Skeletal muscle as an endocrine organ: The role of myokines in exercise adaptations

Cold Spring Harbor Perspectives in Medicine

Volumn 7, Issue 11, 2017, Pages

  Hoffmann, Christoph ^a   Weigert, Cora ^a,b,c  

^a UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

^b UNIVERSITY OF TÜBINGEN   (Germany)

^c GERMAN CENTER FOR DIABETES RESEARCH DZD   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 6; MICRORNA; MYOKINE; MYOSTATIN; PROTEIN; RNA; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; CYTOKINE;

ADAPTATION; ANGIOGENESIS; ANTIINFLAMMATORY ACTIVITY; ARTICLE; BODY WEIGHT; CANCER INHIBITION; CANCER PREVENTION; CARDIOVASCULAR SYSTEM; CLINICAL TRIAL; COGNITION; EXERCISE; EXTRACELLULAR MATRIX; HUMAN; INFLAMMATION; INSULIN SENSITIVITY; METABOLISM; MUSCLE DEVELOPMENT; MUSCLE HYPERTROPHY; OXIDATION; PROTEIN FUNCTION; SKELETAL MUSCLE; CHRONIC DISEASE; PHYSIOLOGY;

ADAPTATION, PHYSIOLOGICAL; CHRONIC DISEASE; CYTOKINES; EXERCISE; HUMANS; MUSCLE, SKELETAL;

EID: 85022202315     PISSN: None     EISSN: 21571422     Source Type: Journal    
DOI: 10.1101/cshperspect.a029793     Document Type: Article

References (226)

1. Agudelo LZ, Femenia T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, Correia JC, Izadi M, Bhat M, Schuppe-Koistinen I, et al. 2014. Skeletal muscle PGC-1a1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159: 33-45.
2. Akira S, Taga T, Kishimoto T. 1993. Interleukin-6 in biology and medicine. Adv Immunol 54: 1–78.
3. Albrecht E, Norheim F, Thiede B, Holen T, Ohashi T, Schering L, Lee S, Brenmoehl J, Thomas S, Drevon CA, et al. 2015. Irisin—A myth rather than an exercise-inducible myokine. Sci Rep 5: 8889.
4. Alfieri A, Martone D, Randers MB, Labruna G, Mancini A, Nielsen JJ, Bangsbo J, Krustrup P, Buono P. 2015. Effects of long-term football training on the expression profile of genes involved in muscle oxidative metabolism. Mol Cell Probes 29: 43–47.
5. Al Khalili L, Bouzakri K, Glund S, Lonnqvist F, Koistinen HA, Krook A. 2006. Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle. Mol Endocrinol 20: 3364–3375.
6. Amir LY, Ciaraldi TP, Mudaliar SR, Phillips SA, Henry RR. 2015. Excessive secretion of IL-8 by skeletal muscle in type 2 diabetes impairs tube growth: Potential role of PI3K and the Tie2 receptor. Am J Physiol Endocrinol Metab 309: E22–E34.
7. Anderson NL, Anderson NG. 2002. The human plasma proteome: History, character, and diagnostic prospects. Mol Cell Proteomics 1: 845–867.
8. Andersson H, Bohn SK, Raastad T, Paulsen G, Blomhoff R, Kadi F. 2010. Differences in the inflammatory plasma cytokine response following two elite female soccer games separated by a 72-h recovery. Scand J Med Sci Sports 20: 740–747.
9. Aoi W, Naito Y, Takagi T, Tanimura Y, Takanami Y, Kawai Y, Sakuma K, Hang LP, Mizushima K, Hirai Y, et al. 2013. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 62: 882–889.
10. Attane C, Foussal C, Le Gonidec S, Benani A, Daviaud D, Wanecq E, Guzman-Ruiz R, Dray C, Bezaire V, Rancoule C, et al. 2012. Apelin treatment increases complete fatty acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes 61: 310–320.
11. Attie KM, Borgstein NG, Yang Y, Condon CH, Wilson DM, Pearsall AE, Kumar R, Willins DA, Seehra JS, Sherman ML. 2013. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle Nerve 47: 416–423.
12. Babapoor-Farrokhran S, Jee K, Puchner B, Hassan SJ, Xin X, Rodrigues M, Kashiwabuchi F, Ma T, Hu K, Deshpande M, et al. 2015. Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Proc Natl Acad Sci 112: E3030–E3039.
13. Baggish AL, Hale A, Weiner RB, Lewis GD, Systrom D, Wang F, Wang TJ, Chan SY. 2011. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J Physiol 589: 3983-3994.
14. Bamman MM, Shipp JR, Jiang J, Gower BA, Hunter GR, Goodman A, McLafferty CL Jr, Urban RJ. 2001.Mechanical load increases muscle IGF-I and androgen receptor mRNA concentrations in humans. Am J Physiol Endocrinol Metab 280: E383–E390.
15. Bang P, Brandt J, Degerblad M, Enberg G, Kaijser L, Thoren M, Hall K. 1990. Exercise-induced changes in insulin-like growth factors and their low molecular weight binding protein in healthy subjects and patients with growth hormone deficiency. Eur J Clin Invest 20: 285–292.
16. Bartoccioni E, Michaelis D, Hohlfeld R. 1994. Constitutive and cytokine-induced production of interleukin-6 by human myoblasts. Immunol Lett 42: 135–138.
17. Ben Zvi D, Barrandon O, Hadley S, Blum B, Peterson QP, Melton DA. 2015. Angptl4 links a-cell proliferation following glucagon receptor inhibitionwith adipose tissue triglyceride metabolism. Proc Natl Acad Sci 112: 15498–15503.
18. Berg U, Gustafsson T, Sundberg CJ, Kaijser L, Carlsson- Skwirut C, Bang P. 2007. Interstitial IGF-I in exercising skeletal muscle in women. Eur J Endocrinol 157: 427–435.
19. Berria R, Wang L, Richardson DK, Finlayson J, Belfort R, Pratipanawatr T, De Filippis EA, Kashyap S, Mandarino LJ. 2006. Increased collagen content in insulin-resistant skeletal muscle. Am J Physiol Endocrinol Metab 290: E560–E565.
20. Besse-Patin A, Montastier E, Vinel C, Castan-Laurell I, Louche K, Dray C, Daviaud D, Mir L, Marques MA, Thalamas C, et al. 2014. Effect of endurance training on skeletal muscle myokine expression in obese men: Identification of apelin as a novel myokine. Int J Obes (Lond) 38: 707–713.
