title: Regulation of Granulocyte Colony-Stimulating Factor and Its Receptor in Skeletal Muscle is Dependent Upon the Type of Inflammatory Stimulus.
abstract: The cytokine granulocyte colony-stimulating factor (G-CSF) binds to its receptor (G-CSFR) to stimulate hematopoietic stem cell mobilization, myelopoiesis, and the production and activation of neutrophils. In response to exercise-induced muscle damage, G-CSF is increased in circulation and G-CSFR has recently been identified in skeletal muscle cells. While G-CSF/G-CSFR activation mediates pro- and anti-inflammatory responses, our understanding of the role and regulation in the muscle is limited. The aim of this study was to investigate, in vitro and in vivo, the role and regulation of G-CSF and G-CSFR in skeletal muscle under conditions of muscle inflammation and damage. First, C2C12 myotubes were treated with lipopolysaccharide (LPS) with and without G-CSF to determine if G-CSF modulates the inflammatory response. Second, the regulation of G-CSF and its receptor was measured following eccentric exercise-induced muscle damage and the expression levels we investigated for redox sensitivity by administering the antioxidant N-acetylcysteine (NAC). LPS stimulation of C2C12 myotubes resulted in increases in G-CSF, interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNFα) messenger RNA (mRNA) and an increase in G-CSF, IL-6, and MCP-1 release from C2C12 myotubes. The addition of G-CSF following LPS stimulation of C2C12 myotubes increased IL-6 mRNA and cytokine release into the media, however it did not affect MCP-1 or TNFα. Following eccentric exercise-induced muscle damage in humans, G-CSF levels were either marginally increased in circulation or remain unaltered in skeletal muscle. Similarly, G-CSFR levels remained unchanged in response to damaging exercise and G-CSF/G-CSFR did not change in response to NAC. Collectively, these findings suggest that G-CSF may cooperate with IL-6 and potentially promote muscle regeneration in vitro, whereas in vivo aseptic inflammation induced by exercise did not change G-CSF and G-CSFR responses. These observations suggest that different models of inflammation produce a different G-CSF response.
authors.affiliation: 1 Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University , Burwood, Victoria, Australia .
authors.forename: Craig Robert
authors.initials: CR
authors.lastname: Wright
authors.affiliation: 1 Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University , Burwood, Victoria, Australia .
authors.forename: Erin Louise
authors.initials: EL
authors.lastname: Brown
authors.affiliation: 1 Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University , Burwood, Victoria, Australia .
authors.forename: Paul A
authors.initials: PA
authors.lastname: Della Gatta
authors.affiliation: 2 Department of Physical Education and Sport Sciences, Democritus University of Thrace , Komotini, Greece .|3 The Institute of Human Performance and Rehabilitation, Center for Research and Technology-Thessaly , Trikala, Greece .
authors.forename: Ioannis G
authors.initials: IG
authors.lastname: Fatouros
authors.affiliation: 4 Nestlé Research Center , Nestec Ltd., Lausanne, Switzerland .|5 School of Physical Education and Sport Sciences, University of Thessaly , Karies, Trikala, Greece .
authors.forename: Leonidas G
authors.initials: LG
authors.lastname: Karagounis
authors.affiliation: 6 Athletics Laboratory, School of Physical Education and Sports Science, University of Athens , Athens, Greece .
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Terzis
authors.affiliation: 7 Endocrine Unit, Second Department of Obstetrics and Gynecology, Athens University Medical School , Athens, Greece .
authors.forename: Georgios
authors.initials: G
authors.lastname: Mastorakos
authors.affiliation: 2 Department of Physical Education and Sport Sciences, Democritus University of Thrace , Komotini, Greece .
authors.forename: Yannis
authors.initials: Y
authors.lastname: Michailidis
authors.affiliation: 6 Athletics Laboratory, School of Physical Education and Sports Science, University of Athens , Athens, Greece .
authors.forename: Dimitris
authors.initials: D
authors.lastname: Mandalidis
authors.affiliation: 8 The 1st Department of Neurology, University of Athens , School of Medicine, Eginition Hospital, Athens, Greece .
authors.forename: Kontantinos
authors.initials: K
authors.lastname: Spengos
authors.affiliation: 2 Department of Physical Education and Sport Sciences, Democritus University of Thrace , Komotini, Greece .
authors.forename: Athanasios
authors.initials: A
authors.lastname: Chatzinikolaou
authors.affiliation: 6 Athletics Laboratory, School of Physical Education and Sports Science, University of Athens , Athens, Greece .
authors.forename: Spiros
authors.initials: S
authors.lastname: Methenitis
authors.affiliation: 2 Department of Physical Education and Sport Sciences, Democritus University of Thrace , Komotini, Greece .
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Draganidis
authors.affiliation: 3 The Institute of Human Performance and Rehabilitation, Center for Research and Technology-Thessaly , Trikala, Greece .|5 School of Physical Education and Sport Sciences, University of Thessaly , Karies, Trikala, Greece .
authors.forename: Athanasios Z
authors.initials: AZ
authors.lastname: Jamurtas
authors.affiliation: 1 Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University , Burwood, Victoria, Australia .
authors.forename: Aaron Paul
authors.initials: AP
authors.lastname: Russell
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism; D015444:Exercise / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D000975:Antioxidants; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D000111:Acetylcysteine