35: 348‐355, 2003.
 237. Tseng YL, Wu MH, Yang HC, Wang CY, Lin CF. Autocrine IL‐6 regulates GRO‐alpha production in thymic epithelial cells. Cytokine 51: 195‐201, 2010.
 238. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne‐Parikka P, Keinanen‐Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344: 1343‐1350, 2001.
 239. Ullum H, Haahr PM, Diamant M, Palmo J, Halkjaer Kristensen J, Pedersen BK. Bicycle exercise enhances plasma IL‐6 but does not change IL‐1alpha, IL‐1beta, IL‐6, or TNF‐alpha pre‐mRNA in BMNC. J Appl Physiol 77: 93‐7., 1994.
 240. van der, V, Janssen TW. The potential anti‐inflammatory effect of exercise in chronic obstructive pulmonary disease. Respiration 79: 160‐174, 2010.
 241. 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: 3005‐3010, 2003.
 242. Wagers AJ, Conboy IM. Cellular and molecular signatures of muscle regeneration: Current concepts and controversies in adult myogenesis. Cell 122: 659‐667, 2005.
 243. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO. Interleukin‐6‐deficient mice develop mature‐onset obesity. Nat Med 8: 75‐79, 2002.
 244. Walsh K. Adipokines, myokines and cardiovascular disease. Circ J 73: 13‐18, 2009.
 245. Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop NC, Fleshner M, Green C, Pedersen BK, Hoffman‐Goetz L, Rogers CJ, Northoff H, Abbasi A, Simon P. Position statement. Part one: Immune function and exercise. Exerc Immunol Rev 17: 6‐63, 2011.
 246. Watt MJ, Dzamko N, Thomas WG, Rose‐John S, Ernst M, Carling D, Kemp BE, Febbraio MA, Steinberg GR. CNTF reverses obesity‐induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12: 541‐548, 2006.
 247. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC‐1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A 106: 20405‐20410, 2009.
 248. Whitmer RA, Gustafson DR, Barrett‐Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology 71: 1057‐1064, 2008.
 249. Willoughby DS, McFarlin B, Bois C. Interleukin‐6 expression after repeated bouts of eccentric exercise. Int J Sports Med 24: 15‐21, 2003.
 250. Wolin KY, Yan Y, Colditz GA, Lee IM. Physical activity and colon cancer prevention: A meta‐analysis. Br J Cancer 100: 611‐616, 2009.
 251. Wolsk E, Mygind H, Grondahl TS, Pedersen BK, van HG. IL‐6 selectively stimulates fat metabolism in human skeletal muscle. Am J Physiol Endocrinol Metab 299: E832‐E840, 2010.
 252. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell; 150: 366‐376, 2012.
 253. Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: A review of the current evidence. Am J Clin Nutr 86: s823‐s835, 2007.
 254. Yoon JH, Yea K, Kim J, Choi YS, Park S, Lee H, Lee CS, Suh PG, Ryu SH. Comparative proteomic analysis of the insulin‐induced L6 myotube secretome. Proteomics 9: 51‐60, 2009.
 255. You T, Nicklas BJ. Effects of exercise on adipokines and the metabolic syndrome. Curr Diab Rep 8: 7‐11, 2008.
 256. Yudkin JS. Inflammation, obesity, and the metabolic syndrome. Horm Metab Res 39: 707‐709, 2007.
 257. Yudkin JS, Eringa E, Stehouwer CD. “ Vasocrine” signalling from perivascular fat: A mechanism linking insulin resistance to vascular disease. Lancet 365: 1817‐1820, 2005.
 258. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425‐432, 1994.
 259. Zhao B, Wall RJ, Yang J. Transgenic expression of myostatin propeptide prevents diet‐induced obesity and insulin resistance. Biochem Biophys Res Commun 337: 248‐255, 2005.

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Article Title: Muscle as a Secretory Organ
 

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Bente K. Pedersen. Muscle as a Secretory Organ. Compr Physiol 2013, 3: 1337-1362. doi: 10.1002/cphy.c120033