21. Bohm A, Hoffmann C, Irmler M, Schneeweiss P, Schnauder G, Sailer C, Schmid V, Hudemann J, Machann J, Schick F, et al. 2016. TGFb contributes to impaired exercise response by suppression of mitochondrial key regulators in skeletal muscle. Diabetes 65: 2849–2861.
22. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, et al. 2012. A PGC1-a-dependent myokine that drives brown-fatlike development of white fat and thermogenesis. Nature 481: 463–468.
23. Bouzakri K, Plomgaard P, Berney T, Donath MY, Pedersen BK, Halban PA. 2011. Bimodal effect on pancreatic bcells of secretory products from normal or insulin-resistant human skeletal muscle. Diabetes 60: 1111–1121.
24. Brahm H, Piehl-Aulin K, Saltin B, Ljunghall S. 1997. Net fluxes over working thigh of hormones, growth factors and biomarkers of bone metabolism during short lasting dynamic exercise. Calcif Tissue Int 60: 175–180.
25. Brandauer J, Vienberg SG, Andersen MA, Ringholm S, Risis S, Larsen PS, Kristensen JM, Frosig C, Leick L, Fentz J, et al. 2013. AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle. J Physiol 591: 5207–5220.
26. Breen ME, Laing EM, Hall DB, Hausman DB, Taylor RG, Isales CM, Ding KH, Pollock NK, Hamrick MW, Baile CA, et al. 2011. 25-Hydroxyvitamin D, insulin-like growth factor-I, and bone mineral accrual during growth. J Clin Endocrinol Metab 96: E89–E98.
27. Broholm C, Mortensen OH, Nielsen S, Akerstrom T, Zankari A, Dahl B, Pedersen BK. 2008. Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle. J Physiol 586: 2195–2201.
28. Broholm C, Laye MJ, Brandt C, Vadalasetty R, Pilegaard H, Pedersen BK, Scheele C. 2011. LIF is a contraction-induced myokine stimulating human myocyte proliferation. J Appl Physiol (1985) 111: 251–259.
29. Burks TN, Cohn RD. 2011. Role of TGF-b signaling in inherited and acquired myopathies. Skelet Muscle 1: 19.
30. Bushby KM, Collins J, Hicks D. 2014. Collagen type VI myopathies. Adv Exp Med Biol 802: 185–199.
31. Camporez JP, Petersen MC, Abudukadier A, Moreira GV, Jurczak MJ, Friedman G, Haqq CM, Petersen KF, Shulman GI. 2016. Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. Proc Natl Acad Sci 113: 2212–2217.
32. Cannon JG, Kluger MJ. 1983. Endogenous pyrogen activity in human plasma after exercise. Science 220: 617–619.
33. Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. 2008. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134: 933–944.
34. Cappon J, Brasel JA, Mohan S, Cooper DM. 1994. Effect of brief exercise on circulating insulin-like growth factor I. J Appl Physiol (1985) 76: 2490–2496.
35. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, et al. 2006. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMPactivated protein kinase. Diabetes 55: 2688–2697.
36. Catoire M, Alex S, Paraskevopulos N, Mattijssen F, Evers-van Gogh I, Schaart G, Jeppesen J, Kneppers A, Mensink M, Voshol PJ, et al. 2014a. Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise. Proc Natl Acad Sci 111: E1043–E1052.
37. Catoire M, Mensink M, Kalkhoven E, Schrauwen P, Kersten S. 2014b. Identification of human exercise-induced myokines using secretome analysis. Physiol Genomics 46: 256–267.
38. Chan MH, Carey AL, Watt MJ, Febbraio MA. 2004. Cytokine gene expression in human skeletal muscle during concentric contraction: Evidence that IL-8, like IL-6, is influenced by glycogen availability. Am J Physiol Regul Integr Comp Physiol 287: R322–R327.
39. Chan CY, Masui O, Krakovska O, Belozerov VE, Voisin S, Ghanny S, Chen J, Moyez D, Zhu P, Evans KR, et al. 2011. Identification of differentially regulated secretome components during skeletal myogenesis. Mol Cell Proteomics 10: M110.
40. Chao MV, Rajagopal R, Lee FS. 2006. Neurotrophin signalling in health and disease. Clin Sci (Lond) 110: 167–173.
41. Coenen-Stass AM, Betts CA, Lee YF, Mager I, Turunen MP, El Andaloussi S, Morgan JE, Wood MJ, Roberts TC. 2016. Selective release of muscle-specific, extracellular micro- RNAs during myogenic differentiation. Hum Mol Genet doi: 10.1093/hmg/ddw237.
42. Coletta DK, Mandarino LJ. 2011. Mitochondrial dysfunction and insulin resistance from the outside in: Extracellular matrix, the cytoskeleton, and mitochondria. Am J Physiol Endocrinol Metab 301: E749–E755.
43. Costford SR, Bajpeyi S, Pasarica M, Albarado DC, Thomas SC, Xie H, Church TS, Jubrias SA, Conley KE, Smith SR. 2010. Skeletal muscle NAMPT is induced by exercise in humans. AmJ Physiol Endocrinol Metab 298: E117–E126.
44. Covington JD, Tam CS, Bajpeyi S, Galgani JE, Noland RC, Smith SR, Redman LM, Ravussin E. 2016. Myokine expression in muscle and myotubes in response to exercise stimulation. Med Sci Sports Exerc 48: 384–390.
45. Croisier JL, Camus G, Venneman I, Deby-Dupont G, Juchmes-Ferir A, Lamy M, Crielaard JM, Deby C, Duchateau J. 1999. Effects of training on exercise-induced muscle damage and interleukin 6 production. Muscle Nerve 22: 208–212.
46. Cron L, Allen T, Febbraio MA. 2016. The role of gp130 receptor cytokines in the regulation of metabolic homeostasis. J Exp Biol 219: 259–265.
47. Della Gatta PA, Cameron-Smith D, Peake JM. 2014. Acute resistance exercise increases the expression of chemotactic factors within skeletal muscle. Eur J Appl Physiol 114: 2157–2167.
48. Dijk W, Beigneux AP, Larsson M, Bensadoun A, Young SG, Kersten S. 2016. Angiopoietin-like 4 (ANGPTL4) promotes intracellular degradation of lipoprotein lipase in adipocytes. J Lipid Res 57: 1670–1683.
49. Doorn J, Roberts SJ, Hilderink J, Groen N, van Apeldoorn A, van Blitterswijk C, Schrooten J, de Boer J. 2013. Insulinlike growth factor-I enhances proliferation and differentiation of human mesenchymal stromal cells in vitro. Tissue Eng Part A 19: 1817–1828.
