Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise

Bone

Volumn 80, Issue , 2015, Pages 115-125

  Schnyder, Svenia ^a   Handschin, Christoph ^a  

^a UNIVERSITY OF BASEL   (Switzerland)

Author keywords

Exercise; Inflammation; Myokines; PGC 1 ; Skeletal muscle

Indexed keywords

3 AMINO 2 METHYLPROPIONIC ACID; ADIPOCYTOKINE; BRAIN DERIVED NEUROTROPHIC FACTOR; CILIARY NEUROTROPHIC FACTOR; DECORIN; FIBROBLAST GROWTH FACTOR 21; INTERLEUKIN 15; INTERLEUKIN 6; INTERLEUKIN 8; IRISIN; METERORIN LIKE PROTEIN; MYOKINE; MYOSTATIN; ONCOSTATIN M; OSTEONECTIN; OSTEOPONTIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; UNCLASSIFIED DRUG; VASCULOTROPIN; PPARGC1A PROTEIN, HUMAN; TRANSCRIPTION FACTOR;

EXERCISE; FUNCTIONAL MORPHOLOGY; HUMAN; MUSCLE FUNCTION; MUSCLE METABOLISM; NONHUMAN; PHYSICAL INACTIVITY; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SEDENTARY LIFESTYLE; SKELETAL MUSCLE; GENETICS; METABOLISM; MUSCLE CONTRACTION; PHYSIOLOGY;

EXERCISE; HUMANS; MUSCLE CONTRACTION; MUSCLE, SKELETAL; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR 1-ALPHA; TRANSCRIPTION FACTORS;

EID: 84943625908     PISSN: 87563282     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bone.2015.02.008     Document Type: Review

References (191)

