title: Inhibition of p38 MAPK signaling promotes late stages of myogenesis.
abstract: Signaling through the p38 mitogen-activated protein kinases (MAPKs) is essential for cartilage formation in primary cultures of limb mesenchyme. Here we show that, concurrent with a decrease in chondrogenesis, inhibition of p38 in limb bud cultures dramatically promotes muscle development. Specifically, treatment of primary limb bud cultures with p38 inhibitors increases the expression of myogenic markers and causes a striking increase in formation of myotubes, which were detected using antibodies specific for myosin heavy chain. These results are surprising in that they contrast with several previous reports describing a requirement for p38 during myogenesis. Nonetheless, the enhanced myogenesis leads to the formation of an extensive network of contractile myofibers, and this enhanced myogenesis can be conferred upon myogenic cells from clonal populations, such as G8 or C2C12 cells, if they are co-cultured with the limb mesenchymal cells. We provide evidence for the maintenance and rapid organization of existing, somitic-derived limb myoblasts in response to p38 inhibitors. These findings imply a novel and unexpected role for p38 MAPK inhibition in myogenesis and highlight the importance of the limb bud microenvironment in promoting the progression of limb myoblasts.
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Weston
authors.forename: Arthur V
authors.initials: AV
authors.lastname: Sampaio
authors.forename: Alan G
authors.initials: AG
authors.lastname: Ridgeway
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002356:Cartilage / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005121:Extremities / Q000196:embryology; D017930:Genes, Reporter; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D024510:Muscle Development; D009132:Muscles / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D001616:beta-Galactosidase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase; D018995:Myosin Heavy Chains