50. Dray C, Knauf C, Daviaud D, Waget A, Boucher J, Buleon M, Cani PD, Attane C, Guigne C, Carpene C, et al. 2008. Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metab 8: 437–445.
51. Duzel E, van Praag H, Sendtner M. 2016. Can physical exercise in old age improve memory and hippocampal function? Brain 139: 662–673.
52. Egan B, Zierath JR. 2013. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab 17: 162–184.
53. Ellingsgaard H, Ehses JA, Hammar EB, Van Lommel L, Quintens R, Martens G, Kerr-Conte J, Pattou F, Berney T, Pipeleers D, et al. 2008. Interleukin-6 regulates pancreatic a-cell mass expansion. Proc Natl Acad Sci 105: 13163–13168.
54. Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest S, Muller YD, et al. 2011. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and a cells. Nat Med 17: 1481–1489.
55. Ettinger MP, Littlejohn TW, Schwartz SL, Weiss SR, McIlwain HH, Heymsfield SB, Bray GA, Roberts WG, Heyman ER, Stambler N, et al. 2003. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: A randomized, dose-ranging study. JAMA289: 1826–1832.
56. Fagerhol MK, Nielsen HG, Vetlesen A, Sandvik K, Lyberg T. 2005. Increase in plasma calprotectin during long-distance running. Scand J Clin Lab Invest 65: 211–220.
57. Ferris LT, Williams JS, Shen CL. 2007. The effect of acute exerciseonserumbrain-derivedneurotrophicfactor levels and cognitive function. Med Sci Sports Exerc 39: 728–734.
58. Frobel J, Hartwig S, Jourdain S, Fischer JC, Zilkens C, Kundgen A, Suckau D, Germing U, Czibere A, Lehr S. 2015. Deep serum discoveries: SDF-1a and HSA fragments in myelodysplastic syndromes. Am J Hematol 90: E185–E187.
59. Gabay C. 2006. Interleukin-6 and chronic inflammation. Arthritis Res Ther 8: S3.
60. Gavin TP, Robinson CB, Yeager RC, England JA, Nifong LW, Hickner RC. 2004. Angiogenic growth factor response to acute systemic exercise in human skeletal muscle. J Appl Physiol (1985) 96: 19–24.
61. Ghanbari-Niaki A, Saghebjoo M, Soltani R, Kirwan JP. 2010. Plasma visfatin is increased after high-intensity exercise. Ann Nutr Metab 57: 3–8.
62. Gianazza E, Miller I, Palazzolo L, Parravicini C, Eberini I. 2016.With or without you—Proteomics with or without major plasma/serum proteins. J Proteomics 140: 62–80.
63. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. 2011. The anti-inflammatory effects of exercise: Mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 11: 607–615.
64. Goldstein MS. 1961. Humoral nature of the hypoglycemic factor of muscular work. Diabetes 10: 232–234.
65. Gorgens SW, Raschke S, Holven KB, Jensen J, Eckardt K, Eckel J. 2013. Regulation of follistatin-like protein 1 expression and secretion in primary human skeletal muscle cells. Arch Physiol Biochem 119: 75–80.
66. Gorgens SW, Eckardt K, Elsen M, Tennagels N, Eckel J. 2014. Chitinase-3-like protein 1 protects skeletal muscle from TNFa-induced inflammation and insulin resistance. Biochem J 459: 479–488.
67. Gorgens SW, Hjorth M, Eckardt K, Wichert S, Norheim F, Holen T, Lee S, Langleite T, Birkeland KI, Stadheim HK, et al. 2016. The exercise-regulated myokine chitinase-3- like protein 1 stimulates human myocyte proliferation. Acta Physiol (Oxf) 216: 330–345.
68. Gray NE, Lam LN, Yang K, Zhou AY, Koliwad S, Wang JC. 2012. Angiopoietin-like 4 (Angptl4) protein is a physiological mediator of intracellular lipolysis in murine adipocytes. J Biol Chem 287: 8444–8456.
69. Gudiksen A, Schwartz CL, Bertholdt L, Joensen E, Knudsen JG, Pilegaard H. 2016. Lack of skeletal muscle IL-6 affects pyruvate dehydrogenase activity at rest and during prolonged exercise. PLoS ONE 11: e0156460.
70. Gustafsson T. 2011. Vascular remodelling in human skeletal muscle. Biochem Soc Trans 39: 1628–1632.
71. Hameed M, Orrell RW, Cobbold M, Goldspink G, Harridge SD. 2003. Expression of IGF-I splice variants in young and old human skeletal muscle after high resistance exercise. J Physiol 547: 247–254.
72. Hamrick MW, Arounleut P, Kellum E, Cain M, Immel D, Liang LF. 2010. Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury. J Trauma 69: 579–583.
73. Hansen JS, Clemmesen JO, Secher NH, Hoene M, Drescher A, Weigert C, Pedersen BK, Plomgaard P. 2015a. Glucagon- to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol Metab 4: 551–560.
74. Hansen JS, Zhao X, Irmler M, Liu X, Hoene M, Scheler M, Li Y, Beckers J, Hrabe dA, Haring HU, et al. 2015b. Type 2 diabetes alters metabolic and transcriptional signatures of glucose and amino acid metabolism during exercise and recovery. Diabetologia 58: 1845–1854.
75. Hartwig S, Raschke S, Knebel B, Scheler M, Irmler M, Passlack W, Muller S, Hanisch FG, Franz T, Li X, et al. 2014. Secretome profiling of primary human skeletal muscle cells. Biochim Biophys Acta 1844: 1011–1017.
76. Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA. 2007. Lactate sensitive transcription factor network in L6 cells: Activation of MCT1 and mitochondrial biogenesis. FASEB J 21: 2602–2612.
77. Haugen F, Norheim F, Lian H, Wensaas AJ, Dueland S, Berg O, Funderud A, Skalhegg BS, Raastad T, Drevon CA. 2010. IL-7 is expressed and secreted by human skeletal muscle cells. Am J Physiol Cell Physiol 298: C807–C816.
78. Heinemeier KM, Bjerrum SS, Schjerling P, Kjaer M. 2013. Expression of extracellular matrix components and related growth factors in human tendon and muscle after acute exercise. Scand J Med Sci Sports 23: e150–e161.
79. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller- Newen G, Schaper F. 2003. Principles of interleukin (IL)- 6-type cytokine signalling and its regulation. Biochem J 374: 1–20.
80. Henningsen J, Rigbolt KT, Blagoev B, Pedersen BK, Kratchmarova I. 2010. Dynamics of the skeletal muscle secretome during myoblast differentiation. Mol Cell Proteomics 9: 2482–2496.
