MINERVA ENDOCRINOLOGICA EDIZIONI MINERVA MEDICA This provisional PDF corresponds to the article as it appeared upon acceptance A copyedited and fully formatted version will be made available soon The final version may contain major or minor changes Role of myokines in the maintenance of whole-body metabolic homeostasis Tatiana Y KOSTROMINOVA Minerva Endocrinol 2016 Mar 22 [Epub ahead of print] MINERVA ENDOCRINOLOGICA Rivista sulle Malattie del Sistema Endocrino pISSN 0391-1977 - eISSN 1827-1634 Article type: Review Article The online version of this article is located at http://www.minervamedica.it Subscription: Information about subscribing to Minerva Medica journals is online at: http://www.minervamedica.it/en/how-to-order-journals.php Reprints and permissions: For information about reprints and permissions send an email to: journals.dept@minervamedica.it - journals2.dept@minervamedica.it - journals6.dept@minervamedica.it COPYRIGHT© 2016 EDIZIONI MINERVA MEDICA Role of myokines in the maintenance of whole-body metabolic homeostasis Tatiana Y Kostrominova Department of Anatomy and Cell Biology, Indiana University School of Medicine-Northwest, Gary, IN, USA Corresponding author: Tatiana Y Kostrominova Department of Anatomy and Cell Biology, Indiana University School of MedicineNorthwest, Gary, IN, USA E-mail: tkostrom@iun.edu This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no ABSTRACT Obesity is reaching epidemic proportions in developed countries and is on the rise in developing countries Obesity-related changes in lipid and glucose metabolism predispose to the development of metabolic syndrome and type diabetes Skeletal muscle constitutes about 40 percent of total body weight and is unique compared to other muscle types since it is one of the most important organs for insulin-dependent glucose metabolism in humans Abnormalities in skeletal muscle lipid and glucose metabolism as well as abnormal accumulation of intramyocellular lipids could predispose for the development of type diabetes Skeletal muscle synthesizes and secretes factors with autocrine/paracrine/endocrine functions that can regulate skeletal muscle metabolism as well as affect other organs These factors secreted by skeletal muscle are called myokines Secretion and action of myokines is regulated by physiological conditions Some myokines have positive effect on metabolism, improving functions of multiple organs Yet, other myokines are released under pathological conditions and might exacerbate abnormal metabolic functions Expression and/or secretion of a number of myokines are regulated by exercise and therefore might mediate positive effects of physical activity on whole-body metabolism In the current review we summarized current knowledge on some of the myokines with important physiological functions in lipid and glucose metabolism A better understanding of the effects of myokines on whole-body metabolism can aid in development of the future pharmacologic therapies for counteracting the current worldwide obesity epidemic and obesity-mediated abnormalities This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no Key words: skeletal muscle, myokines, obesity, metabolism This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no TEXT Introduction Obesity has reached epidemic proportions worldwide and the rate of obesity continues to increase According to the World Health Organization, in 2014 about 39% (1.9 billion) of adults worldwide were overweight and 13% (over 600 million) were obese The World Obesity Federation estimates that if current trends continue, around billion adults worldwide will be overweight by the 2025 In order to combat the increasing rate of obesity it is essential to understand molecular mechanisms and factors that mediate the development of obesity-induced abnormalities Due to the extensive studies performed in the last two decades the critical role of factors secreted by adipose tissue (adipokines) in regulation of the whole-body lipid and glucose metabolism is now well established There are more than 600 factors secreted by adipocytes and circulating in the blood that could have autocrine/paracrine/endocrine functions [1] Some adipokines have beneficial effects on metabolism and improve insulin sensitivity, as well as lipid and glucose metabolism (adiponectin, vaspin, FGF21) Their secretion usually is decreased by obesity Other adpokines have negative effect on metabolism, promoting insulin resistance and dyslipidemia (resistin, visfatin, RBP4) and their secretion is increased by obesity Current medical textbooks describe adipose tissue as an adipokine-secreting endocrine organ, with a well-established role in whole-body metabolism Adipokines circulating in the blood can affect the function of many organs, including skeletal muscle A number of previous and current This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no studies are focused on using adipokines for the development of the treatment for obesity-induced abnormalities in humans Currently it is much less appreciated that skeletal muscle also can secrete many of the same factors with autocrine/paracrine/endocrine functions that are