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The Role of Leukemia Inhibitory Factor Receptor Signaling in Skeletal Muscle Growth, Injury and Disease

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Book cover Growth Factors and Cytokines in Skeletal Muscle Development, Growth, Regeneration and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 900))

Abstract

Cytokines are an incredibly diverse group of secreted proteins with equally diverse functions. The actions of cytokines are mediated by the unique and sometimes overlapping receptors to which the soluble ligands bind. Classified within the interleukin-6 family of cytokines are leukemia inhibitory factor (LIF), oncostatin-M (OSM), cardiotrophin-1 (CT-1) and ciliary neurotrophic factor (CNTF). These cytokines all bind to the leukemia inhibitory factor receptor (LIFR) and gp130, and in some cases an additional receptor subunit, leading to activation of downstream kinases and transcriptional activators. LIFR is expressed on a broad range of cell types and can generate pleiotropic effects. In the context of skeletal muscle physiology, these cytokines have been shown to exert effects on motor neurons, inflammatory and muscle cells. From isolated cells through to whole organisms, manipulations of LIFR signaling cytokines have a wide range of outcomes influencing muscle cell growth, myogenic differentiation, response to exercise, metabolism, neural innervation and recruitment of inflammatory cells to sites of muscle injury. This article will discuss the shared and distinct processes that LIFR cytokines regulate in a variety of experimental models with the common theme of skeletal muscle physiology.

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References

  • Aubert J et al (1999) Leukemia inhibitory factor and its receptor promote adipocyte differentiation via the mitogen-activated protein kinase cascade. J Biol Chem 274(35):24965–24972

    Article  CAS  PubMed  Google Scholar 

  • Austin L, Burgess A (1991) Stimulation of myoblast proliferation in culture by leukaemia inhibitory factor and other cytokines. J Neurol Sci 101(2):193–197

    Article  CAS  PubMed  Google Scholar 

  • Austin L et al (2000) Leukemia inhibitory factor ameliorates muscle fiber degeneration in the mdx mouse. Muscle Nerve 23(11):1700–1705

    Article  CAS  PubMed  Google Scholar 

  • Barnard W et al (1994) Leukemia inhibitory factor (LIF) infusion stimulates skeletal muscle regeneration after injury: injured muscle expresses lif mRNA. J Neurol Sci 123(1–2):108–113

    Article  CAS  PubMed  Google Scholar 

  • Boström P et al (2012) A PGC1-[agr]-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481(7382):463–468

    Article  PubMed  PubMed Central  Google Scholar 

  • Broholm C et al (2008) Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle. J Physiol 586(8):2195–2201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Broholm C et al (2011) LIF is a contraction-induced myokine stimulating human myocyte proliferation. J Appl Physiol 111(1):251–259

    Article  CAS  PubMed  Google Scholar 

  • Chen X et al (2005) Dedifferentiation of adult human myoblasts induced by ciliary neurotrophic factor in vitro. Mol Biol Cell 16(7):3140–3151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25(1):4–7

    Article  CAS  PubMed  Google Scholar 

  • Davis S et al (1993) LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science 260(5115):1805–1808

    Article  CAS  PubMed  Google Scholar 

  • Elson GC et al (2000) CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex. Nat Neurosci 3(9):867–872

    Article  CAS  PubMed  Google Scholar 

  • Febbraio MA, Pedersen BK (2005) Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 33(3):114–119

    Article  PubMed  Google Scholar 

  • Gadient RA, Patterson PH (1999) Leukemia inhibitory factor, interleukin 6, and other cytokines using the GP130 transducing receptor: roles in inflammation and injury. Stem Cells 17(3):127–137

    Article  CAS  PubMed  Google Scholar 

  • Gearing DP, Bruce AG (1992) Oncostatin M binds the high-affinity leukemia inhibitory factor receptor. New Biol 4(1):61–65

    CAS  PubMed  Google Scholar 

  • Gearing D et al (1987) Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J 6(13):3995

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gearing D et al (1991) Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. EMBO J 10(10):2839

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gearing D et al (1992) The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science 255(5050):1434–1437

