title: Interleukin-6 promotes myogenic differentiation of mouse skeletal muscle cells: role of the STAT3 pathway.
abstract: Myogenic differentiation of skeletal muscle cells is characterized by a sequence of events that include activation of signal transducer and activator of transcription 3 (STAT3) and enhanced expression of its target gene Socs3. Autocrine effects of IL-6 may contribute to the activation of the STAT3-Socs3 cascade and thus to myogenic differentiation. The importance of IL-6 and STAT3 for the differentiation process was studied in C2C12 cells and in primary mouse wild-type and IL-6(-/-) skeletal muscle cells. In differentiating C2C12 myoblasts, the upregulation of IL-6 mRNA expression and protein secretion started after increased phosphorylation of STAT3 on tyrosine 705 and increased mRNA expression of Socs3 was observed. Knockdown of STAT3 and IL-6 mRNA in differentiating C2C12 myoblasts impaired the expression of the myogenic markers myogenin and MyHC IIb and subsequently myotube fusion. However, the knockdown of IL-6 did not prevent the induction of STAT3 tyrosine phosphorylation. The IL-6-independent activation of STAT3 was verified in differentiating primary IL-6(-/-) myoblasts. The phosphorylation of STAT3 and the expression levels of STAT3, Socs3, and myogenin during differentiation were comparable in the primary myoblasts independent of the genotype. However, IL-6(-/-) cells failed to induce MyHC IIb expression to the same level as in wild-type cells and showed reduced myotube formation. Supplementation of IL-6 could partially restore the fusion of IL-6(-/-) cells. These data demonstrate that IL-6 depletion during myogenic differentiation does not reduce the activation of the STAT3-Socs3 cascade, while IL-6 and STAT3 are both necessary to promote myotube fusion.
authors.affiliation: Division of Pathobiochemistry and Clinical Chemistry, University Tuebingen, Tuebingen, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Hoene
authors.forename: Heike
authors.initials: H
authors.lastname: Runge
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Erwin D
authors.initials: ED
authors.lastname: Schleicher
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology*; D018008:Myogenin / Q000096:biosynthesis; D018995:Myosin Heavy Chains / Q000096:biosynthesis; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis; D014443:Tyrosine / Q000378:metabolism
chemical_list: D015850:Interleukin-6; C572750:MyHC IIb protein, mouse; C503801:Myog protein, mouse; D018008:Myogenin; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; D018995:Myosin Heavy Chains