secreted by adipocytes, as well as some muscle-specific factors These factors secreted by skeletal muscle are called myokines This term, derived from Greek words for “muscle” and “motion” was proposed to describe factors with endocrine function that are produced and secreted by skeletal muscle cells [2] Skeletal muscle is the second largest organ of the human body It is the largest target organ for insulinstimulated glucose utilization Therefore, abnormalities in skeletal muscle glucose and lipid metabolism can lead to pronounced whole-body metabolic abnormalities Skeletal muscle-secreted myokines can regulate metabolism by endocrine mechanism acting on distant organs such as liver and adipose tissue (Figure 1) Myokines are also capable of regulating muscle functions by an autocrine mechanism as well as function of the located nearby tendon and bone tissues by a paracrine mechanism (Figure 1) A number of myokines have already been identified For many of myokines we have only limited knowledge We know that they potentially can be myokines but their functions are not yet studied Analysis of the secretory profile of human skeletal muscle cells has identified 305 proteins as potential myokines [3] Expression of some of these myokines is regulated by exercise Fifteen out of the 236 proteins first identified in cultured skeletal muscle cells were later shown to be significantly up-regulated in human skeletal muscle in vivo in response to strength training [4] This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no A number of myokines have been previously described in detail (FGF21, adiponectin, LIF, IL-6, CTRPs, irisin, apelin, lipocalins, etc.) although the mechanism regulating their secretion by skeletal muscle and their effect on other organs and whole-body metabolism are not yet completely elucidated Multiple studies suggest that myokine secretion is regulated by diverse physiological changes including obesity, cancer cachexia, insulin resistance and exercise Unlike adipokines, myokines are not yet mentioned in medical textbooks and are not discussed in medical school curricula As a result, the role of myokines as regulators of the whole-body lipid and glucose metabolism is currently underappreciated in the medical community A better understanding of the mechanisms by which myokines can affect obesity-induced abnormalities will help to develop future therapies In this review we will focus on selected myokines that, in our opinion, play crucial roles in whole-body lipid and glucose metabolism and have a potential to be used in the future as diagnostic or therapeutic tools to diminish obesity-induced abnormalities and prevent type diabetes Myostatin, also known as GDF-8, is a member of TGF beta family and is one of the first described myokines [5] Binding of myostatin to the activin receptor type IIB promotes skeletal muscle atrophy in many physiological conditions, including denervation and fasting Myostatin also inhibits activation of skeletal muscle-specific stem cells, satellite cells, in response to injury and slows down muscle differentiation [6] Myostatin mediates skeletal muscle atrophy through activation of the forkhead box O transcription factors (FoxO) leading to increased expression of muscle- This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1) E3 ligases target muscle myofibrillar and intracellular proteins for degradation through the ubiquitin–proteasome system Myostatin also increases skeletal muscle oxidative stress via NF-κB- and NADPH-mediated signaling cascades [7] Myostatin-null mice have significantly increased lean skeletal muscle mass when compared with wild type littermates [5] Increased muscle mass results from both hypertrophy (increase in muscle fiber size) and hyperplasia (proliferation of muscle stem cells to increase the number of muscle fibers) [5] Myostatin-null mice also are protected from dietinduced obesity, they have enhanced peripheral tissue fatty acid oxidation and increased thermogenesis [8] Myostatin-induced catabolic processes mediate skeletal muscle atrophy in cancer cachexia [9] Myostatin expression can be regulated by endocrine hormones In rats hypothyroidism is associated with increased myostatin mRNA expression [10] It is currently unclear whether hypothyroidism in humans is also associated with increased myostatin levels in skeletal muscle The endocrine function of myostatin could be mediated by its effects on adipose tissue Myostatin treatment has been shown to increase proliferation of adipocytes and inhibit their differentiation [11] Myostatin treatment also influenced the expression and secretion of adiponectin, resistin, and visfatin by adipocytes [11] Brain-derived neurotrophic factor (BDNF) is a myokine that affects myogenesis and skeletal muscle regeneration [12] The expression of BDNF is high in myoblasts but it is decreased in differentiated myotubes [13] BDNF effects are This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no mediated by binding to specific cell surface receptors Human myocytes express p75NTR and not TrkB BDNF receptors [14] BDNF is expressed at different levels in fast and slow muscle fibers Mostly slow rat