    Article  CAS  PubMed  Google Scholar 

  • Gregorevic P, Williams DA, Lynch GS (2002) Effects of leukemia inhibitory factor on rat skeletal muscles are modulated by clenbuterol. Muscle Nerve 25(2):194–201

    Article  CAS  PubMed  Google Scholar 

  • Grounds MD, Torrisi J (2004) Anti-TNFα (Remicade®) therapy protects dystrophic skeletal muscle from necrosis. FASEB J 18(6):676–682

    Article  CAS  PubMed  Google Scholar 

  • Heinrich P et al (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiatt K et al (2012) Ciliary neurotrophic factor (CNTF) promotes skeletal muscle progenitor cell (MPC) viability via the phosphatidylinositol 3-kinase–Akt pathway. J Tissue Eng Regen Med. n/a–n/a

    Google Scholar 

  • Hogan JC, Stephens JM (2005) Effects of leukemia inhibitory factor on 3T3-L1 adipocytes. J Endocrinol 185(3):485–496

    Article  CAS  PubMed  Google Scholar 

  • Hojman P et al (2011) Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab 301(3):E504–E510

    Article  CAS  PubMed  Google Scholar 

  • Holtmann B et al (2005) Triple knock-out of CNTF, LIF, and CT-1 defines cooperative and distinct roles of these neurotrophic factors for motoneuron maintenance and function. J Neurosci 25(7):1778–1787

    Article  CAS  PubMed  Google Scholar 

  • Hunt L, Tudor E, White J (2010) Leukemia inhibitory factor-dependent increase in myoblast cell number is associated with phosphotidylinositol 3-kinase-mediated inhibition of apoptosis and not mitosis. Exp Cell Res 316(6):1002–1009

    Article  CAS  PubMed  Google Scholar 

  • Hunt LC et al (2011a) Caspase-3, myogenic transcription factors and cell cycle inhibitors are regulated by leukemia inhibitory factor to mediate inhibition of myogenic differentiation. Skelet Muscle 1(1):17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hunt LC et al (2011) Alterations in the expression of leukemia inhibitory factor following exercise: comparisons between wild-type and mdx muscles. PLoS Curr 3:RRN1277

    Google Scholar 

  • Hunt LC et al (2013) An anti-inflammatory role for leukemia inhibitory factor receptor signaling in regenerating skeletal muscle. Histochem Cell Biol 139(1):13–34

    Article  CAS  PubMed  Google Scholar 

  • Ichihara M et al (1997) Oncostatin M and leukemia inhibitory factor do not use the same functional receptor in mice. Blood 90(1):165–173

    CAS  PubMed  Google Scholar 

  • Ito Y et al (1998) Differential temporal expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFRα, LIFRβ, IL-6Rα and gp130) in injured peripheral nerves. Brain Res 793(1–2):321–327

    Article  CAS  PubMed  Google Scholar 

  • Kami K et al (2000) Gene expression of receptors for IL-6, LIF, and CNTF in regenerating skeletal muscles. J Histochem Cytochem 48(9):1203–1213

    Article  CAS  PubMed  Google Scholar 

  • Kerr BJ, Patterson PH (2004) Potent pro-inflammatory actions of leukemia inhibitory factor in the spinal cord of the adult mouse. Exp Neurol 188(2):391–407

    Article  CAS  PubMed  Google Scholar 

  • Kodama H et al (1997) Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, activates the JAK/STAT pathway in rat cardiomyocytes. Circ Res 81(5):656–663

    Article  CAS  PubMed  Google Scholar 

  • Kurek J et al (1996) Leukaemia inhibitory factor treatment stimulates muscle regeneration in the mdx mouse. Neurosci Lett 212(3):167–170

    Article  CAS  PubMed  Google Scholar 

  • Kurek JB et al (1997) The role of leukemia inhibitory factor in skeletal muscle regeneration. Muscle Nerve 20(7):815–822

    Article  CAS  PubMed  Google Scholar 

  • Kwon YW et al (1995) Leukemia inhibitory factor influences the timing of programmed synapse withdrawal from neonatal muscles. J Neurobiol 28(1):35–50