1. Hoppeler H., Baum O., Lurman G., Mueller M. Molecular mechanisms of muscle plasticity with exercise. Compr Physiol 2011, 1(3):1383-1412.
2. Schiaffino S., Reggiani C. Fiber types in mammalian skeletal muscles. Physiol Rev 2011, 91(4):1447-1531.
3. Blaauw B., Schiaffino S., Reggiani C. Mechanisms modulating skeletal muscle phenotype. Compr Physiol 2013, 3(4):1645-1687.
4. Nikolaidis M.G., et al. Redox biology of exercise: an integrative and comparative consideration of some overlooked issues. J Exp Biol 2012, 215(Pt 10):1615-1625.
5. Handschin C., Rhee J., Lin J., Tarr P.T., Spiegelman B.M. An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proc Natl Acad Sci U S A 2003, 100(12):7111-7116.
6. Lin J., Handschin C., Spiegelman B.M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 2005, 1(6):361-370.
7. Handschin C. Regulation of skeletal muscle cell plasticity by the peroxisome proliferator-activated receptor gamma coactivator 1alpha. J Recept Signal Transduct Res 2010, 30(6):376-384.
8. Abstracts of the 2004 APS Intersociety Meeting: The Integrative Biology of Exercise. October 6-9, 2004, Austin, Texas, USA. Physiologist 2004, 47(4):271-359.
9. Perez-Schindler J., et al. The corepressor NCoR1 antagonizes PGC-1alpha and estrogen-related receptor alpha in the regulation of skeletal muscle function and oxidative metabolism. Mol Cell Biol 2012, 32(24):4913-4924.
10. Mootha V.K., et al. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A 2004, 101(17):6570-6575.
11. Lin J., et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 2002, 418(6899):797-801.
12. Handschin C., et al. Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. J Clin Invest 2007, 117(11):3463-3474.
13. Handschin C., et al. Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J Biol Chem 2007, 282(41):30014-30021.
14. Wright D.C., et al. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J Biol Chem 2007, 282(1):194-199.
15. Jager S., et al. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 2007, 104(29):12017-12022.
16. Pilegaard H., Saltin B., Neufer P.D. Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 2003, 546(Pt 3):851-858.
17. Pérez-Schindler J., Handschin C. New insights in the regulation of skeletal muscle PGC-1alpha by exercise and metabolic diseases. Drug Discov Today Dis Model 2013, 10(2):e79-e85.
18. Russell A.P., et al. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 2003, 52(12):2874-2881.
19. Svensson K., Handschin C. Modulation of PGC-1alpha activity as a treatment for metabolic and muscle-related diseases. Drug Discov Today 2014, 19(7):1024-1029.
20. Handschin C. The biology of PGC-1alpha and its therapeutic potential. Trends Pharmacol Sci 2009, 30(6):322-329.
21. Chan M.C., et al. Post-natal induction of PGC-1alpha protects against severe muscle dystrophy independently of utrophin. Skelet Muscle 2014, 4(1):2.
22. Handschin C., et al. PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev 2007, 21(7):770-783.
23. Wenz T., et al. Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab 2008, 8(3):249-256.
24. Summermatter S., Handschin C. PGC-1alpha and exercise in the control of body weight. Int J Obes (Lond) 2012, 36(11):1428-1435.
25. Summermatter S., et al. PGC-1alpha Improves glucose homeostasis in skeletal muscle in an activity-dependent manner. Diabetes 2013, 62(1):85-95.
26. Lopez A.D., et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006, 367(9524):1747-1757.
27. Booth F.W., Roberts C.K., Laye M.J. Lack of exercise is a major cause of chronic diseases. Compr Physiol 2012, 2(2):1143-1211.
28. Tuomilehto J., et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001, 344(18):1343-1350.
29. Nocon M., et al. Association of physical activity with all-cause and cardiovascular mortality: a systematic review and meta-analysis. European Journal of Cardiovascular Prevention and Rehabilitation: Official Journal of the European Society of Cardiology 2008, 15:239-246. 3.
30. Manson J.E., et al. The escalating pandemics of obesity and sedentary lifestyle. A call to action for clinicians. Arch Intern Med 2004, 164(3):249-258.
31. Jebb S.A., Moore M.S. Contribution of a sedentary lifestyle and inactivity to the etiology of overweight and obesity: current evidence and research issues. Med Sci Sports Exerc 1999, 31(11 Suppl):S534-S541.
32. Monninkhof E.M., et al. Physical activity and breast cancer: a systematic review. Epidemiology 2007, 18(1):137-157.
33. Rovio S., et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 2005, 4(11):705-711.
34. Paffenbarger R.S., Lee I.M., Leung R. Physical activity and personal characteristics associated with depression and suicide in American college men. Acta Psychiatr Scand Suppl 1994, 377:16-22.
35. Booth F.W., et al. Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy. J Appl Physiol 2002, 93(1):3-30.
36. Handschin C., Spiegelman B.M. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature 2008, 454(7203):463-469.
