IGF-1 induces IP3-dependent calcium signal involved in the regulation of myostatin gene expression mediated by NFAT during myoblast differentiation

Juan A. Valdés, Sylvia Flores, Eduardo N. Fuentes, Cesar Osorio-Fuentealba, Enrique Jaimovich, Alfredo Molina

Resultado de la investigación: Contribución a una revistaArtículo

27 Citas (Scopus)

Resumen

Skeletal muscle differentiation is a complex and highly regulated process characterized by cell cycle arrest, which is associated with morphological changes including myoblast alignment, elongation, and fusion into multinucleated myotubes. This is a balanced process dynamically coordinated by positive and negative signals such as the insulin-like growth factor I (IGF-1) and myostatin (MSTN), respectively. In this study, we report that the stimulation of skeletal myoblasts during differentiation with IGF-1 induces a rapid and transient calcium increase from intracellular stores, which are principally mediated through the phospholipase C gamma (PLC γ)/inositol 1,4,5-triphosphate (IP3)-dependent signaling pathways. This response was completely blocked when myoblasts were incubated with LY294002 or transfected with the dominant-negative p110 gamma, suggesting a fundamental role of phosphatidylinositol 3-kinase (PI3K) in PLCγ activation. Additionally, we show that calcium released via IP3 and induced by IGF-1 stimulates NFAT-dependent gene transcription and nuclear translocation of the GFP-labeled NFATc3 isoform. This activation was independent of extracellular calcium influx and calcium release mediated by ryanodine receptor (RyR). Finally, we examined mstn mRNA levels and mstn promoter activity in myoblasts stimulated with IGF-1. We found a significant increase in mRNA contents and in reporter activity, which was inhibited by cyclosporin A, 11R-VIVIT, and by inhibitors of the PI3Kγ, PLCγ, and IP3 receptor. Our results strongly suggest that IGF-1 regulates myostatin transcription through the activation of the NFAT transcription factor in an IP3/calcium-dependent manner. This is the first study to demonstrate a role of calcium-dependent signaling pathways in the mRNA expression of myostatin.

Idioma originalInglés
Páginas (desde-hasta)1452-1463
Número de páginas12
PublicaciónJournal of Cellular Physiology
Volumen228
N.º7
DOI
EstadoPublicada - 1 jul 2013

Áreas temáticas de ASJC Scopus

  • Fisiología
  • Bioquímica clínica
  • Biología celular

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