soleus muscle has 2-fold higher levels of BDNF expression than mostly fast gastrocnemius muscle [15] BDNF has beneficial effects on nerve growth and regeneration via paracrine mechanism [16] Following denervation skeletal muscle increases BDNF expression and retrograde transport of BDNF to spinal cord [16] BDNF also affects whole-body metabolism via autocrine and endocrine mechanisms Systemic treatment of mice with BDNF reduces total food intake and inhibits weight gain [17] These effects are mediated by increased GLUT4 expression in skeletal muscle [17] In obese diabetic mice BDNF treatment enhances glucose utilization in skeletal muscle and brown adipose tissue [18] Insulin-like growth factor (IGF-1) is released by skeletal muscle and affects skeletal muscle growth Mutant mice with reduced IGF-1 content in muscle are ~30% smaller, have reduced levels of circulating IGF-1, have smaller muscles and decreased bone mineral density [19] Growth defects are diminished by administration of recombinant IGF-1 [19] IGF-1 regulates whole-body metabolism Skeletal muscle-specific inactivation of IFG-1 receptors leads to the development of insulin resistance [20] High fat diet-induced obesity in mice reduces expression of IGF-1 in intact muscles and diminishes up-regulation of IGF-1 in response to muscle injury [21] This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no Fibroblast Growth Factor (FGF-2), also known as basic FGF, is a myokine that has pleiotropic effects in a range of cell types During myogenic differentiation expression of FGFs and FGF receptors are downregulated [22] FGF-2 secreted by muscle cells may act as a paracrine and autocrine regulator of skeletal muscle development in vivo [23] During ischemia, increased expression of FGF-2 in skeletal muscle promotes angiogenesis via its paracrine effects on blood vessels [24] Treatment with FGF-2 stimulates proliferation of tendon cells [25] suggesting that skeletal muscle released FGF-2 may have paracrine effects on tendon FGF-2 also plays an important role in bone formation and remodeling Mechanical wounding of muscle cells increases release of FGF-2 into media [26] and may have paracrine effect on tendon and bone Fibroblast growth factor 21 (FGF21) is a well described adipocytokine/ hepatokine/ myokine with glucose and lipid-lowering properties The liver is considered the major source of the plasma FGF21 Under normal physiological conditions the level of hepatic FGF21 expression is low but it increases during prolonged fasting, liver injury, exposure to toxic chemicals and viral infections [27] In mice chronic infusion of FGF21 improves insulin responsiveness due to the reduced diacylglycerol content and reduced protein kinase C activation in skeletal muscle [28] In human clinical trials FGF21 treatment of obese type diabetic patients improved total body weight, dyslipidemia, insulin sensitivity and adiponectin levels [29] [27] FGF21 works through the FGF receptors (FGFR1 and FGFR2) and requires transmembrane protein beta-Klotho (KLB) as a co-receptor for activation of This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 13 Miura P, Amirouche A, Clow C, Belanger G, Jasmin BJ (2012) Brain-derived neurotrophic factor expression is repressed during myogenic differentiation by miR-206 J Neurochem 120: 230-238 14 Colombo E, Bedogni F, Lorenzetti I, Landsberger N, Previtali SC, et al (2013) Autocrine and immune cell-derived BDNF in human skeletal muscle: implications for myogenesis and tissue regeneration J Pathol 231: 190-198 15 Ogborn DI, Gardiner PF (2010) Effects of exercise and muscle type on BDNF, NT-4/5, and TrKB expression in skeletal muscle Muscle Nerve 41: 385-391 16 Gao L, Li LH, Xing RX, Ou S, Liu GD, et al (2012) Gastrocnemius-derived BDNF promotes motor function recovery in spinal cord transected rats Growth Factors 30: 167-175 17 Suwa M, Yamamoto KI, Nakano H, Sasaki H, Radak Z, et al (2010) Brainderived neurotrophic factor treatment increases the skeletal muscle glucose transporter protein expression in mice Physiol Res 59: 619-623 18 Yamanaka M, Tsuchida A, Nakagawa T, Nonomura T, Ono-Kishino M, et al (2007) Brain-derived neurotrophic factor enhances glucose utilization in peripheral tissues of diabetic mice Diabetes Obes Metab 9: 59-64 19 Barton ER, Park S, James JK, Makarewich CA, Philippou A, et al (2012) Deletion of muscle GRP94 impairs both muscle and body growth by inhibiting local IGF production FASEB J 26: 3691-3702 20 Fernandez AM, Kim JK, Yakar S, Dupont J, Hernandez-Sanchez C, et al (2001) Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type diabetes Genes Dev 15: 1926-1934 21 Brown LA, Lee DE, Patton JF, Perry RA, Jr., Brown JL, et al (2015) Dietinduced obesity alters anabolic signalling in mice at the onset of skeletal muscle regeneration Acta Physiol (Oxf) 215: 46-57 22 Moore JW, Dionne C, Jaye M, Swain JL (1991) The mRNAs encoding acidic FGF, basic FGF and FGF receptor are coordinately downregulated during myogenic differentiation Development 111: 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electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 35 fibroblast-like cells from human rotator cuff