    Article  CAS  PubMed  Google Scholar 

  • Layton MJ et al (1992) A major binding protein for leukemia inhibitory factor in normal mouse serum: identification as a soluble form of the cellular receptor. Proc Natl Acad Sci 89(18):8616–8620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li M, Sendtner M, Smith A (1995) Essential function of LIF receptor in motor neurons. Nature 378(6558):724–727

    Article  CAS  PubMed  Google Scholar 

  • Lin L et al (1989) Purification, cloning, and expression of ciliary neurotrophic factor (CNTF). Science 246(4933):1023–1025

    Article  CAS  PubMed  Google Scholar 

  • Ljubicic V et al (2011) Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle. Hum Mol Genet 20(17):3478–3493

    Article  CAS  PubMed  Google Scholar 

  • Malik N et al (1989) Molecular cloning, sequence analysis, and functional expression of a novel growth regulator, oncostatin M. Mol Cell Biol 9(7):2847–2853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marques MJ, Santo Neto H (1997) Ciliary neurotrophic factor stimulates in vivo myotube formation in mice. Neurosci Lett 234(1):43–46

    Article  CAS  PubMed  Google Scholar 

  • Marshall MK et al (1994) Leukemia inhibitory factor induces changes in lipid metabolism in cultured adipocytes. Endocrinology 135(1):141–147

    CAS  PubMed  Google Scholar 

  • Miyake T et al (2009) Cardiotrophin-1 maintains the undifferentiated state in skeletal myoblasts. J Biol Chem 284(29):19679–19693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyaoka Y et al (2006) Oncostatin M inhibits adipogenesis through the RAS/ERK and STAT5 signaling pathways. J Biol Chem 281(49):37913–37920

    Article  CAS  PubMed  Google Scholar 

  • Moreno-Aliaga MJ et al (2011) Cardiotrophin-1 is a key regulator of glucose and lipid metabolism. Cell Metab 14(2):242–253

    Article  CAS  PubMed  Google Scholar 

  • Morikawa Y et al (2004) Essential function of oncostatin m in nociceptive neurons of dorsal root ganglia. J Neurosci 24(8):1941–1947

    Article  CAS  PubMed  Google Scholar 

  • Mosley B et al (1996) Dual oncostatin M (OSM) receptors cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J Biol Chem 271(51):32635–32643

    Article  CAS  PubMed  Google Scholar 

  • Ott V et al (2004) Ciliary neurotrophic factor influences endocrine adipocyte function: inhibition of leptin via PI 3-kinase. Mol Cell Endocrinol 224(1–2):21–27

    Article  CAS  PubMed  Google Scholar 

  • Pedersen BK, Fischer CP (2007) Beneficial health effects of exercise–the role of IL-6 as a myokine. Trends Pharmacol Sci 28(4):152–156

    Article  CAS  PubMed  Google Scholar 

  • Pedersen B et al (2004) The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor? Proc Nutr Soc 63(2):263–268

    Article  CAS  PubMed  Google Scholar 

  • Pennica D et al (1995a) Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci 92(4):1142–1146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pennica D et al (1995b) Cardiotrophin-1 biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J Biol Chem 270(18):10915–10922

    Article  CAS  PubMed  Google Scholar 

  • Reardon KA et al (2001) Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy. Muscle Nerve 24(7):893–899

    Article  CAS  PubMed  Google Scholar 

  • Robertson TA et al (1993) The role of macrophages in skeletal muscle regeneration with particular reference to chemotaxis. Exp Cell Res 207(2):321–331

    Article  CAS  PubMed  Google Scholar 

  • Robledo O et al (1997) Signaling of the cardiotrophin-1 receptor evidence for a third receptor component. J Biol Chem 272(8):4855–4863

    Article  CAS  PubMed  Google Scholar 

  • Rose TM, Bruce AG (1991) Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6. Proc Natl Acad Sci 88(19):8641–8645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sammels LM et al (2004) Innate inflammatory cells are not responsible for early death of donor myoblasts after myoblast transfer therapy. Transplantation 77(12):1790–1797

    Article  PubMed  Google Scholar 

  • Scheller J et al (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813(5):878–888

