The ever-expanding myokinome: discovery challenges and therapeutic implications (original) (raw)

• Pedersen, B. K. & Febbraio, M. A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457–465 (2012).
  CAS PubMed Google Scholar
• Booth, F. W., Roberts, C. K. & Laye, M. J. Lack of exercise is a major cause of chronic diseases. Comp. Physiol. 2, 1143–1211 (2012).
  Google Scholar
• Hawley, J. A., Hargreaves, M., Joyner, M. J. & Zierath, J. R. Integrative biology of exercise. Cell 159, 738–749 (2014).
  CAS PubMed Google Scholar
• Starkie, R., Ostrowski, S., Jauffred, S., Febbraio, M. & Pedersen, B. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-α production in humans. FASEB J. 17, 884–886 (2003).
  CAS PubMed Google Scholar
• Walhin, J.-P., Richardson, J., Betts, J. & Thompson, D. Exercise counteracts the effects of short-term overfeeding and reduced physical activity independent of energy imbalance in healthy young men. J. Physiol. 591, 6231–6243 (2013).
  CAS PubMed PubMed Central Google Scholar
• Hagobian, T. A. & Braun, B. Interactions between energy surplus and short-term exercise on glucose and insulin responses in healthy people with induced, mild insulin insensitivity. Metabolism 55, 402–408 (2006).
  CAS PubMed Google Scholar
• Goldstein, M. S. Humoral nature of the hypoglycemic factor of muscular work. Diabetes 10, 232–234 (1961). The first paper to propose that skeletal muscle might secrete 'exercise factors'.
  CAS PubMed Google Scholar
• Febbraio, M. A., Hiscock, N., Sacchetti, M., Fischer, C. P. & Pedersen, B. K. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53, 1643–1648 (2004). A significant finding in the identification of IL-6 as a secreted product of skeletal muscle that carries out endocrine functions.
  CAS PubMed Google Scholar
• Pedersen, B. K. & Febbraio, M. A. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88, 1379–1406 (2008).
  CAS PubMed Google Scholar
• Febbraio, M. A. & Pedersen, B. K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J. 16, 1335–1347 (2002).
  CAS PubMed Google Scholar
• Pal, M., Febbraio, M. A. & Whitham, M. From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol. Cell Biol. 92, 331–339 (2014).
  CAS PubMed Google Scholar
• Benatti, F. B. & Pedersen, B. K. Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation. Nat. Rev. Rheumatol. 11, 86–97 (2015).
  CAS PubMed Google Scholar
• Görgens, S. W., Eckardt, K., Jensen, J., Drevon, C. A. & Eckel, J. Exercise and regulation of adipokine and myokine production. Prog. Mol. Biol. Transl. Sci. 135, 313–336 (2015).
  PubMed Google Scholar
• Schnyder, S. & Handschin, C. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone 80, 115–125 (2015).
  CAS PubMed PubMed Central Google Scholar
• Uhlen, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
  PubMed Google Scholar
• Catoire, M., Mensink, M., Kalkhoven, E., Schrauwen, P. & Kersten, S. Identification of human exercise-induced myokines using secretome analysis. Physiol. Genom. 46, 256–267 (2014).
  CAS Google Scholar
• Geiger, T. et al. Initial quantitative proteomic map of twenty-eight mouse tissues using the SILAC mouse. Mol. Cell. Proteom. 12, 1709–1722 (2013).
  CAS Google Scholar
• Su, A. I. et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc. Natl Acad. Sci. USA 101, 6062–6067 (2004).
  CAS PubMed PubMed Central Google Scholar
• Azimifar, S. B., Nagaraj, N., Cox, J. & Mann, M. Cell-type-resolved quantitative proteomics of murine liver. Cell. Metab. 20, 1076–1087 (2014).
  CAS PubMed Google Scholar
• Williams, E. G. et al. Systems proteomics of liver mitochondria function. Science 352, aad0189 (2016).
  PubMed Google Scholar
• Kawamoto, S., Matsumoto, Y., Mizuno, K., Okubo, K. & Matsubara, K. Expression profiles of active genes in human and mouse livers. Gene 174, 151–158 (1996).
  CAS PubMed Google Scholar
• Steen, H. & Mann, M. The ABC's (and XYZ's) of peptide sequencing. Nat. Rev. Mol. Cell. Biol. 5, 699–711 (2004).
  CAS PubMed Google Scholar
• Matthiesen, R. & Bunkenborg, J. Introduction to mass spectrometry-based proteomics. Methods Mol. Biol. 1007, 1–45 (2013).