37. Hotamisligil G.S., Spiegelman B.M. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 1994, 43(11):1271-1278.
38. Hotamisligil G.S., Shargill N.S., Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993, 259(5091):87-91.
39. McNelis J.C., Olefsky J.M. Macrophages, immunity, and metabolic disease. Immunity 2014, 41(1):36-48.
40. Esser N., et al. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 2014, 105(2):141-150.
41. Handschin C. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha in muscle links metabolism to inflammation. Clin Exp Pharmacol Physiol 2009, 36(12):1139-1143.
42. Eisele P.S., et al. The peroxisome proliferator-activated receptor gamma coactivator 1alpha/beta (PGC-1) coactivators repress the transcriptional activity of NF-kappaB in skeletal muscle cells. J Biol Chem 2013, 288(4):2246-2260.
43. Holloszy J.O., et al. Effect of voluntary exercise on longevity of rats. J Appl Physiol 1985, 59(3):826-831.
44. Navarro A., et al. Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol Regul Integr Comp Physiol 2004, 286(3):R505-R511.
45. Richter E.A., et al. Metabolic responses to exercise. Effects of endurance training and implications for diabetes. Diabetes Care 1992, 15(11):1767-1776.
46. Bhaskarabhatla K.V., Birrer R. Physical activity and diabetes mellitus. Compr Ther 2005, 31(4):291-298.
47. Stone N.J. Successful control of dyslipidemia in patients with metabolic syndrome: focus on lifestyle changes. Clin Cornerstone 2006, 8(Suppl. 1):S15-S20.
48. Kokkinos P.F., Narayan P., Papademetriou V. Exercise as hypertension therapy. Cardiol Clin 2001, 19(3):507-516.
49. Brechue W.F., Pollock M.L. Exercise training for coronary artery disease in the elderly. Clin Geriatr Med 1996, 12(1):207-229.
50. Radak Z., et al. Adaptation to exercise-induced oxidative stress: from muscle to brain. Exerc Immunol Rev 2001, 7:90-107.
51. Colcombe S.J., et al. Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci 2003, 58(2):176-180.
52. Booth F.W., Laye M.J. Lack of adequate appreciation of physical exercise's complexities can pre-empt appropriate design and interpretation in scientific discovery. J Physiol 2009, 587(Pt 23):5527-5539.
53. Gleeson M., Nieman D.C., Pedersen B.K. Exercise, nutrition and immune function. J Sports Sci 2004, 22(1):115-125.
54. Nieman D.C. Current perspective on exercise immunology. Curr Sports Med Rep 2003, 2(5):239-242.
55. Gleeson M., McFarlin B., Flynn M. Exercise and Toll-like receptors. Exerc Immunol Rev 2006, 12:34-53.
56. Gleeson M. Immune function in sport and exercise. J Appl Physiol 2007, 103(2):693-699.
57. Pedersen B.K., Febbraio M.A. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008, 88(4):1379-1406.
58. McPherron A.C., Lawler A.M., Lee S.J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997, 387(6628):83-90.
59. Kambadur R., et al. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res 1997, 7(9):910-916.
60. Grobet L., et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet 1997, 17(1):71-74.
61. McPherron A.C., Lee S.J. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci U S A 1997, 94(23):12457-12461.
62. Mosher D.S., et al. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet 2007, 3(5):e79.
63. Schuelke M., et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004, 350(26):2682-2688.
64. McPherron A.C., Lee S.J. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 2002, 109(5):595-601.
65. Lin J., et al. Myostatin knockout in mice increases myogenesis and decreases adipogenesis. Biochem Biophys Res Commun 2002, 291(3):701-706.
66. Kim H.S., et al. Inhibition of preadipocyte differentiation by myostatin treatment in 3T3-L1 cultures. Biochem Biophys Res Commun 2001, 281(4):902-906.
67. Stolz L.E., et al. Administration of myostatin does not alter fat mass in adult mice. Diabetes Obes Metab 2008, 10(2):135-142.
68. Artaza J.N., et al. Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells. Endocrinology 2005, 146(8):3547-3557.
69. Feldman B.J., et al. Myostatin modulates adipogenesis to generate adipocytes with favorable metabolic effects. Proc Natl Acad Sci U S A 2006, 103(42):15675-15680.
70. Matsakas A., et al. Short-term endurance training results in a muscle-specific decrease of myostatin mRNA content in the rat. Acta Physiol Scand 2005, 183(3):299-307.
71. Kopple J.D., et al. Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients. J Ren Nutr Off J Counc Ren Nutr Nat Kidney Found 2006, 16(4):312-324.
72. Konopka A.R., et al. Molecular adaptations to aerobic exercise training in skeletal muscle of older women. J Gerontol A Biol Sci Med Sci 2010, 65(11):1201-1207.
73. Hittel D.S., et al. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc 2010, 42(11):2023-2029.
74. Ruas J.L., et al. A PGC-1alpha isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 2012, 151(6):1319-1331.
75. Laurentino G.C., et al. Strength training with blood flow restriction diminishes myostatin gene expression. Med Sci Sports Exerc 2012, 44(3):406-412.
