title: β-Arrestin scaffolds and signaling elements essential for the obestatin/GPR39 system that determine the myogenic program in human myoblast cells.
abstract: Obestatin/GPR39 signaling stimulates skeletal muscle repair by inducing the expansion of satellite stem cells as well as myofiber hypertrophy. Here, we describe that the obestatin/GPR39 system acts as autocrine/paracrine factor on human myogenesis. Obestatin regulated multiple steps of myogenesis: myoblast proliferation, cell cycle exit, differentiation and recruitment to fuse and form multinucleated hypertrophic myotubes. Obestatin-induced mitogenic action was mediated by ERK1/2 and JunD activity, being orchestrated by a G-dependent mechanism. At a later stage of myogenesis, scaffolding proteins β-arrestin 1 and 2 were essential for the activation of cell cycle exit and differentiation through the transactivation of the epidermal growth factor receptor (EGFR). Upon obestatin stimulus, β-arrestins are recruited to the membrane, where they functionally interact with GPR39 leading to Src activation and signalplex formation to EGFR transactivation by matrix metalloproteinases. This signalplex regulated the mitotic arrest by p21 and p57 expression and the mid- to late stages of differentiation through JNK/c-Jun, CAMKII, Akt and p38 pathways. This finding not only provides the first functional activity for β-arrestins in myogenesis but also identify potential targets for therapeutic approaches by triggering specific signaling arms of the GPR39 signaling involved in myogenesis.
authors.affiliation: Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.
authors.forename: Icía
authors.initials: I
authors.lastname: Santos-Zas
authors.affiliation: Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain.|Sprott Centre for Stem Cell Research, Ottawa Health Research Institute, Ottawa, Canada.
authors.forename: Uxía
authors.initials: U
authors.lastname: Gurriarán-Rodríguez
authors.affiliation: Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Cid-Díaz
authors.affiliation: Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Figueroa
authors.affiliation: Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: González-Sánchez
authors.affiliation: Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Bouzo-Lorenzo
authors.affiliation: Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Mosteiro
authors.affiliation: Servicio de Cirugía Ortopédica y Traumatología, CHUS, SERGAS, Santiago de Compostela, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Señarís
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.|Departamento de Medicina, USC, Santiago de Compostela, Spain.
authors.forename: Felipe F
authors.initials: FF
authors.lastname: Casanueva
authors.affiliation: Departamento de Fisiología, USC, Santiago de Compostela, Spain.
authors.forename: Xesús
authors.initials: X
authors.lastname: Casabiell
authors.affiliation: Departamento de Ciencias Morfológicas, USC, Santiago de Compostela, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Gallego
authors.affiliation: Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Pazos
authors.affiliation: Institut de Myologie, INSERM, and Sorbonne Universités, Université Pierre et Marie Curie, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mouly
authors.affiliation: Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain. jesus.perez@usc.es.|CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain. jesus.perez@usc.es.
authors.forename: Jesús P
authors.initials: JP
authors.lastname: Camiña
mesh_terms: D019390:Arrestins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D054439:Ghrelin / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D024510:Muscle Development / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; D019390:Arrestins; C495797:GPR39 protein, human; D054439:Ghrelin; D043562:Receptors, G-Protein-Coupled; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C505799:obestatin, human
keywords: Obestatin signaling; Skeletal muscle; Skeletal muscle regeneration