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

  • Liam C. HuntEmail author
  • Jason White
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 900)


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.


Leukemia inhibitory factor Leukemia inhibitory factor receptor Oncostatin M Cardiotrophin-1 Ciliary neutrophic factor Skeletal muscle 


  1. 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):24965–24972CrossRefPubMedGoogle Scholar
  2. Austin L, Burgess A (1991) Stimulation of myoblast proliferation in culture by leukaemia inhibitory factor and other cytokines. J Neurol Sci 101(2):193–197CrossRefPubMedGoogle Scholar
  3. Austin L et al (2000) Leukemia inhibitory factor ameliorates muscle fiber degeneration in the mdx mouse. Muscle Nerve 23(11):1700–1705CrossRefPubMedGoogle Scholar
  4. 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):108–113CrossRefPubMedGoogle Scholar
  5. Boström P et al (2012) A PGC1-[agr]-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481(7382):463–468CrossRefPubMedPubMedCentralGoogle Scholar
  6. Broholm C et al (2008) Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle. J Physiol 586(8):2195–2201CrossRefPubMedPubMedCentralGoogle Scholar
  7. Broholm C et al (2011) LIF is a contraction-induced myokine stimulating human myocyte proliferation. J Appl Physiol 111(1):251–259CrossRefPubMedGoogle Scholar
  8. Chen X et al (2005) Dedifferentiation of adult human myoblasts induced by ciliary neurotrophic factor in vitro. Mol Biol Cell 16(7):3140–3151CrossRefPubMedPubMedCentralGoogle Scholar
  9. Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25(1):4–7CrossRefPubMedGoogle Scholar
  10. Davis S et al (1993) LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science 260(5115):1805–1808CrossRefPubMedGoogle Scholar
  11. Elson GC et al (2000) CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex. Nat Neurosci 3(9):867–872CrossRefPubMedGoogle Scholar
  12. Febbraio MA, Pedersen BK (2005) Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 33(3):114–119CrossRefPubMedGoogle Scholar
  13. 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):127–137CrossRefPubMedGoogle Scholar
  14. Gearing DP, Bruce AG (1992) Oncostatin M binds the high-affinity leukemia inhibitory factor receptor. New Biol 4(1):61–65PubMedGoogle Scholar
  15. Gearing D et al (1987) Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J 6(13):3995PubMedPubMedCentralGoogle Scholar
  16. Gearing D et al (1991) Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. EMBO J 10(10):2839PubMedPubMedCentralGoogle Scholar
  17. 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):1434–1437CrossRefPubMedGoogle Scholar
  18. Gregorevic P, Williams DA, Lynch GS (2002) Effects of leukemia inhibitory factor on rat skeletal muscles are modulated by clenbuterol. Muscle Nerve 25(2):194–201CrossRefPubMedGoogle Scholar
  19. Grounds MD, Torrisi J (2004) Anti-TNFα (Remicade®) therapy protects dystrophic skeletal muscle from necrosis. FASEB J 18(6):676–682CrossRefPubMedGoogle Scholar
  20. Heinrich P et al (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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/aGoogle Scholar
  22. Hogan JC, Stephens JM (2005) Effects of leukemia inhibitory factor on 3T3-L1 adipocytes. J Endocrinol 185(3):485–496CrossRefPubMedGoogle Scholar
  23. Hojman P et al (2011) Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab 301(3):E504–E510CrossRefPubMedGoogle Scholar
  24. 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):1778–1787CrossRefPubMedGoogle Scholar
  25. 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):1002–1009CrossRefPubMedGoogle Scholar
  26. 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):17CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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:RRN1277Google Scholar
  28. Hunt LC et al (2013) An anti-inflammatory role for leukemia inhibitory factor receptor signaling in regenerating skeletal muscle. Histochem Cell Biol 139(1):13–34CrossRefPubMedGoogle Scholar
  29. Ichihara M et al (1997) Oncostatin M and leukemia inhibitory factor do not use the same functional receptor in mice. Blood 90(1):165–173PubMedGoogle Scholar
  30. 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):321–327CrossRefPubMedGoogle Scholar
  31. Kami K et al (2000) Gene expression of receptors for IL-6, LIF, and CNTF in regenerating skeletal muscles. J Histochem Cytochem 48(9):1203–1213CrossRefPubMedGoogle Scholar
  32. 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):391–407CrossRefPubMedGoogle Scholar
  33. 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):656–663CrossRefPubMedGoogle Scholar
  34. Kurek J et al (1996) Leukaemia inhibitory factor treatment stimulates muscle regeneration in the mdx mouse. Neurosci Lett 212(3):167–170CrossRefPubMedGoogle Scholar
  35. Kurek JB et al (1997) The role of leukemia inhibitory factor in skeletal muscle regeneration. Muscle Nerve 20(7):815–822CrossRefPubMedGoogle Scholar
  36. Kwon YW et al (1995) Leukemia inhibitory factor influences the timing of programmed synapse withdrawal from neonatal muscles. J Neurobiol 28(1):35–50CrossRefPubMedGoogle Scholar
  37. 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):8616–8620CrossRefPubMedPubMedCentralGoogle Scholar
  38. Li M, Sendtner M, Smith A (1995) Essential function of LIF receptor in motor neurons. Nature 378(6558):724–727CrossRefPubMedGoogle Scholar