tendon Tohoku J Exp Med 198: 207-214 26 Hamrick MW, McNeil PL, Patterson SL (2010) Role of muscle-derived growth factors in bone formation J Musculoskelet Neuronal Interact 10: 64-70 27 Kharitonenkov A, Adams AC (2014) Inventing new medicines: The FGF21 story Mol Metab 3: 221-229 28 Camporez JP, Jornayvaz FR, Petersen MC, Pesta D, Guigni BA, et al (2013) Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice Endocrinology 154: 3099-3109 29 Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, et al (2013) The effects of LY2405319, an FGF21 analog, in 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article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 36 38 Tsai S, Sitzmann JM, Dastidar SG, Rodriguez AA, Vu SL, et al (2015) Musclespecific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity J Clin Invest 125: 2952-2964 39 Crooks DR, Natarajan TG, Jeong SY, Chen C, Park SY, et al (2014) Elevated FGF21 secretion, PGC-1alpha and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle Hum Mol Genet 23: 24-39 40 Lee MS, Choi SE, Ha ES, An SY, Kim TH, et al (2012) Fibroblast growth factor21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and NF-kappaB 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or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 37 49 Di Chiara T, Licata A, Argano C, Duro G, Corrao S, et al (2013) Plasma adiponectin: A contributing factor for cardiac changes in visceral obesityassociated hypertension Blood Press 50 Ji ZY, Li HF, Lei Y, Rao YW, Tan ZX, et al (2015) Association of adiponectin gene polymorphisms with an elevated risk of diabetic peripheral neuropathy in type diabetes patients J Diabetes Complications 29: 887-892 51 Hou M, Chu Z, Liu T, Lv H, Sun L, et al (2015) A high-fat maternal diet decreases adiponectin 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one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 38 62 Kim KY, Kim HY, Kim JH, Lee CH, Kim DH, et al (2006) Tumor necrosis factoralpha and interleukin-1beta increases CTRP1 expression in adipose tissue FEBS Lett 580: 3953-3960 63 Han S, Park JS, Lee S, Jeong AL, Oh KS, et al (2015) CTRP1 protects against diet-induced hyperglycemia by enhancing glycolysis and fatty acid oxidation J Nutr Biochem 64 Maeda T, Abe M, Kurisu K, Jikko A, Furukawa S (2001) 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copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 39 73 Enomoto T, Ohashi K, Shibata R, Kambara T, Uemura Y, et al (2013) Transcriptional regulation of an insulin-sensitizing adipokine adipolin/CTRP12 in adipocytes by Kruppel-like factor 15 PLoS One 8: e83183 74 Fathi R, Ghanbari-Niaki A, Kraemer RR, Talebi-Garakani E, 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Physiol (1985) 81: 355-361 This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 45 144 Cho JK, Kim S, Hong HR, Yoon JH, Kang H (2015) Exercise Training Improves Whole Body Insulin Resistance via Adiponectin Receptor Int J Sports Med 145 Covington JD, Tam CS, Bajpeyi S, Galgani JE, Noland RC, et al (2015) Myokine Expression in Muscle and Myotubes in Response to Exercise Stimulation Med Sci Sports Exerc 146 Broholm C, Mortensen OH, Nielsen S, Akerstrom T, Zankari A, et al (2008) Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle J Physiol 586: 2195-2201 147 Alfieri A, Martone D, Randers MB, Labruna G, Mancini A, et al (2015) Effects of long-term football training on the expression profile of genes involved in muscle oxidative metabolism Mol Cell Probes 29: 43-47 148 Loffler D, Muller U, Scheuermann K, Friebe D, Gesing J, et al (2015) Serum irisin levels are regulated by acute strenuous exercise J Clin Endocrinol Metab 100: 1289-1299 149 Tsuchiya Y, Ando D, Takamatsu K, Goto K (2015) Resistance exercise induces a greater irisin response than endurance exercise Metabolism 64: 10421050 Acknowledgements: The author is grateful to Dr Stephen Echtenkamp for the helpful discussions and advice during preparation of this manuscript This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 46 Funding: This work was supported by the funds from the IUSM-NW Conflicts of interest: None This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 47 TITLES OF FIGURES Figure Skeletal muscle-secreted myokines can work via autocrine, paracrine, and endocrine mechanisms Abbreviations: BDNF, brain-derived neurotrophic factor; IGF-1, insulin-like growth factor 1; FGF-2, fibroblast growth factor 2; FGF21, fibroblast growth factor 21; CTRP, C1q/TNF-related proteins; LCN13, lipocalin 13; IL-6, interleukin 6; LIF, leukemia inhibitory factor; CNTF, ciliary neurotrophic factor; CT-1, cardiotrophin-1 This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no 48 This document is protected by international copyright laws No additional reproduction is authorized It is permitted for personal use to download and save only one file and print only one copy of this Article It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article The use of all or an part of the Article for any Commercial Use is not permitted The creation of derivative works from the Article is not permitted The production of reprints for personal or commercial use is no