  CAS PubMed Google Scholar
• Hartwig, S. et al. Secretome profiling of primary human skeletal muscle cells. Biochim. Biophys. Acta 1844, 1011–1017 (2014).
  CAS PubMed Google Scholar
• Henningsen, J., Rigbolt, K. T., Blagoev, B., Pedersen, B. K. & Kratchmarova, I. Dynamics of the skeletal muscle secretome during myoblast differentiation. Mol. Cell. Proteom. 9, 2482–2496 (2010).
  CAS Google Scholar
• Norheim, F. et al. Proteomic identification of secreted proteins from human skeletal muscle cells and expression in response to strength training. Am. J. Physiol. Endocrinol. Metab. 301, E1013–E1021 (2011).
  CAS PubMed Google Scholar
• Henningsen, J., Pedersen, B. K. & Kratchmarova, I. Quantitative analysis of the secretion of the MCP family of chemokines by muscle cells. Mol. Biosyst. 7, 311–321 (2011).
  CAS PubMed Google Scholar
• Yoon, J. H. et al. Comparative proteomic analysis of the insulin-induced L6 myotube secretome. Proteomics 9, 51–60 (2009).
  CAS PubMed Google Scholar
• Yoon, J. H. et al. Proteomic analysis of the palmitate-induced myotube secretome reveals involvement of the annexin A1-formyl peptide receptor 2 (FPR2) pathway in insulin resistance. Mol. Cell. Proteom. 14, 882–892 (2015).
  CAS Google Scholar
• Chan, C. Y., McDermott, J. C. & Siu, K. W. Secretome analysis of skeletal myogenesis using SILAC and shotgun proteomics. Int. J. Proteom. 2011, 329467 (2011).
  Google Scholar
• Raschke, S., Eckardt, K., Bjørklund Holven, K., Jensen, J. & Eckel, J. Identification and validation of novel contraction-regulated myokines released from primary human skeletal muscle cells. PLoS ONE 8, e62008 (2013).
  CAS PubMed PubMed Central Google Scholar
• Haugen, F. et al. IL-7 is expressed and secreted by human skeletal muscle cells. Am. J. Physiol. Cell Physiol. 298, C807–C816 (2010).
  CAS PubMed Google Scholar
• Deshmukh, A. S. et al. Deep proteomics of mouse skeletal muscle enables quantitation of protein isoforms, metabolic pathways, and transcription factors. Mol. Cell. Proteom. 14, 841–853 (2015). The deepest quantitation of the skeletal muscle proteome thus far and an insight into the power of discovery-based proteomics.
  CAS Google Scholar
• Anderson, N. L. & Anderson, N. G. The human plasma proteome: history, character, and diagnostic prospects. Mol. Cell. Proteom. 1, 845–867 (2002).
  CAS Google Scholar
• Omenn, G. S. et al. Overview of the HUPO Plasma Proteome Project: results from the pilot phase with 35 collaborating laboratories and multiple analytical groups, generating a core dataset of 3020 proteins and a publicly-available database. Proteomics 5, 3226–3245 (2005).
  CAS PubMed Google Scholar
• States, D. J. et al. Challenges in deriving high-confidence protein identifications from data gathered by a HUPO plasma proteome collaborative study. Nat. Biotechnol. 24, 333–338 (2006).
  CAS PubMed Google Scholar
• Pernemalm, M., Lewensohn, R. & Lehtio, J. Affinity prefractionation for MS-based plasma proteomics. Proteomics 9, 1420–1427 (2009).
  CAS PubMed Google Scholar
• Liu, X. et al. Mapping the human plasma proteome by SCX-LC-IMS-MS. J. Am. Soc. Mass Spectrom. 18, 1249–1264 (2007).
  CAS PubMed PubMed Central Google Scholar
• Pocsfalvi, G. et al. Mass spectrometry of extracellular vesicles. Mass Spectrom. Rev. 35, 3–21 (2015).
  PubMed Google Scholar
• Harel, M., Oren-Giladi, P., Kaidar-Person, O., Shaked, Y. & Geiger, T. Proteomics of microparticles with SILAC Quantification (PROMIS-Quan): a novel proteomic method for plasma biomarker quantification. Mol. Cell. Proteom. 14, 1127–1136 (2015).
  CAS Google Scholar
• Forterre, A. et al. Proteomic analysis of C2C12 myoblast and myotube exosome-like vesicles: a new paradigm for myoblast-myotube cross talk? PLoS ONE 9, e84153 (2014).