76. Louis E., et al. Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle. J Appl Physiol 2007, 103(5):1744-1751.
77. Roth S.M., et al. Myostatin gene expression is reduced in humans with heavy-resistance strength training: a brief communication. Exp Biol Med 2003, 228(6):706-709.
78. Mascher H., et al. Repeated resistance exercise training induces different changes in mRNA expression of MAFbx and MuRF-1 in human skeletal muscle. Am J Physiol Endocrinol Metab 2008, 294(1):E43-E51.
79. Saremi A., et al. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol 2010, 317(1-2):25-30.
80. Kanzleiter T., et al. The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem Biophys Res Commun 2014, 450(2):1089-1094.
81. Fearon K.C., Glass D.J., Guttridge D.C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 2012, 16(2):153-166.
82. Kristiansen O.P., Mandrup-Poulsen T. Interleukin-6 and diabetes: the good, the bad, or the indifferent?. Diabetes 2005, 54(Suppl. 2):S114-S124.
83. Franckhauser S., et al. Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 2008, 51(7):1306-1316.
84. Ostrowski K., Schjerling P., Pedersen B.K. Physical activity and plasma interleukin-6 in humans-effect of intensity of exercise. Eur J Appl Physiol 2000, 83(6):512-515.
85. Ostrowski K., et al. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. J Physiol 1999, 515(Pt 1):287-291.
86. Akira S., Taga T., Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol 1993, 54:1-78.
87. Ostrowski K., et al. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. J Physiol 1998, 508(Pt 3):949-953.
88. Jonsdottir I.H., et al. Muscle contractions induce interleukin-6 mRNA production in rat skeletal muscles. J Physiol 2000, 528(Pt 1):157-163.
89. Steensberg A., et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol 2000, 529(Pt 1):237-242.
90. Pedersen B.K. Muscles and their myokines. J Exp Biol 2011, 214(Pt 2):337-346.
91. Febbraio M.A., Pedersen B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J Off Publ Fed Am Soc Exp Biol 2002, 16(11):1335-1347.
92. Steensberg A., et al. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol 2001, 537(Pt 2):633-639.
93. Keller C., et al. Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content. FASEB J Off Publ Fed Am Soc Exp Biol 2001, 15(14):2748-2750.
94. Croisier J.L., et al. Effects of training on exercise-induced muscle damage and interleukin 6 production. Muscle Nerve 1999, 22(2):208-212.
95. Pedersen B.K., et al. Role of myokines in exercise and metabolism. J Appl Physiol 2007, 103(3):1093-1098.
96. Carey A.L., et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 2006, 55(10):2688-2697.
97. Bruce C.R., Dyck D.J. Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-alpha. Am J Physiol Endocrinol Metab 2004, 287(4):E616-E621.
98. Kelly M., et al. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun 2004, 320(2):449-454.
99. Gleeson M. Interleukins and exercise. J Physiol 2000, 529(Pt 1):1.
100. Ellingsgaard H., et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 2011, 17(11):1481-1489.
101. Wueest S., et al. Interleukin-6 contributes to early fasting-induced free fatty acid mobilization in mice. Am J Physiol Regul Integr Comp Physiol 2014, 306(11):R861-R867.
102. Baggiolini M., Clark-Lewis I. Interleukin-8, a chemotactic and inflammatory cytokine. FEBS Lett 1992, 307(1):97-101.
103. Bek E.L., et al. The effect of diabetes on endothelin, interleukin-8 and vascular endothelial growth factor-mediated angiogenesis in rats. Clin Sci 2002, 103(Suppl. 48):424S-429S.
104. Koch A.E., et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 1992, 258(5089):1798-1801.
105. Norrby K. Interleukin-8 and de novo mammalian angiogenesis. Cell Prolif 1996, 29(6):315-323.
106. Nieman D.C., et al. Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plasma cytokine levels after a 3-h run. J Appl Physiol 2003, 94(5):1917-1925.
107. Akerstrom T., et al. Exercise induces interleukin-8 expression in human skeletal muscle. J Physiol 2005, 563(Pt 2):507-516.
108. Chan M.H., et al. 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 2004, 287(2):R322-R327.
109. Nieman D.C., et al. Influence of vitamin C supplementation on oxidative and immune changes after an ultramarathon. J Appl Physiol 2002, 92(5):1970-1977.
110. Nieman D.C., et al. Cytokine changes after a marathon race. J Appl Physiol 2001, 91(1):109-114.
111. Ostrowski K., et al. Chemokines are elevated in plasma after strenuous exercise in humans. Eur J Appl Physiol 2001, 84(3):244-245.
112. Suzuki K., et al. Impact of a competitive marathon race on systemic cytokine and neutrophil responses. Med Sci Sports Exerc 2003, 35(2):348-355.
113. Henson D.A., et al. Influence of carbohydrate on cytokine and phagocytic responses to 2h of rowing. Med Sci Sports Exerc 2000, 32(8):1384-1389.
114. Frydelund-Larsen L., et al. Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle. Exp Physiol 2007, 92(1):233-240.
115. Giri J.G., et al. IL-15, a novel T cell growth factor that shares activities and receptor components with IL-2. J Leukoc Biol 1995, 57(5):763-766.
