title: Action of obestatin in skeletal muscle repair: stem cell expansion, muscle growth, and microenvironment remodeling.
abstract: The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Overall, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration.
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, Spain; Current address: 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, 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; CIBER Fisiopatología de la Obesidad y Nutrición, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: González-Sánchez
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Spain; Departamento de Fisiología, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Beiroa
authors.affiliation: Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy; Interuniversity Institute of Myology, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Moresi
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, Spain.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Mosteiro
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Unidad de Inmunología, CHUS, Santiago de Compostela, Spain.
authors.forename: Juan E
authors.initials: JE
authors.lastname: Viñuela
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: Departamento de Ciencias Morfológicas, USC, Santiago de Compostela, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: García-Caballero
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, Spain; Departamento de Medicina, USC, Santiago de Compostela, Spain.
authors.forename: Felipe F
authors.initials: FF
authors.lastname: Casanueva
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Spain; Departamento de Fisiología, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
authors.affiliation: Departamento de Ciencias Morfológicas, USC, Santiago de Compostela, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Gallego
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Renaud
authors.affiliation: Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy; Interuniversity Institute of Myology, Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Adamo
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, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Pazos
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, Spain. Electronic address: jesus.perez@usc.es.
authors.forename: Jesús P
authors.initials: JP
authors.lastname: Camiña
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D054439:Ghrelin / Q000494:pharmacology*; D007273:Injections, Intramuscular; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024510:Muscle Development / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009135:Muscular Diseases / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C512928:GPR39 protein, mouse; D054439:Ghrelin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D042442:Vascular Endothelial Growth Factors; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048051:p38 Mitogen-Activated Protein Kinases