title: LIF is a contraction-induced myokine stimulating human myocyte proliferation.
abstract: The cytokine leukemia inhibitory factor (LIF) is expressed by skeletal muscle and induces proliferation of myoblasts. We hypothesized that LIF is a contraction-induced myokine functioning in an autocrine fashion to activate gene regulation of human muscle satellite cell proliferation. Skeletal muscle LIF expression, regulation, and action were examined in two models: 1) young men performing a bout of heavy resistance exercise of the quadriceps muscle and 2) cultured primary human satellite cells. Resistance exercise induced a ninefold increase in LIF mRNA content in skeletal muscle, but LIF was not detectable in plasma of the subjects. However, electrically stimulated cultured human myotubes produced and secreted LIF, suggesting that LIF is a myokine with local effects. The well established exercise-induced signaling molecules PI3K, Akt, and mTor contributed to the regulation of LIF in cultured human myotubes as chemical inhibition of PI3K and mTor and siRNA knockdown of Akt1 were independently sufficient to downregulate LIF. Human myoblast proliferation was increased by recombinant exogenous LIF and decreased by siRNA knockdown of the endogenous LIF receptor. Finally, the transcription factors JunB and c-Myc, which promote myoblast proliferation, were induced by LIF in cultured human myotubes. Indeed, both JunB and c-Myc were also increased in skeletal muscle following resistance exercise. Our data suggest that LIF is a contraction-induced myokine, potentially acting in an autocrine or paracrine fashion to promote satellite cell proliferation.
authors.affiliation: Rigshospitalet, Centre of Inflammation and Metabolism (CIM) 7641, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. christa.broholm@gmail.com
authors.forename: Christa
authors.initials: C
authors.lastname: Broholm
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Laye
authors.forename: Claus
authors.initials: C
authors.lastname: Brandt
authors.forename: Radhika
authors.initials: R
authors.lastname: Vadalasetty
authors.forename: Henriette
authors.initials: H
authors.lastname: Pilegaard
authors.forename: Bente Klarlund
authors.initials: BK
authors.lastname: Pedersen
authors.forename: Camilla
authors.initials: C
authors.lastname: Scheele
mesh_terms: D000328:Adult; D001706:Biopsy; D002450:Cell Communication / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004558:Electric Stimulation; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D052097:Quadriceps Muscle / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D053606:Receptors, OSM-LIF / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D055070:Resistance Training; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
chemical_list: D053605:Leukemia Inhibitory Factor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D053606:Receptors, OSM-LIF; D011994:Recombinant Proteins; D058570:TOR Serine-Threonine Kinases; C507837:LIF protein, human; C489427:MYC protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human