title: Skeletal muscle myogenesis is regulated by G protein-coupled receptor kinase 2.
abstract: G protein-coupled receptor kinase 2 (GRK2) is an important serine/threonine-kinase regulating different membrane receptors and intracellular proteins. Attenuation of Drosophila Gprk2 in embryos or adult flies induced a defective differentiation of somatic muscles, loss of fibers, and a flightless phenotype. In vertebrates, GRK2 hemizygous mice contained less but more hypertrophied skeletal muscle fibers than wild-type littermates. In C2C12 myoblasts, overexpression of a GRK2 kinase-deficient mutant (K220R) caused precocious differentiation of cells into immature myotubes, which were wider in size and contained more fused nuclei, while GRK2 overexpression blunted differentiation. Moreover, p38MAPK and Akt pathways were activated at an earlier stage and to a greater extent in K220R-expressing cells or upon kinase downregulation, while the activation of both kinases was impaired in GRK2-overexpressing cells. The impaired differentiation and fewer fusion events promoted by enhanced GRK2 levels were recapitulated by a p38MAPK mutant, which was able to mimic the inhibitory phosphorylation of p38MAPK by GRK2, whereas the blunted differentiation observed in GRK2-expressing clones was rescued in the presence of a constitutively active upstream stimulator of the p38MAPK pathway. These results suggest that balanced GRK2 function is necessary for a timely and complete myogenic process.
authors.affiliation: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University, 28040 Madrid, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08017 Barcelona, Spain Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain CIBER de enfermedades neurodegenerativas (CIBERNED), 28049 Madrid, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Garcia-Guerra
authors.affiliation: Departament of Molecular Biology and Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain Instituto de Investigación Sanitaria la Princesa, 28006 Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Vila-Bedmar
authors.affiliation: Centro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Carrasco-Rando
authors.affiliation: Departament of Molecular Biology and Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain Instituto de Investigación Sanitaria la Princesa, 28006 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cruces-Sande
authors.affiliation: Centro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049 Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martín
authors.affiliation: Centro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Gómez
authors.affiliation: Centro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049 Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Ruiz-Gómez
authors.affiliation: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University, 28040 Madrid, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08017 Barcelona, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Lorenzo
authors.affiliation: CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08017 Barcelona, Spain Hospital Universitari de Tarragona Joan XXIII. IISPV. Universitat Rovira i Virgili, 43007 Tarragona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Veledo
authors.affiliation: Departament of Molecular Biology and Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain Instituto de Investigación Sanitaria la Princesa, 28006 Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Mayor
authors.affiliation: Departament of Molecular Biology and Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain Instituto de Investigación Sanitaria la Princesa, 28006 Madrid, Spain irianieto@farm.ucm.es cmurga@cbm.uam.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Murga
authors.affiliation: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University, 28040 Madrid, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08017 Barcelona, Spain irianieto@farm.ucm.es cmurga@cbm.uam.es.
authors.forename: Iria
authors.initials: I
authors.lastname: Nieto-Vázquez
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D004331:Drosophila melanogaster / Q000254:growth & development / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D054769:G-Protein-Coupled Receptor Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Akt; GRK2; myogenesis; p38MAPK; skeletal muscle