  PubMed PubMed Central Google Scholar
• Kalra, H. et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 10, e1001450 (2012).
  CAS PubMed PubMed Central Google Scholar
• Lancaster, G. I. & Febbraio, M. A. Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J. Biol. Chem. 280, 23349–23355 (2005).
  CAS PubMed Google Scholar
• 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. 529, 237–242 (2000).
  CAS PubMed PubMed Central Google Scholar
• Wiles, M. V., Qin, W., Cheng, A. W. & Wang, H. CRISPR–Cas9-mediated genome editing and guide RNA design. Mamm. Genome 26, 501–510 (2015).
  CAS PubMed PubMed Central Google Scholar
• Yang, Y. et al. A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat. Biotechnol. 34, 334–338 (2016).
  CAS PubMed PubMed Central Google Scholar
• Kamran, P. et al. Parabiosis in mice: a detailed protocol. J. Vis. Exp. http://dx.doi.org/10.3791/50556 (2013).
• Chambers, A. G., Percy, A. J., Simon, R. & Borchers, C. H. MRM for the verification of cancer biomarker proteins: recent applications to human plasma and serum. Exp. Rev. Proteom. 11, 137–148 (2014).
  CAS Google Scholar
• Peterson, A. C., Russell, J. D., Bailey, D. J., Westphall, M. S. & Coon, J. J. Parallel reaction monitoring for high resolution and high mass accuracy quantitative, targeted proteomics. Mol. Cell. Proteom. 11, 1475–1488 (2012).
  Google Scholar
• Horsley, V., Jansen, K. M., Mills, S. T. & Pavlath, G. K. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113, 483–494 (2003).
  CAS PubMed Google Scholar
• Nieman, D. C. et al. Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plasma cytokine levels after a 3-h run. J. Appl. Physiol. 94, 1917–1925 (2003).
  CAS PubMed Google Scholar
• Ouchi, N. et al. Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J. Biol. Chem. 283, 32802–32811 (2008).
  CAS PubMed PubMed Central Google Scholar
• Hamrick, M. W., McNeil, P. L. & Patterson, S. L. Role of muscle-derived growth factors in bone formation. J. Musculoskelet. Neuronal Interact. 10, 64–70 (2010).
  CAS PubMed Google Scholar
• McPherron, A. C., Lawler, A. M. & Lee, S. J. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 387, 83–90 (1997).
  CAS PubMed Google Scholar
• Hittel, D. S., Berggren, J. R., Shearer, J., Boyle, K. & Houmard, J. A. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 58, 30–38 (2009).
  CAS PubMed PubMed Central Google Scholar
• McPherron, A. C. & Lee, S. J. Suppression of body fat accumulation in myostatin-deficient mice. J. Clin. Invest. 109, 595–601 (2002).
  CAS PubMed PubMed Central Google Scholar
• Wilkes, J. J., Lloyd, D. J. & Gekakis, N. Loss-of-function mutation in myostatin reduces tumor necrosis factor α production and protects liver against obesity-induced insulin resistance. Diabetes 58, 1133–1143 (2009).
  CAS PubMed PubMed Central Google Scholar
• Camporez, J-. P. G. et al. Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. Proc. Natl Acad. Sci. USA 113, 2212–2217 (2016).
  CAS PubMed PubMed Central Google Scholar
• Moon, H. Y. et al. Running-induced systemic cathepsin B secretion is associated with memory function. Cell. Metab. http://dx.doi.org/10.1016/j.cmet.2016.05.025 (2016).
• Bartelt, A. & Heeren, J. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10, 24–36 (2014).
  CAS PubMed Google Scholar
• Cousin, B. et al. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J. Cell Sci. 103, 931–942 (1992).
  CAS PubMed Google Scholar
• Barbatelli, G. et al. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am. J. Physiol. Endocrinol. Metab. 298, E1244–E1253 (2010).
  CAS PubMed Google Scholar
• Yoshida, T. et al. Nicotine induces uncoupling protein 1 in white adipose tissue of obese mice. Int. J. Obes. Relat. Metab. Disord. 23, 570–575 (1999).
  CAS PubMed Google Scholar
• Boström, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).
  PubMed PubMed Central Google Scholar
• Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).
  CAS PubMed Google Scholar
• Raschke, S. et al. Evidence against a beneficial effect of irisin in humans. PLoS ONE 8, e73680 (2013).