116. Grabstein K.H., et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science 1994, 264(5161):965-968.
117. Bassuk S.S., Manson J.E. Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease. J Appl Physiol 2005, 99(3):1193-1204.
118. Giri J.G., et al. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J 1995, 14(15):3654-3663.
119. Nielsen A.R., et al. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J Physiol 2007, 584(Pt 1):305-312.
120. Quinn L.S., Haugk K.L., Grabstein K.H. Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology 1995, 136(8):3669-3672.
121. Quinn L.S., et al. Overexpression of interleukin-15 induces skeletal muscle hypertrophy in vitro: implications for treatment of muscle wasting disorders. Exp Cell Res 2002, 280(1):55-63.
122. Carbo N., et al. Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats. Br J Cancer 2000, 83(4):526-531.
123. Pistilli E.E., Quinn L.S. From anabolic to oxidative: reconsidering the roles of IL-15 and IL-15Ralpha in skeletal muscle. Exerc Sport Sci Rev 2013, 41(2):100-106.
124. Pistilli E.E., et al. Loss of IL-15 receptor alpha alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles. J Clin Invest 2011, 121(8):3120-3132.
125. Busquets S., et al. Interleukin-15 increases glucose uptake in skeletal muscle. An antidiabetogenic effect of the cytokine. Biochim Biophys Acta 2006, 1760(11):1613-1617.
126. Almendro V., et al. Effects of interleukin-15 on lipid oxidation: disposal of an oral [(14)C]-triolein load. Biochim Biophys Acta 2006, 1761(1):37-42.
127. Rinnov A., et al. Endurance training enhances skeletal muscle interleukin-15 in human male subjects. Endocrine 2014, 45(2):271-278.
128. Nielsen A.R., et al. Association between interleukin-15 and obesity: interleukin-15 as a potential regulator of fat mass. J Clin Endocrinol Metab 2008, 93(11):4486-4493.
129. Lopez-Soriano J., et al. Rat liver lipogenesis is modulated by interleukin-15. Int J Mol Med 2004, 13(6):817-819.
130. Carbo N., et al. Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control. Biochim Biophys Acta 2001, 1526(1):17-24.
131. Almendro V., et al. Effects of IL-15 on rat brown adipose tissue: uncoupling proteins and PPARs. Obesity 2008, 16(2):285-289.
132. Huang E.J., Reichardt L.F. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24:677-736.
133. Matthews V.B., et al. 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 2009, 52(7):1409-1418.
134. Hofer M.M., Barde Y.A. Brain-derived neurotrophic factor prevents neuronal death in vivo. Nature 1988, 331(6153):261-262.
135. Mattson M.P., Maudsley S., Martin B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 2004, 27(10):589-594.
136. Wisse B.E., Schwartz M.W. The skinny on neurotrophins. Nat Neurosci 2003, 6(7):655-656.
137. Tyler W.J., et al. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 2002, 9(5):224-237.
138. Connor B., et al. Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Brain Res Mol Brain Res 1997, 49(1-2):71-81.
139. Karege F., et al. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 2002, 109(2):143-148.
140. Krabbe K.S., et al. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 2007, 50(2):431-438.
141. Matthews D.R., et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28(7):412-419.
142. Rasmussen P., et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol 2009, 94(10):1062-1069.
143. Miura P., et al. Brain-derived neurotrophic factor expression is repressed during myogenic differentiation by miR-206. J Neurochem 2012, 120(2):230-238.
144. Clow C., Jasmin B.J. Brain-derived neurotrophic factor regulates satellite cell differentiation and skeltal muscle regeneration. Mol Biol Cell 2010, 21(13):2182-2190.
145. Omura T., et al. Different expressions of BDNF, NT3, and NT4 in muscle and nerve after various types of peripheral nerve injuries. J Peripher Nerv Syst JPNS 2005, 10(3):293-300.
146. Ogborn D.I., Gardiner P.F. Effects of exercise and muscle type on BDNF, NT-4/5, and TrKB expression in skeletal muscle. Muscle Nerve 2010, 41(3):385-391.
147. McGregor N.E., et al. Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling. Calcif Tissue Int 2010, 86(3):261-270.
148. Johnson R.W., et al. Myokines (muscle-derived cytokines and chemokines) including ciliary neurotrophic factor (CNTF) inhibit osteoblast differentiation. Bone 2014, 64:47-56.
149. Tischer E., et al. Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem Biophys Res Commun 1989, 165(3):1198-1206.
150. Jensen L., Schjerling P., Hellsten Y. Regulation of VEGF and bFGF mRNA expression and other proliferative compounds in skeletal muscle cells. Angiogenesis 2004, 7(3):255-267.
151. Lloyd P.G., et al. Angiogenic growth factor expression in rat skeletal muscle in response to exercise training. Am J Physiol Heart Circ Physiol 2003, 284(5):H1668-H1678.
152. Jensen L., Bangsbo J., Hellsten Y. Effect of high intensity training on capillarization and presence of angiogenic factors in human skeletal muscle. J Physiol 2004, 557(Pt 2):571-582.
