title: Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation.
abstract: Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors.
authors.affiliation: Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile.
authors.forename: A
authors.initials: A
authors.lastname: Retamales
authors.affiliation: Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile.
authors.forename: R
authors.initials: R
authors.lastname: Zuloaga
authors.affiliation: Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile.
authors.forename: C A
authors.initials: CA
authors.lastname: Valenzuela
authors.affiliation: Laboratory of Biotechnology and Aquatic Genomics, Universidad de Concepción, Concepción, Chile; Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción, Chile.
authors.forename: C
authors.initials: C
authors.lastname: Gallardo-Escarate
authors.affiliation: Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile; Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción, Chile.
authors.forename: A
authors.initials: A
authors.lastname: Molina
authors.affiliation: Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile; Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción, Chile. Electronic address: jvaldes@unab.cl.
authors.forename: J A
authors.initials: JA
authors.lastname: Valdés
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology; D055435:Myostatin / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: D055435:Myostatin; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D007334:Insulin-Like Growth Factor I
keywords: Crosstalk; IGF-1; Myoblast differentiation; Myostatin