  CAS PubMed PubMed Central Google Scholar
• Albrecht, E. et al. Irisin – a myth rather than an exercise-inducible myokine. Sci. Rep. 5, 8889 (2015).
  CAS PubMed PubMed Central Google Scholar
• Erickson, H. P. Irisin and FNDC5 in retrospect: an exercise hormone or a transmembrane receptor? Adipocyte 2, 289–293 (2013).
  CAS PubMed PubMed Central Google Scholar
• Schumacher, M. A., Chinnam, N., Ohashi, T., Shah, R. S. & Erickson, H. P. The structure of irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer: implications for receptor activation. J. Biol. Chem. 288, 33738–33744 (2013).
  CAS PubMed PubMed Central Google Scholar
• Jedrychowski, M. P. et al. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell. Metab. 22, 734–740 (2015). An example of how targeted proteomics can validate myokine expression in exercise contexts.
  CAS PubMed PubMed Central Google Scholar
• Lee, P. et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell. Metab. 19, 302–309 (2014).
  CAS PubMed PubMed Central Google Scholar
• Rao, R. R. et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291 (2014).
  CAS PubMed PubMed Central Google Scholar
• Izumiya, Y., Hopkins, T., Morris, C., Sato, K. & Zeng, L. Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell. Metab. 7, 159–172 (2008).
  CAS PubMed PubMed Central Google Scholar
• Izumiya, Y. et al. FGF21 is an Akt-regulated myokine. FEBS Lett. 582, 3805–3810 (2008).
  CAS PubMed PubMed Central Google Scholar
• Kim, K. H. et al. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS ONE 8, e63517 (2013).
  CAS PubMed PubMed Central Google Scholar
• Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005).
  CAS PubMed PubMed Central Google Scholar
• Coskun, T. et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149, 6018–6027 (2008).
  CAS PubMed Google Scholar
• Hansen, J. S. et al. Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol. Met. 4, 551–560 (2015). An insightful examination of the source of circulating FGF21 during exercise.
  CAS Google Scholar
• Markan, K. R. et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 63, 4057–4063 (2014).
  CAS PubMed PubMed Central Google Scholar
• Hondares, E. et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J. Biol. Chem. 286, 12983–12990 (2011).
  CAS PubMed PubMed Central Google Scholar
• Fisher, F. M. et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012).
  CAS PubMed PubMed Central Google Scholar
• Samms, R. J. et al. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep. 11, 991–999 (2015).
  CAS PubMed Google Scholar
• Véniant, M. M. et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell. Metab. 21, 731–738 (2015).
  PubMed Google Scholar
• Degirolamo, C., Sabbà, C. & Moschetta, A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat. Rev. Drug. Discov. 15, 51–69 (2016).
  CAS PubMed Google Scholar
• Roberts, L. D. et al. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell. Metab. 19, 96–108 (2014).
  CAS PubMed PubMed Central Google Scholar
• Seldin, M. M., Peterson, J. M., Byerly, M. S., Wei, Z. & Wong, G. W. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J. Biol. Chem. 287, 11968–11980 (2012).
  CAS PubMed PubMed Central Google Scholar
• Seldin, M. M. et al. Skeletal muscle-derived myonectin activates the mammalian target of rapamycin (mTOR) pathway to suppress autophagy in liver. J. Biol. Chem. 288, 36073–36082 (2013).
  CAS PubMed PubMed Central Google Scholar
• Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell. Metab. 11, 467–478 (2010).
  CAS PubMed PubMed Central Google Scholar
• Leitzmann, M. et al. European Code against Cancer 4th Edition: physical activity and cancer. Cancer Epidemiol. 39 (Suppl. 1), 46–55 (2015).
  Google Scholar
• Brown, J. C., Winters-Stone, K., Lee, A. & Schmitz, K. H. Cancer, physical activity, and exercise. Comp. Physiol. 2, 2775–2809 (2012).
  Google Scholar
• Goh, J. et al. Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dose-dependent manner. PLoS ONE 8, e80123 (2013).
  PubMed PubMed Central Google Scholar
• Pedersen, L. et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell. Metab. 23, 554–562 (2016). A comprehensive demonstration that voluntary wheel running in mouse models of cancer is a beneficial effect partially mediated by the myokine IL-6.
  CAS PubMed Google Scholar
• Hojman, P. et al. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am. J. Physiol. Endocrinol. Metab. 301, E504–E510 (2011).