81. Hiscock N, Chan MH, Bisucci T, Darby IA, Febbraio MA. 2004. Skeletal myocytes are a source of interleukin-6 mRNAexpression and protein release during contraction: Evidence of fiber type specificity. FASEB J 18: 992–994.
82. Hittel DS, Berggren JR, Shearer J, Boyle K, Houmard JA. 2009. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 58: 30–38.
83. Hittel DS, Axelson M, Sarna N, Shearer J, Huffman KM, Kraus WE. 2010. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc 42: 2023–2029.
84. Hjorth M, Norheim F, Meen AJ, Pourteymour S, Lee S, Holen T, Jensen J, Birkeland KI, Martinov VN, Langleite TM, et al. 2015. The effect of acute and long-term physical activity on extracellular matrix and serglycin in human skeletal muscle. Physiol Rep 3: e12473.
85. Hjorth M, Pourteymour S, Gorgens SW, Langleite TM, Lee S, Holen T, Gulseth HL, Birkeland KI, Jensen J, Drevon CA, et al. 2016. Myostatin in relation to physical activity and dysglycaemia and its effect on energy metabolism in human skeletal muscle cells. Acta Physiol (Oxf) 217: 45–60.
86. Hoene M, Weigert C. 2008. The role of interleukin-6 in insulin resistance, body fat distribution and energy balance. Obes Rev 9: 20–29.
87. Hoene M, Runge H, Haring HU, Schleicher ED, Weigert C. 2013. Interleukin-6 promotes myogenic differentiation of mouse skeletal muscle cells: Role of the STAT3 pathway. Am J Physiol Cell Physiol 304: C128–C136.
88. Hoier B, Hellsten Y. 2014. Exercise-induced capillary growth in human skeletal muscle and the dynamics of VEGF. Microcirculation 21: 301–314.
89. Hoier B, Prats C, Qvortrup K, Pilegaard H, Bangsbo J, Hellsten Y. 2013. Subcellular localization and mechanism of secretion of vascular endothelial growth factor in human skeletal muscle. FASEB J 27: 3496–3504.
90. Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L, Pedersen BK. 2011. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. AmJ Physiol Endocrinol Metab 301: E504–E510.
91. Hong EG, Ko HJ, Cho YR, Kim HJ, Ma Z, Yu TY, Friedline RH, Kurt-Jones E, Finberg R, Fischer MA, et al. 2009. Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle. Diabetes 58: 2525–2535.
92. Hubal MJ, Chen TC, Thompson PD, Clarkson PM. 2008. Inflammatory gene changes associated with the repeatedbout effect. Am J Physiol Regul Integr Comp Physiol 294: R1628–R1637.
93. Hwang H, Bowen BP, Lefort N, Flynn CR, De Filippis EA, Roberts C, Smoke CC, Meyer C, Hojlund K, Yi Z, et al. 2010. Proteomics analysis of human skeletal muscle reveals novel abnormalities in obesity and type 2 diabetes. Diabetes 59: 33–42.
94. Hyldahl RD, Nelson B, Xin L, Welling T, Groscost L, Hubal MJ, Chipkin S, Clarkson PM, Parcell AC. 2015. Extracellular matrix remodeling and its contribution to protective adaptation following lengthening contractions in human muscle. FASEB J 29: 2894–2904.
95. Hynes RO. 2009. The extracellular matrix: Not just pretty fibrils. Science 326: 1216–1219.
96. Idorn M, Hojman P. 2016. Exercise-dependent regulation of NK cells in cancer protection. Trends Mol Med 22: 565-577.
97. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, et al. 2003. Free fatty acids regulate insulin secretion from pancreatic b cells through GPR40. Nature 422: 173–176.
98. Jankowski CM, Gozansky WS, MacLean PS, Shulman B, Wolfe P, Schwartz RS, Kohrt WM. 2013. N-acetyl-4-aminophenol and musculoskeletal adaptations to resistance exercise training. Eur J Appl Physiol 113: 1127–1136.
99. Jedrychowski MP, Wrann CD, Paulo JA, Gerber KK, Szpyt J, Robinson MM, Nair KS, Gygi SP, Spiegelman BM. 2015. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab 22: 734–740.
100. Kadoglou NP, Vrabas IS, Kapelouzou A, Lampropoulos S, Sailer N, Kostakis A, Liapis CD, Angelopoulou N. 2012. The impact of aerobic exercise training on novel adipokines, apelin and ghrelin, in patients with type 2 diabetes. Med Sci Monit 18: CR290–CR295.
101. Kang L, Lantier L, Kennedy A, Bonner JS, Mayes WH, Bracy DP, Bookbinder LH, Hasty AH, Thompson CB, Wasserman DH. 2013. Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance. Diabetes 62: 1888–1896.
102. Kang L, Mokshagundam S, Reuter B, Lark DS, Sneddon CC, Hennayake C, Williams AS, Bracy DP, James FD, Pozzi A, et al. 2016. Integrin-linked kinase in muscle is necessary for the development of insulin resistance in diet-induced obese mice. Diabetes 65: 1590–1600.
103. Kanzleiter T, Rath M, Gorgens SW, Jensen J, Tangen DS, Kolnes AJ, Kolnes KJ, Lee S, Eckel J, Schurmann A, et al. 2014. Themyokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem Biophys Res Commun 450: 1089–1094.
104. Keipert S, Ost M, Johann K, Imber F, Jastroch M, van Schothorst EM, Keijer J, Klaus S. 2014. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am J Physiol Endocrinol Metab 306: E469–E482.
105. Keller C, Steensberg A, Pilegaard H, Osada T, Saltin B, Pedersen BK, Neufer PD. 2001. Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: Influence of muscle glycogen content. FASEB J 15: 2748-2750.
106. Keller C, Hellsten Y, Steensberg A, Pedersen BK. 2006. Differential regulation of IL-6 and TNF-a via calcineurin in human skeletal muscle cells. Cytokine 36: 141–147.
107. Kersten S, Lichtenstein L, Steenbergen E, Mudde K, Hendriks HF, Hesselink MK, Schrauwen P, Muller M. 2009. Caloric restriction and exercise increase plasma ANGPTL4 levels in humans via elevated free fatty acids. Arterioscler Thromb Vasc Biol 29: 969–974.
108. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, Kim SS, Kim dH, Hur KY, Kim HK, et al. 2013a. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 19: 83–92.
109. Kim KH, Kim SH, Min YK, Yang HM, Lee JB, Lee MS. 2013b. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS ONE 8: e63517.