    Article  CAS  PubMed  Google Scholar 

  • Seto DN et al (2015) A key role for leukemia inhibitory factor in C26 cancer cachexia. J Biol Chem 290(32):19976–19986

    Article  CAS  PubMed  Google Scholar 

  • Spangenburg EE, Booth FW (2006) Leukemia inhibitory factor restores the hypertrophic response to increased loading in the LIF (−/−) mouse. Cytokine 34(3):125–130

    Article  CAS  PubMed  Google Scholar 

  • Steinberg GR et al (2009) Ciliary neurotrophic factor stimulates muscle glucose uptake by a PI3-kinase–dependent pathway that is impaired with obesity. Diabetes 58(4):829–839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugiura S et al (2000) Leukaemia inhibitory factor is required for normal inflammatory responses to injury in the peripheral and central nervous systems in vivo and is chemotactic for macrophages in vitro. Eur J Neurosci 12(2):457–466

    Article  CAS  PubMed  Google Scholar 

  • Upadhyay A et al (2009) Role of a LIF antagonist in LIF and OSM induced MMP-1, MMP-3, and TIMP-1 expression by primary articular chondrocytes. Cytokine 46(3):332–338

    Article  CAS  PubMed  Google Scholar 

  • Wahl AF, Wallace PM (2001) Oncostatin M in the anti-inflammatory response. Ann Rheum Dis 60(suppl 3):iii75–iii80

    Google Scholar 

  • Walker EC et al (2010) Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. J Clin Invest 120(2):582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X et al (2008) Effects of interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor on the proliferation and differentiation of adult human myoblasts. Cell Mol Neurobiol 28(1):113–124

    Article  PubMed  Google Scholar 

  • Ware CB et al (1995) Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development 121(5):1283–1299

    CAS  PubMed  Google Scholar 

  • Watt MJ et al (2006) CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12(5):541–548

    Article  CAS  PubMed  Google Scholar 

  • White UA, Stephens JM (2011) The gp130 receptor cytokine family: regulators of adipocyte development and function. Curr Pharm Des 17(4):340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • White J, Davies M, Grounds M (2001a) Leukaemia inhibitory factor increases myoblast replication and survival and affects extracellular matrix production: combined in vivo and in vitro studies in post-natal skeletal muscle. Cell Tissue Res 306(1):129–141

    Article  CAS  PubMed  Google Scholar 

  • White JD et al (2001b) Leukemia inhibitory factor enhances regeneration in skeletal muscles after myoblast transplantation. Muscle Nerve 24(5):695–697

    Article  CAS  PubMed  Google Scholar 

  • White JD et al (2002) An evaluation of leukaemia inhibitory factor as a potential therapeutic agent in the treatment of muscle disease. Neuromuscul Disord 12(10):909–916

    Article  PubMed  Google Scholar 

  • Xiao F et al (2010) Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration. Cell Res 21(2):350–364

    Article  PubMed  PubMed Central  Google Scholar 

  • Zvonic S et al (2003) The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. J Biol Chem 278(4):2228–2235

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Murdoch Childrens Research Institute, Royal Childrens Hospital, Parkville, VIC, Australia

    Liam C. Hunt & Jason White

  2. Faculty of Veterinary Science, University of Melbourne, Flemington Road, Parkville, VIC, 3010, Australia

    Jason White

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  1. Liam C. Hunt
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  2. Jason White
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Correspondence to Liam C. Hunt .

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Editors and Affiliations

  1. Faculty of Veterinary Science, Univ of Melbourne, Parkville, VIC, Australia

    Jason White

  2. Faculty of Science, Charles Sturt University, Albury, New South Wales, Australia

    Gayle Smythe

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Hunt, L.C., White, J. (2016). The Role of Leukemia Inhibitory Factor Receptor Signaling in Skeletal Muscle Growth, Injury and Disease. In: White, J., Smythe, G. (eds) Growth Factors and Cytokines in Skeletal Muscle Development, Growth, Regeneration and Disease. Advances in Experimental Medicine and Biology, vol 900. Springer, Cham. https://doi.org/10.1007/978-3-319-27511-6_3

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