title: IL-6 induced STAT3 signalling is associated with the proliferation of human muscle satellite cells following acute muscle damage.
abstract: BACKGROUND
  Although the satellite cell (SC) is a key regulator of muscle growth during development and muscle adaptation following exercise, the regulation of human muscle SC function remains largely unexplored. STAT3 signalling mediated via interleukin-6 (IL-6) has recently come to the forefront as a potential regulator of SC proliferation. The early response of the SC population in human muscle to muscle-lengthening contractions (MLC) as mediated by STAT3 has not been studied.
  
  
  RESULTS
  Twelve male subjects (21±2 y; 83±12 kg) performed 300 maximal MLC of the quadriceps femoris at 180°•s(-1) over a 55° range of motion with muscle samples (vastus lateralis) and blood samples (antecubital vein) taken prior to exercise (PRE), 1 hour (T1), 3 hours (T3) and 24 hours (T24) post-exercise. Cytoplasmic and nuclear fractions of muscle biopsies were purified and analyzed for total and phosphorylated STAT3 (p-STAT3) by western blot. p-STAT3 was detected in cytoplasmic fractions across the time course peaking at T24 (p<0.01 vs. PRE). Nuclear total and p-STAT3 were not detected at appreciable levels. However, immunohistochemical analysis revealed a progressive increase in the proportion of SCs expressing p-STAT3 with ∼60% of all SCs positive for p-STAT3 at T24 (p<0.001 vs. PRE). Additionally, cMyc, a STAT3 downstream gene, was significantly up-regulated in SCs at T24 versus PRE (p<0.05). Whole muscle mRNA analysis revealed induction of the STAT3 target genes IL-6, SOCS3, cMyc (peaking at T3, p<0.05), IL-6Rα and GP130 (peaking at T24, p<0.05). In addition, Myf5 mRNA was up-regulated at T24 (p<0.05) with no appreciable change in MRF4 mRNA.
  
  
  CONCLUSIONS
  We demonstrate that IL-6 induction of STAT3 signaling occurred exclusively in the nuclei of SCs in response to MLC. An increase in the number of cMyc+ SCs indicated that human SCs were induced to proliferate under the control of STAT3 signaling.
authors.affiliation: Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Toth
authors.forename: Bryon R
authors.initials: BR
authors.lastname: McKay
authors.forename: Michael
authors.initials: M
authors.lastname: De Lisio
authors.forename: Jonathon P
authors.initials: JP
authors.lastname: Little
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
authors.forename: Gianni
authors.initials: G
authors.lastname: Parise
mesh_terms: D000208:Acute Disease; D002467:Cell Nucleus / Q000201:enzymology; D049109:Cell Proliferation; D003402:Creatine Kinase / Q000097:blood; D015444:Exercise; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D051763:PAX7 Transcription Factor / Q000378:metabolism; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D013997:Time Factors; D055815:Young Adult
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D003402:Creatine Kinase