110. Kivela R, Kyrolainen H, Selanne H, Komi PV, Kainulainen H, Vihko V. 2007. A single bout of exercise with high mechanical loading induces the expression of Cyr61/ CCN1 and CTGF/CCN2 in human skeletal muscle. J Appl Physiol 103: 1395–1401.
111. Kjaer M. 2004. Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading. Physiol Rev 84: 649–698.
112. Kollias HD, McDermott JC. 2008. Transforming growth factor- b and myostatin signaling in skeletal muscle. J Appl Physiol (1985) 104: 579–587.
113. Lancaster GI, Febbraio MA. 2014. The immunomodulating role of exercise in metabolic disease. Trends Immunol 35: 262–269.
114. Landers-Ramos RQ, Jenkins NT, Spangenburg EE, Hagberg JM, Prior SJ. 2014. Circulating angiogenic and inflammatory cytokine responses to acute aerobic exercise in trained and sedentary young men. Eur J Appl Physiol 114: 1377–1384.
115. Le Bihan MC, Bigot A, Jensen SS, Dennis JL, Rogowska- Wrzesinska A, Laine J, Gache V, Furling D, Jensen ON, Voit T, et al. 2012. In-depth analysis of the secretome identifies three major independent secretory pathways in differentiating human myoblasts. J Proteomics 77: 344–356.
116. Lee YS, Huynh TV, Lee SJ. 2016. Paracrine and endocrine modes of myostatin action. J Appl Physiol (1985) 120: 592–598.
117. Li A, Dubey S, Varney ML, Dave BJ, Singh RK. 2003. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170: 3369–3376.
118. Li Y, Li J, Zhu J, Sun B, Branca M, Tang Y, Foster W, Xiao X, Huard J. 2007. Decorin gene transfer promotes muscle cell differentiation and muscle regeneration. Mol Ther 15: 1616–1622.
119. Louis E, Raue U, Yang Y, Jemiolo B, Trappe S. 2007. Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle. J Appl Physiol (1985) 103: 1744–1751.
120. MacDonald C, Wojtaszewski JF, Pedersen BK, Kiens B, Richter EA. 2003. Interleukin-6 release from human skeletal muscle during exercise: Relation to AMPKactivity. J Appl Physiol 95: 2273–2277.
121. Machida M, Takemasa T. 2010. Ibuprofen administration during endurance training cancels running-distance-dependent adaptations of skeletal muscle in mice. J Physiol Pharmacol 61: 559–563.
122. Malm C, Sjodin TL, Sjoberg B, Lenkei R, Renstrom P, Lundberg IE, Ekblom B. 2004. Leukocytes, cytokines, growth factors and hormones in human skeletalmuscle and blood after uphill or downhill running. J Physiol 556: 983–1000.
123. Mann CJ, Perdiguero E, Kharraz Y, Aguilar S, Pessina P, Serrano AL, Munoz-Canoves P. 2011. Aberrant repair and fibrosis development in skeletal muscle. SkeletMuscle 1: 21.
124. Massague J, Cheifetz S, Endo T, Nadal-Ginard B. 1986. Type b transforming growth factor is an inhibitor ofmyogenic differentiation. Proc Natl Acad Sci 83: 8206–8210.
125. Matthews VB, Astrom MB, Chan MH, Bruce CR, Krabbe KS, Prelovsek O, Akerstrom T, Yfanti C, Broholm C, Mortensen OH, et al. 2009. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMPactivated protein kinase. Diabetologia 52: 1409–1418.
126. Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, Theurich S, Hausen AC, Schmitz J, Bronneke HS, et al. 2014. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15: 423–430.
127. Maynard CL, Weaver CT. 2008. Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol Rev 226: 219–233.
128. McKay BR, De Lisio M, Johnston AP, O’Reilly CE, Phillips SM, Tarnopolsky MA, Parise G. 2009. Association of interleukin- 6 signalling with the muscle stem cell response following muscle-lengthening contractions in humans. PloS ONE 4: e6027.
129. McPherron AC, Lawler AM, Lee SJ. 1997. Regulation of skeletal muscle mass in mice by a new TGF-b superfamily member. Nature 387: 83–90.
130. Mera P, Laue K, Ferron M, Confavreux C, Wei J, Galan-Diez M, Lacampagne A, Mitchell SJ, Mattison JA, Chen Y, et al. 2016. Osteocalcin signaling inmyofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metab 23: 1078–1092.
131. Mikkelsen UR, Langberg H, Helmark IC, Skovgaard D, Andersen LL, Kjaer M, Mackey AL. 2009. Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise. J Appl Physiol (1985) 107: 1600–1611.
132. Miyabe M, Ohashi K, Shibata R, Uemura Y, Ogura Y, Yuasa D, Kambara T, Kataoka Y, Yamamoto T, Matsuo K, et al. 2014. Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury. Cardiovasc Res 103: 111–120.
133. Moon HY, Becke A, Berron D, Becker B, Sah N, Benoni G, Janke E, Lubejko ST, Greig NH, Mattison JA, et al. 2016. Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab 24: 332–340.
134. Mooren FC, Lechtermann A, Fobker M, Brandt B, Sorg C, Volker K, Nacken W. 2006. The response of the novel proinflammatory molecules S100A8/A9 to exercise. Int J Sports Med 27: 751–758.
135. Mortensen OH, Andersen K, Fischer C, Nielsen AR, Nielsen S, Akerstrom T, Aastrom MB, Borup R, Pedersen BK. 2008. Calprotectin is released from human skeletal muscle tissue during exercise. J Physiol 586: 3551–3562.
136. Neubauer O, Sabapathy S, Ashton KJ, Desbrow B, Peake JM, Lazarus R, Wessner B, Cameron-Smith D, Wagner KH, Haseler LJ, et al. 2014. Time course-dependent changes in the transcriptome of human skeletal muscle during recovery from endurance exercise: From inflammation to adaptive remodeling. J Appl Physiol (1985) 116: 274–287.
137. Nielsen AR, Mounier R, Plomgaard P, Mortensen OH, Penkowa M, Speerschneider T, Pilegaard H, Pedersen BK. 2007. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J Physiol 584: 305–312.
138. Nielsen S, Scheele C, Yfanti C, Akerstrom T, Nielsen AR, Pedersen BK, Laye MJ. 2010. Muscle specific microRNAs are regulated by endurance exercise in human skeletal muscle. J Physiol 588: 4029–4037.
