title: The TORC1/P70S6K and TORC1/4EBP1 signaling pathways have a stronger contribution on skeletal muscle growth than MAPK/ERK in an early vertebrate: Differential involvement of the IGF system and atrogenes.
abstract: Knowledge about the underlying mechanisms, particularly the signaling pathways that account for muscle growth in vivo in early vertebrates is still scarce. Fish (Paralichthys adspersus) were fasted for 3weeks to induce a catabolic period of strong muscle atrophy. Subsequently, fish were refed for 2weeks to induce compensatory muscle hypertrophy. During refeeding, the fish were treated daily with either rapamycin (TORC blocker), PD98059 (MEK blocker), or PBS (V; vehicle), or were untreated (C; control). Rapamycin and PD98059 differentially impaired muscle cellularity in vivo, growth performance, and the expression of growth-related genes, and the inhibition of TORC1 had a greater impact on fish muscle growth than the inhibition of MAPK. Blocking TORC1 inhibited the phosphorylation of P70S6K and 4EBP1, two downstream components activated by TORC1, thus affecting protein contents in muscle. Concomitantly, the gene expression in muscle of igf-1, 2 and igfbp-4, 5 was down-regulated while the expression of atrogin-1, murf-1, and igfbp-2, 3 was up-regulated. Muscle hypertrophy was abolished and muscle atrophy was promoted, which finally affected body weight. TORC2 complex was not affected by rapamycin. On the other hand, the PD98059 treatment triggered ERK inactivation, a downstream component activated by MEK. mRNA contents of igf-1 in muscle were down-regulated, and muscle hypertrophy was partially impaired. The present study provides the first direct data on the in vivo contribution of TORC1/P70S6K, TORC1/4EBP1, and MAPK/ERK signaling pathways in the skeletal muscle of an earlier vertebrate, and highlights the transcendental role of TORC1 in growth from the cellular to organism level.
authors.affiliation: Interdisciplinary Center for Aquaculture Research (INCAR), Víctor Lamas 1290, PO Box 160-C, Concepción, Chile; Laboratorio de Biotecnologia Molecular, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas, Universidad Andres Bello, Av. Republica 217, Santiago, Chile. Electronic address: edua.fuentes@uandresbello.edu.
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Fuentes
authors.affiliation: Fish Endocrinology Laboratory, Department of Biological and Environmental Sciences, University of Gothenburg, Box 463, S-40530 Gothenburg, Sweden.
authors.forename: Ingibjörg Eir
authors.initials: IE
authors.lastname: Einarsdottir
authors.affiliation: Escuela de Medicina Veterinaria, Facultad de Ecologia y Recursos Naturales, Universidad Andres Bello, Av. Republica 440, Santiago, Chile.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Paredes
authors.affiliation: Escuela de Medicina Veterinaria, Facultad de Ecologia y Recursos Naturales, Universidad Andres Bello, Av. Republica 440, Santiago, Chile.
authors.forename: Christian
authors.initials: C
authors.lastname: Hidalgo
authors.affiliation: Interdisciplinary Center for Aquaculture Research (INCAR), Víctor Lamas 1290, PO Box 160-C, Concepción, Chile; Laboratorio de Biotecnologia Molecular, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas, Universidad Andres Bello, Av. Republica 217, Santiago, Chile.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Valdes
authors.affiliation: Fish Endocrinology Laboratory, Department of Biological and Environmental Sciences, University of Gothenburg, Box 463, S-40530 Gothenburg, Sweden.
authors.forename: Björn Thrandur
authors.initials: BT
authors.lastname: Björnsson
authors.affiliation: Interdisciplinary Center for Aquaculture Research (INCAR), Víctor Lamas 1290, PO Box 160-C, Concepción, Chile; Laboratorio de Biotecnologia Molecular, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas, Universidad Andres Bello, Av. Republica 217, Santiago, Chile. Electronic address: amolina@unab.cl.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molina
mesh_terms: D000818:Animals; D039642:Eukaryotic Initiation Factors / Q000502:physiology*; D005412:Flatfishes / Q000254:growth & development* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D046912:Multiprotein Complexes / Q000502:physiology*; D024510:Muscle Development / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D013002:Somatomedins / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D039642:Eukaryotic Initiation Factors; D005419:Flavonoids; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D013002:Somatomedins; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus
keywords: Atrophy; ERK; Hypertrophy; IGF system; TORC; Teleost fish