  CAS PubMed Google Scholar
• Aoi, W. et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 62, 882–889 (2013).
  CAS PubMed Google Scholar
• Kanzleiter, T. et al. The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem. Biophys. Res. Comm. 450, 1089–1094 (2014).
  CAS PubMed Google Scholar
• Soria-Valles, C. et al. The anti-metastatic activity of collagenase-2 in breast cancer cells is mediated by a signaling pathway involving decorin and miR-21. Oncogene 33, 3054–3063 (2014).
  CAS PubMed Google Scholar
• Araki, K. et al. Decorin suppresses bone metastasis in a breast cancer cell line. Oncology 77, 92–99 (2009).
  CAS PubMed Google Scholar
• Laye, M. J. et al. Cessation of daily wheel running differentially alters fat oxidation capacity in liver, muscle, and adipose tissue. J. Appl. Physiol. 106, 161–168 (2009).
  CAS PubMed Google Scholar
• Carotta, S. Targeting, N. K. Cells for anticancer immunotherapy: clinical and preclinical approaches. Front. Immunol. 7, 152 (2016).
  PubMed PubMed Central Google Scholar
• Morikawa, T. et al. Prospective analysis of body mass index, physical activity, and colorectal cancer risk associated with β-catenin (CTNNB1) status. Cancer Res. 73, 1600–1610 (2013).
  CAS PubMed PubMed Central Google Scholar
• Je, Y., Jeon, J. Y., Giovannucci, E. L. & Meyerhardt, J. A. Association between physical activity and mortality in colorectal cancer: a meta-analysis of prospective cohort studies. Int. J. Cancer 133, 1905–1913 (2013).
  CAS PubMed Google Scholar
• Murphy-Ullrich, J. E. & Sage, E. H. Revisiting the matricellular concept. Matrix Biol. 37, 1–14 (2014).
  CAS PubMed PubMed Central Google Scholar
• Brekken, R. A. et al. Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. J. Clin. Invest. 111, 487–495 (2003).
  CAS PubMed PubMed Central Google Scholar
• Neill, T., Schaefer, L. & Iozzo, R. V. Decorin: a guardian from the matrix. Am. J. Pathol. 181, 380–387 (2012).
  CAS PubMed PubMed Central Google Scholar
• Rahman, M., Chan, A. P. K. & Tai, I. T. A peptide of SPARC interferes with the interaction between caspase8 and Bcl2 to resensitize chemoresistant tumors and enhance their regression in vivo. PLoS ONE 6, e26390 (2011).
  CAS PubMed PubMed Central Google Scholar
• Nishizawa, H. et al. Musclin, a novel skeletal muscle-derived secretory factor. J. Biol. Chem. 279, 19391–19395 (2004).
  CAS PubMed Google Scholar
• Subbotina, E. et al. Musclin is an activity-stimulated myokine that enhances physical endurance. Proc. Natl Acad. Sci. USA 112, 16042–16047 (2015).
  CAS PubMed PubMed Central Google Scholar
• Myers, J. et al. Exercise capacity and mortality among men referred for exercise testing. N. Engl. J. Med. 346, 793–801 (2002).
  PubMed Google Scholar
• Korpelainen, R. et al. Exercise capacity and mortality - a follow-up study of 3033 subjects referred to clinical exercise testing. Ann. Med. http://dx.doi.org/10.1080/07853890.2016.1178856 (2016).
• Lua, L. H. L. & Chuan, Y. P. in Biopharmaceutical Production Technology Vol. 1 & Vol. 2 43–77 (Wiley-VCH Verlag GmbH & Co. KGaA, 2012).
  Google Scholar
• Pisal, D. S., Kosloski, M. P. & Balu-Iyer, S. V. Delivery of therapeutic proteins. J. Pharm. Sci. 99, 2557–2575 (2010).
  CAS PubMed PubMed Central Google Scholar
• Harris, J. M. & Chess, R. B. Effect of pegylation on pharmaceuticals. Nat. Rev. Drug. Discov. 2, 214–221 (2003).
  CAS PubMed Google Scholar
• Jazayeri, J. A. & Carroll, G. J. Fc-based cytokines: prospects for engineering superior therapeutics. Biodrugs 22, 11–26 (2008).
  CAS PubMed Google Scholar
• Huang, C. Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology. Curr. Opin. Biotechnol. 20, 692–699 (2009).
  CAS PubMed Google Scholar
• Rath, T. et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit. Rev. Biotechnol. 35, 235–254 (2015).