139. Nielsen S, Akerstrom T, Rinnov A, Yfanti C, Scheele C, Pedersen BK, Laye MJ. 2014. The miRNA plasma signature in response to acute aerobic exercise and endurance training. PloS ONE 9: e87308.
140. Nieman DC, Henson DA, Smith LL, Utter AC, Vinci DM, Davis JM, Kaminsky DE, Shute M. 2001. Cytokine changes after a marathon race. J Appl Physiol (1985) 91: 109–114.
141. Nieman DC, Davis JM, Henson DA, Walberg-Rankin J, Shute M, Dumke CL, Utter AC, Vinci DM, Carson JA, Brown A, et al. 2003. Carbohydrate ingestion influences skeletal muscle cytokinemRNA and plasma cytokine levels after a 3-h run. J Appl Physiol (1985) 94: 1917–1925.
142. Nishimune H, Stanford JA, Mori Y. 2014. Role of exercise in maintaining the integrity of the neuromuscular junction. Muscle Nerve 49: 315–324.
143. Norheim F, Raastad T, Thiede B, Rustan AC, Drevon CA, Haugen F. 2011. 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.
144. Olfert IM, Baum O, Hellsten Y, Egginton S. 2016. Advances and challenges in skeletal muscle angiogenesis. Am J Physiol Heart Circ Physiol 310: H326–H336.
145. Oliveira M, Gleeson M. 2010. The influence of prolonged cycling on monocyte Toll-like receptor 2 and 4 expression in healthy men. Eur J Appl Physiol 109: 251–257.
146. Ost M, Coleman V, Kasch J, Klaus S. 2016. Regulation of myokine expression: Role of exercise and cellular stress. Free Radic Biol Med 98: 78–89.
147. Ostrowski K, Hermann C, Bangash A, Schjerling P, Nielsen JN, Pedersen BK. 1998a. A trauma-like elevation of plasma cytokines in humans in response to treadmill running. J Physiol 513: 889–894.
148. Ostrowski K, Rohde T, Zacho M, Asp S, Pedersen BK. 1998b. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. J Physiol 508: 949–953.
149. Palsgaard J, Brons C, Friedrichsen M, Dominguez H, Jensen M, Storgaard H, Spohr C, Torp-Pedersen C, Borup R, De Meyts P, et al. 2009. Gene expression in skeletal muscle biopsies from people with type 2 diabetes and relatives: Differential regulation of insulin signaling pathways. PloS ONE 4: e6575.
150. Pataquiva-Mateus AY, Wu HC, Lucchesi C, Ferraz MP, Monteiro FJ, Spector M. 2012. Supplementation of collagen scaffolds with SPARC to facilitate mineralization. J Biomed Mater Res B Appl Biomater 100: 862–870.
151. Paulsen G, Mikkelsen UR, Raastad T, Peake JM. 2012. Leucocytes, cytokines and satellite cells: What role do they play in muscle damage and regeneration following eccentric exercise? Exerc Immunol Rev 18: 42–97.
152. Peake JM, Suzuki K, Hordern M, Wilson G, Nosaka K, Coombes JS. 2005. Plasma cytokine changes in relation to exercise intensity and muscle damage. Eur J Appl Physiol 95: 514–521.
153. Pedersen BK, Febbraio MA. 2012. Muscles, exercise and obesity: Skeletal muscle as a secretory organ. Nat Rev Endocrinol 8: 457–465.
154. Pedersen BK, Saltin B. 2015. Exercise as medicine—Evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports 25: 1–72.
155. Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Febbraio M, Saltin B. 2003. Searching for the exercise factor: Is IL-6 a candidate? J Muscle Res Cell Motil 24: 113–119.
156. Pedersen L, Idorn M, Olofsson GH, Lauenborg B, Nookaew I, Hansen RH, Johannesen HH, Becker JC, Pedersen KS, Dethlefsen C, et al. 2016. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab 23: 554–562.
157. Perbal B. 2004. CCN proteins: Multifunctional signaling regulators. Lancet 363: 62–64.
158. Petersen EW, Carey AL, Sacchetti M, Steinberg GR, Macaulay SL, Febbraio MA, Pedersen BK. 2005. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Am J Physiol Endocrinol Metab 288: E155–E162.
159. Pierce JR, Maples JM, Hickner RC. 2015. IL-15 concentrations in skeletal muscle and subcutaneous adipose tissue in lean and obese humans: Local effects of IL-15 on adipose tissue lipolysis. Am J Physiol Endocrinol Metab 308: E1131–E1139.
160. Pillon NJ, Bilan PJ, Fink LN, Klip A. 2012. Crosstalk between skeletal muscle and immune cells: muscle-derived mediators and metabolic implications. Am J Physiol Endocrinol Metab 304: E453–E465.
161. Pistilli EE, Bogdanovich S, Garton F, Yang N, Gulbin JP, Conner JD, Anderson BG, Quinn LS, North K, Ahima RS, et al. 2011. Loss of IL-15 receptor a alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles. J Clin Invest 121: 3120–3132.
162. Quinn LS, Anderson BG, Strait-Bodey L, Stroud AM, Argiles JM. 2009. Oversecretion of interleukin-15 fromskeletal muscle reduces adiposity. Am J Physiol Endocrinol Metab 296: E191–E202.
163. Quinn LS, Anderson BG, Conner JD, Wolden-Hanson T. 2013. IL-15 overexpression promotes endurance, oxidative energy metabolism, and muscle PPARd, SIRT1, PGC-1a, and PGC-1b expression in male mice. Endocrinology 154: 232–245.
164. Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC, et al. 2014. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157: 1279–1291.
165. Raschke S, Eckardt K, Bjorklund HK, Jensen J, Eckel J. 2013a. Identification and validation of novel contraction- regulated myokines released from primary human skeletal muscle cells. PloS ONE 8: e62008.
166. Raschke S, Elsen M, Gassenhuber H, Sommerfeld M, Schwahn U, Brockmann B, Jung R, Wisloff U, Tjonna AE, Raastad T, et al. 2013b. Evidence against a beneficial effect of irisin in humans. PloS ONE 8: e73680.
167. Revollo JR, Korner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C, Townsend RR, et al. 2007. Nampt/PBEF/Visfatin regulates insulin secretion in b cells as a systemic NAD biosynthetic enzyme. Cell Metab 6: 363–375.
168. Riechman SE, Balasekaran G, Roth SM, Ferrell RE. 2004. Association of interleukin-15 protein and interleukin- 15 receptor genetic variation with resistance exercise training responses. J Appl Physiol (1985) 97: 2214–2219.