  39. Lin L et al (1989) Purification, cloning, and expression of ciliary neurotrophic factor (CNTF). Science 246(4933):1023–1025CrossRefPubMedGoogle Scholar
  40. 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):3478–3493CrossRefPubMedGoogle Scholar
  41. Malik N et al (1989) Molecular cloning, sequence analysis, and functional expression of a novel growth regulator, oncostatin M. Mol Cell Biol 9(7):2847–2853CrossRefPubMedPubMedCentralGoogle Scholar
  42. Marques MJ, Santo Neto H (1997) Ciliary neurotrophic factor stimulates in vivo myotube formation in mice. Neurosci Lett 234(1):43–46CrossRefPubMedGoogle Scholar
  43. Marshall MK et al (1994) Leukemia inhibitory factor induces changes in lipid metabolism in cultured adipocytes. Endocrinology 135(1):141–147PubMedGoogle Scholar
  44. Miyake T et al (2009) Cardiotrophin-1 maintains the undifferentiated state in skeletal myoblasts. J Biol Chem 284(29):19679–19693CrossRefPubMedPubMedCentralGoogle Scholar
  45. Miyaoka Y et al (2006) Oncostatin M inhibits adipogenesis through the RAS/ERK and STAT5 signaling pathways. J Biol Chem 281(49):37913–37920CrossRefPubMedGoogle Scholar
  46. Moreno-Aliaga MJ et al (2011) Cardiotrophin-1 is a key regulator of glucose and lipid metabolism. Cell Metab 14(2):242–253CrossRefPubMedGoogle Scholar
  47. Morikawa Y et al (2004) Essential function of oncostatin m in nociceptive neurons of dorsal root ganglia. J Neurosci 24(8):1941–1947CrossRefPubMedGoogle Scholar
  48. 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):32635–32643CrossRefPubMedGoogle Scholar
  49. 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):21–27CrossRefPubMedGoogle Scholar
  50. Pedersen BK, Fischer CP (2007) Beneficial health effects of exercise–the role of IL-6 as a myokine. Trends Pharmacol Sci 28(4):152–156CrossRefPubMedGoogle Scholar
  51. 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):263–268CrossRefPubMedGoogle Scholar
  52. Pennica D et al (1995a) Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci 92(4):1142–1146CrossRefPubMedPubMedCentralGoogle Scholar
  53. 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):10915–10922CrossRefPubMedGoogle Scholar
  54. 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):893–899CrossRefPubMedGoogle Scholar
  55. Robertson TA et al (1993) The role of macrophages in skeletal muscle regeneration with particular reference to chemotaxis. Exp Cell Res 207(2):321–331CrossRefPubMedGoogle Scholar
  56. Robledo O et al (1997) Signaling of the cardiotrophin-1 receptor evidence for a third receptor component. J Biol Chem 272(8):4855–4863CrossRefPubMedGoogle Scholar
  57. 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):8641–8645CrossRefPubMedPubMedCentralGoogle Scholar
  58. Sammels LM et al (2004) Innate inflammatory cells are not responsible for early death of donor myoblasts after myoblast transfer therapy. Transplantation 77(12):1790–1797CrossRefPubMedGoogle Scholar
  59. Scheller J et al (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813(5):878–888CrossRefPubMedGoogle Scholar
  60. Seto DN et al (2015) A key role for leukemia inhibitory factor in C26 cancer cachexia. J Biol Chem 290(32):19976–19986CrossRefPubMedGoogle Scholar
  61. Spangenburg EE, Booth FW (2006) Leukemia inhibitory factor restores the hypertrophic response to increased loading in the LIF (−/−) mouse. Cytokine 34(3):125–130CrossRefPubMedGoogle Scholar
  62. 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):829–839CrossRefPubMedPubMedCentralGoogle Scholar
  63. 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):457–466CrossRefPubMedGoogle Scholar
  64. 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):332–338CrossRefPubMedGoogle Scholar
  65. Wahl AF, Wallace PM (2001) Oncostatin M in the anti-inflammatory response. Ann Rheum Dis 60(suppl 3):iii75–iii80Google Scholar
  66. 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):582CrossRefPubMedPubMedCentralGoogle Scholar
  67. 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):113–124CrossRefPubMedGoogle Scholar
  68. 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):1283–1299PubMedGoogle Scholar
  69. Watt MJ et al (2006) CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12(5):541–548CrossRefPubMedGoogle Scholar
  70. White UA, Stephens JM (2011) The gp130 receptor cytokine family: regulators of adipocyte development and function. Curr Pharm Des 17(4):340CrossRefPubMedPubMedCentralGoogle Scholar
  71. 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):129–141CrossRefPubMedGoogle Scholar
  72. White JD et al (2001b) Leukemia inhibitory factor enhances regeneration in skeletal muscles after myoblast transplantation. Muscle Nerve 24(5):695–697CrossRefPubMedGoogle Scholar
  73. 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):909–916CrossRefPubMedGoogle Scholar
  74. Xiao F et al (2010) Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration. Cell Res 21(2):350–364CrossRefPubMedPubMedCentralGoogle Scholar
  75. Zvonic S et al (2003) The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. J Biol Chem 278(4):2228–2235CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Murdoch Childrens Research InstituteRoyal Childrens HospitalParkvilleAustralia
  2. 2.Faculty of Veterinary ScienceUniversity of MelbourneParkvilleAustralia

Personalised recommendations