  CAS PubMed Google Scholar
• Panyam, J. & Labhasetwar, V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv. Drug. Deliv. Rev. 55, 329–347 (2003).
  CAS PubMed Google Scholar
• Davis, M. E., Chen, Z. G. & Shin, D. M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug. Discov. 7, 771–782 (2008).
  CAS PubMed Google Scholar
• Popielarski, S. R., Hu-Lieskovan, S., French, S. W., Triche, T. J. & Davis, M. E. A nanoparticle-based model delivery system to guide the rational design of gene delivery to the liver. 2. In vitro and in vivo uptake results. Bioconjug. Chem. 16, 1071–1080 (2005).
  CAS PubMed Google Scholar
• Febbraio, M. A. gp130 receptor ligands as potential therapeutic targets for obesity. J. Clin. Invest. 117, 841–849 (2007).
  CAS PubMed PubMed Central Google Scholar
• Ostrowski, K., Rohde, T., Zacho, M., Asp, S. & Pedersen, B. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. J. Physiol. 508, 949–953 (1998).
  CAS PubMed PubMed Central Google Scholar
• Febbraio, M. A. et al. Hepatosplanchnic clearance of interleukin-6 in humans during exercise. Am. J. Physiol. Endocrinol. Metab. 285, E397–E402 (2003).
  CAS PubMed Google Scholar
• Hiscock, N., Chan, M., Bisucci, T., Darby, I. & Febbraio, M. Skeletal myocytes are a source of interleukin-6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J. 18, 992–994 (2004).
  CAS PubMed Google Scholar
• Starkie, R. L., Arkinstall, M. J., Koukoulas, I., Hawley, J. A. & Febbraio, M. A. 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 (2001).
  CAS PubMed PubMed Central Google Scholar
• Steensberg, A. et al. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J. Physiol. 537, 633–639 (2001).
  CAS PubMed PubMed Central Google Scholar
• Richter, E. A. & Galbo, H. Diabetes, insulin and exercise. Sports Med. 3, 275–288 (1986).
  CAS PubMed Google Scholar
• Wasserman, D. H. Regulation of glucose fluxes during exercise in the postabsorptive state. Annu. Rev. Physiol. 57, 191–218 (1995).
  CAS PubMed Google Scholar
• Whitham, M. et al. Contraction-induced interleukin-6 gene transcription in skeletal muscle is regulated by c-Jun terminal kinase/activator protein-1. J. Biol. Chem. 287, 10771–10779 (2012).
  CAS PubMed PubMed Central Google Scholar
• Kelly, M. et al. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem. Biophys. Res. Comm. 320, 449–454 (2004).
  CAS PubMed Google Scholar
• Al-Khalili, L. et al. Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle. Mol. Endocrinol. 20, 3364–3375 (2006).
  CAS PubMed Google Scholar
• 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 55, 2688–2697 (2006).
  CAS PubMed Google Scholar
• Petersen, A. M. & Pedersen, B. K. The anti-inflammatory effect of exercise. J. Appl. Physiol. 98, 1154–1162 (2005).
  CAS PubMed Google Scholar
• van Hall, G. et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J. Clin. Endocrinol. Metab. 88, 3005–3010 (2003).
  CAS PubMed Google Scholar
• Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011).
  CAS PubMed PubMed Central Google Scholar
• Shirazi, R. et al. Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6. Proc. Natl Acad. Sci. USA 110, 16199–16204 (2013).
  CAS PubMed PubMed Central Google Scholar
• ALS CNTF Treatment Study Group. A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 46, 1244–1249 (1996).
• Duff, E. & Baile, C. A. Ciliary neurotrophic factor: a role in obesity? Nutr. Rev. 61, 423–426 (2003).
  PubMed Google Scholar
• Ettinger, M. P. et al. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. J. Am. Med. Assoc. 289, 1826–1832 (2003).
  CAS Google Scholar
• Kraakman, M. et al. Targeting gp130 to prevent inflammation and promote insulin action. Diabetes Obes. Metab. 15 (Suppl. 3), 170–175 (2013).
  CAS Google Scholar
• Tsiloulis, T. & Watt, M. J. Exercise and the regulation of adipose tissue metabolism. Prog. Mol. Biol. Transl. Sci. 135, 175–201 (2015).
  CAS PubMed Google Scholar
• Vosselman, M. J. et al. Low brown adipose tissue activity in endurance-trained compared with lean sedentary men. Int. J. Obes. 39, 1696–1702 (2015).
  CAS Google Scholar