169. Rinnov A, Yfanti C, Nielsen S, Akerstrom TC, Peijs L, Zankari A, Fischer CP, Pedersen BK. 2014. Endurance train-ing enhances skeletal muscle interleukin-15 in human male subjects. Endocrine 45: 271–278.
170. Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Bluher M. 2009. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci 106: 8665-8670.
171. Roberts LD, Bostrom P, O’Sullivan JF, Schinzel RT, Lewis GD, Dejam A, Lee YK, Palma MJ, Calhoun S, Georgiadi A, et al. 2014. b-Aminoisobutyric acid induces browning of white fat and hepatic b-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab 19: 96–108.
172. Rosendal L, Sogaard K, Kjaer M, Sjogaard G, Langberg H, Kristiansen J. 2005. Increase in interstitial interleukin-6 of human skeletal muscle with repetitive low-force exercise. J Appl Physiol (1985) 98: 477–481.
173. Ruderman NB, Keller C, Richard AM, Saha AK, Luo Z, Xiang X, Giralt M, Ritov VB, Menshikova EV, Kelley DE, et al. 2006. Interleukin-6 regulation of AMP-activated protein kinase: Potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes 55: S48–S54.
174. Rue N, Vissing J, Galbo H. 2014. Insulin resistance and increased muscle cytokine levels in patients with mitochondrial myopathy. J Clin Endocrinol Metab 99: 3757-3765.
175. Rullman E, Rundqvist H, Wagsater D, Fischer H, Eriksson P, Sundberg CJ, Jansson E, Gustafsson T. 2007. A single bout of exercise activates matrix metalloproteinase in human skeletal muscle. J Appl Physiol (1985) 102: 2346–2351.
176. Russell AP, Lamon S. 2015. Exercise, skeletal muscle and circulating microRNAs. Prog Mol Biol Transl Sci 135: 471–496.
177. Russell AP, Lamon S, Boon H, Wada S, Guller I, Brown EL, Chibalin AV, Zierath JR, Snow RJ, Stepto N, et al. 2013. Regulation of miRNAs in human skeletal muscle following acute endurance exercise and short-term endurance training. J Physiol 591: 4637–4653.
178. Safdar A, Saleem A, Tarnopolsky MA. 2016. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat Rev Endocrinol 12: 504–517.
179. SaucedoMarquez CM, Vanaudenaerde B, Troosters T, Wenderoth N. 2015. High-intensity interval training evokes larger serum BDNF levels compared with intense continuous exercise. J Appl Physiol (1985) 119: 1363–1373.
180. Scheler M, Irmler M, Lehr S, Hartwig S, Staiger H, Al Hasani H, Beckers J, de Angelis MH, Haring HU, Weigert C. 2013. Cytokine response of primary human myotubes in an in vitro exercise model. Am J Physiol Cell Physiol 305: C877–C886.
181. Schlittler M, Goiny M, Agudelo LZ, Venckunas T, Brazaitis M, Skurvydas A, Kamandulis S, Ruas JL, Erhardt S, Westerblad H, et al. 2016. Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans. Am J Physiol Cell Physiol 310: C836–C840.
182. Schluns KS, Kieper WC, Jameson SC, Lefrancois L. 2000. Interleukin-7 mediates the homeostasis of I and memory CD8 T cells in vivo. Nat Immunol 1: 426–432.
183. Schoonjans K, Staels B, Auwerx J. 1996. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res 37: 907–925.
184. Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, Komen W, Braun T, Tobin JF, Lee SJ. 2004. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 350: 2682–2688.
185. Seldin MM, Peterson JM, Byerly MS, Wei Z, Wong GW. 2012. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J Biol Chem 287: 11968–11980.
186. Serrano AL, Baeza-Raja B, Perdiguero E, Jardi M, Munoz- Canoves P. 2008. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab 7: 33–44.
187. Smith LL, Anwar A, Fragen M, Rananto C, Johnson R, Holbert D. 2000. Cytokines and cell adhesion molecules associated with high-intensity eccentric exercise. Eur J Appl Physiol 82: 61–67.
188. Staiger H, Haas C, Machann J, Werner R, Weisser M, Schick F, Machicao F, Stefan N, Fritsche A, Haring HU. 2009. Muscle-derived angiopoietin-like protein 4 is induced by fatty acids via peroxisome proliferator-activated receptor (PPAR)-d and is of metabolic relevance in humans. Diabetes 58: 579–589.
189. Starkie RL, Arkinstall MJ, Koukoulas I, Hawley JA, Febbraio MA. 2001. Carbohydrate ingestion attenuates the increase in plasma interleukin-6, but not skeletal muscle interleukin-6 mRNA, during exercise in humans. J Physiol 533: 585–591.
190. Steensberg A, van Hall G, Osada T, Sacchetti M, Saltin B, Klarlund PB. 2000. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise- induced increase in plasma interleukin-6. J Physiol 529: 237–242.
191. Steensberg A, Febbraio MA, Osada T, Schjerling P, vanHall G, Saltin B, Pedersen BK. 2001. Interleukin-6 production in contracting human skeletal muscle is influenced by preexercise muscle glycogen content. J Physiol 537: 633–639.
192. Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA, Pedersen BK. 2002. IL-6 and TNF-a expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab 283: E1272–E1278.
193. Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK. 2003. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. AmJ Physiol Endocrinol Metab 285: E433–E437.
194. Stewart LK, Flynn MG, Campbell WW, Craig BA, Robinson JP, McFarlin BK, Timmerman KL, Coen PM, Felker J, Talbert E. 2005. Influence of exercise training and age on CD14þ cell-surface expression of toll-like receptor 2 and 4. Brain Behav Immun 19: 389–397.
195. Strobel NA, Peake JM, Matsumoto A, Marsh SA, Coombes JS, Wadley GD. 2011. Antioxidant supplementation reduces skeletal muscle mitochondrial biogenesis. Med Sci Sports Exerc 43: 1017–1024.
196. Stromberg A, Olsson K, Dijksterhuis JP, Rullman E, Schulte G, Gustafsson T. 2016. CX3CL1—A macrophage chemoattractant induced by a single bout of exercise in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 310: R297–R304.
197. Subbotina E, Sierra A, Zhu Z, Gao Z, Koganti SR, Reyes S, Stepniak E, Walsh SA, Acevedo MR, Perez-Terzic CM, et al. 2015. Musclin is an activity-stimulated myokine that enhances physical endurance. Proc Natl Acad Sci 112: 16042–16047.
198. Suzuki K, Peake J, Nosaka K, Okutsu M, Abbiss CR, Surriano R, Bishop D, Quod MJ, Lee H, Martin DT, et al. 2006. Changes in markers of muscle damage, inflammation and HSP70 after an Ironman Triathlon race. Eur J Appl Physiol 98: 525–534.