153. Jensen L., et al. Effect of acute exercise and exercise training on VEGF splice variants in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2004, 287(2):R397-R402.
154. Hoffner L., et al. Exercise but not prostanoids enhance levels of vascular endothelial growth factor and other proliferative agents in human skeletal muscle interstitium. J Physiol 2003, 550(Pt 1):217-225.
155. Arcondeguy T., et al. VEGF-A mRNA processing, stability and translation: a paradigm for intricate regulation of gene expression at the post-transcriptional level. Nucleic Acids Res 2013, 41(17):7997-8010.
156. Arany Z., et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature 2008, 451(7181):1008-1012.
157. Rowe G.C., et al. PGC-1alpha Induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circ Res 2014, 115(5):504-517.
158. Itoh N., Ornitz D.M. Evolution of the Fgf and Fgfr gene families. Trends Genet TIG 2004, 20(11):563-569.
159. Kharitonenkov A. FGFs and metabolism. Curr Opin Pharmacol 2009, 9(6):805-810.
160. Nishimura T., et al. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 2000, 1492(1):203-206.
161. Fon Tacer K., et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010, 24(10):2050-2064.
162. Badman M.K., et al. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007, 5(6):426-437.
163. Hondares E., et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011, 286(15):12983-12990.
164. Potthoff M.J., et al. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci U S A 2009, 106(26):10853-10858.
165. Kharitonenkov A., et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005, 115(6):1627-1635.
166. Hojman P., et al. Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia. Diabetes 2009, 58(12):2797-2801.
167. Lee P., et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014, 19(2):302-309.
168. Tyynismaa H., et al. Mitochondrial myopathy induces a starvation-like response. Hum Mol Genet 2010, 19(20):3948-3958.
169. Arnold A.S., Egger A., Handschin C. PGC-1alpha and myokines in the aging muscle - a mini-review. Gerontology 2011, 57(1):37-43.
170. Bostrom P., et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012, 481(7382):463-468.
171. Roberts L.D., et al. beta-Aminoisobutyric acid induces browning of white fat and hepatic beta-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab 2014, 19(1):96-108.
172. Rao R.R., et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 2014, 157(6):1279-1291.
173. Ferrer-Martinez A., Ruiz-Lozano P., Chien K.R. Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development. Dev Dyn 2002, 224(2):154-167.
174. Teufel A., et al. Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene 2002, 297(1-2):79-83.
175. Wrann C.D., et al. Exercise induces hippocampal BDNF through a PGC-1alpha/FNDC5 pathway. Cell Metab 2013, 18(5):649-659.
176. Vaughan R.A., et al. Characterization of the metabolic effects of irisin on skeletal muscle in vitro. Diabetes Obes Metab 2014, 16(8):711-718.
177. Elsen M., Raschke S., Eckel J. Browning of white fat: does irisin play a role in humans?. J Endocrinol 2014, 222(1):R25-R38.
178. Ivanov I.P., et al. Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences. Nucleic Acids Res 2011, 39(10):4220-4234.
179. Starck S.R., et al. Leucine-tRNA initiates at CUG start codons for protein synthesis and presentation by MHC class I. Science 2012, 336(6089):1719-1723.
180. Nedergaard J., Cannon B. The browning of white adipose tissue: some burning issues. Cell Metab 2014, 20(3):396-407.
181. Virtanen K.A. BAT thermogenesis: linking shivering to exercise. Cell Metab 2014, 19(3):352-354.
182. Booth F.W., et al. Waging war on modern chronic diseases: primary prevention through exercise biology. J Appl Physiol 2000, 88(2):774-787.
183. American Institute for Cancer Research. and World Cancer Research Fund. Food, nutrition, physical activity and the prevention of cancer: a global perspective: a project of World Cancer Research Fund International 2007, xxv. American Institute for Cancer Research, Washington, D.C, [517pp.].
184. Aoi W., et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 2013, 62(6):882-889.
185. Hojman P., et al. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab 2011, 301(3):E504-E510.
186. Catoire M., Kersten S. The search for exercise factors in humans. FASEB J 2015, [in press].
187. Hawley J.A., et al. Integrative biology of exercise. Cell 2014, 159(4):738-749.
188. Scheler M., et al. Cytokine response of primary human myotubes in an in vitro exercise model. Am J Physiol Cell Physiol 2013, 305(8):C877-C886.
189. Raschke S., et al. Identification and validation of novel contraction-regulated myokines released from primary human skeletal muscle cells. PLoS One 2013, 8(4):e62008.
190. Hartwig S., et al. Secretome profiling of primary human skeletal muscle cells. Biochim Biophys Acta 2014, 1844(5):1011-1017.
191. Agudelo L.Z., et al. Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 2014, 159(1):33-45.