199. Tamura Y, Watanabe K, Kantani T, Hayashi J, Ishida N, Kaneki M. 2011. Upregulation of circulating IL-15 by treadmill running in healthy individuals: Is IL-15 an endocrine mediator of the beneficial effects of endurance exercise? Endocr J 58: 211–215.
200. Tantiwong P, Shanmugasundaram K, Monroy A, Ghosh S, Li M, DeFronzo RA, Cersosimo E, Sriwijitkamol A, Mohan S, Musi N. 2010. NF-kB activity in muscle from obese and type 2 diabetic subjects under basal and exercise- stimulated conditions. Am J Physiol Endocrinol Metab 299: E794–E801.
201. Tiano JP, Springer DA, Rane SG. 2015. SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor g coactivator 1-a (PGC-1a) during exercise. J Biol Chem 290: 7671-7684.
202. Timmerman KL, Flynn MG, Coen PM, Markofski MM, Pence BD. 2008. Exercise training-induced lowering of inflammatory (CD14+CD16+) monocytes: A role in the anti-inflammatory influence of exercise? J Leukoc Biol 84: 1271–1278.
203. Toft AD, Falahati A, Steensberg A. 2011. Source and kinetics of interleukin-6 in humans during exercise demonstrated by a minimally invasive model. Eur J Appl Physiol 111: 1351–1359.
204. Toth KG, McKay BR, De Lisio M, Little JP, Tarnopolsky MA, Parise G. 2011. IL-6 induced STAT3 signalling is associated with the proliferation of human muscle satellite cells following acute muscle damage. PLoS ONE 6: e17392.
205. Trappe TA, White F, Lambert CP, Cesar D, Hellerstein M, Evans WJ. 2002. Effect of ibuprofen and acetaminophen on postexercise muscle protein synthesis. Am J Physiol Endocrinol Metab 282: E551–E556.
206. Trappe TA, Carroll CC, Dickinson JM, LeMoine JK, Haus JM, Sullivan BE, Lee JD, Jemiolo B, Weinheimer EM, Hollon CJ. 2011. Influence of acetaminophen and ibuprofen on skeletal muscle adaptations to resistance exercise in older adults. Am J Physiol Regul Integr Comp Physiol 300: R655–R662.
207. Turner CH. 2006. Bone strength: Current concepts. Ann NY Acad Sci 1068: 429–446.
208. Urso ML. 2013. Anti-inflammatory interventions and skeletal muscle injury: Benefit or detriment? J Appl Physiol (1985) 115: 920–928.
209. van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, et al. 2003. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88: 3005-3010.
210. Velloso CP. 2008. Regulation of muscle mass by growth hormone and IGF-I. Br J Pharmacol 154: 557–568.
211. Wahl P, Zinner C, Achtzehn S, Behringer M, Bloch W, Mester J. 2011. Effects of acid-base balance and high or low intensity exercise on VEGF and bFGF. Eur J Appl Physiol 111: 1405–1413.
212. Walker KS, Kambadur R, Sharma M, Smith HK. 2004. Resistance training alters plasmamyostatin but not IGF-1 in healthy men. Med Sci Sports Exerc 36: 787–793.
213. Watt MJ, Dzamko N, Thomas WG, Rose-John S, Ernst M, Carling D, Kemp BE, Febbraio MA, Steinberg GR. 2006. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12: 541–548.
214. Weigert C, Hennige AM, Lehmann R, Brodbeck K, Baumgartner F, Schauble M, Haring HU, Schleicher ED. 2006. Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells. J Biol Chem 281: 7060–7067.
215. Weigert C, Lehmann R, Hartwig S, Lehr S. 2014. The secretome of the working human skeletal muscle—A promising opportunity to combat the metabolic disaster? Proteomics Clin Appl 8: 5–18.
216. WHO. 2010. Global recommendations on physical activity for health. WHO Press, Geneva.
217. Wilkes JJ, Lloyd DJ, Gekakis N. 2009. Loss-of-function mutation in myostatin reduces tumor necrosis factor a production and protects liver against obesity-induced insulin resistance. Diabetes 58: 1133–1143.
218. Williams AS, Kang L, Wasserman DH. 2015. The extracellular matrix and insulin resistance. Trends Endocrinol Metab 26: 357–366.
219. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM. 2013. Exercise induces hippocampal BDNF through a PGC-1a/FNDC5 pathway. Cell Metab 18: 649–659.
220. Xu G, Hansen JS, Zhao XJ, Chen S, Hoene M, Wang XL, Clemmesen JO, Secher NH, Haring HU, Pedersen BK, et al. 2016. Liver and muscle contribute differently to the plasma acylcarnitine pool during fasting and exercise in humans. J Clin Endocrinol Metab 101: 5044–5052.
221. Yadav H, Quijano C, Kamaraju AK, Gavrilova O, Malek R, Chen W, Zerfas P, Zhigang D, Wright EC, Stuelten C, et al. 2011. Protection from obesity and diabetes by blockade of TGF-b/Smad3 signaling. Cell Metab 14: 67–79.
222. Yamamoto T, Habata Y, Matsumoto Y, Yasuhara Y, Hashimoto T, Hamajyo H, Anayama H, Fujii R, Fuse H, Shintani Y, et al. 2011. Apelin-transgenic mice exhibit a resistance against diet-induced obesity by increasing vascular mass and mitochondrial biogenesis in skeletal muscle. Biochim Biophys Acta 1810: 853–862.
223. Yeh SH, Chuang H, Lin LW, Hsiao CY, Eng HL. 2006. Regular tai chi chuan exercise enhances functional mobility and CD4CD25 regulatory T cells. Br J Sports Med 40: 239–243.
224. Zamurs LK, Idoate MA, Hanssen E, Gomez-Ibanez A, Pastor P, Lamande SR. 2015. Aberrant mitochondria in a Bethlem myopathy patient with a homozygous amino acid substitution that destabilizes the collagen VI a2(VI) chain. J Biol Chem 290: 4272–4281.
225. Zeng L, Akasaki Y, Sato K, Ouchi N, Izumiya Y, Walsh K. 2010. Insulin-like 6 is induced by muscle injury and functions as a regenerative factor. J Biol Chem 285: 36060-36069.
226. Zhao B, Wall RJ, Yang J. 2005. Transgenic expression of myostatin propeptide prevents diet-induced obesity and insulin resistance. Biochem Biophys Res Commun 337: 248–255.