IGF-1 Induces IP3-Dependent Calcium Signal Involved in the Regulation of Myostatin Gene Expression Mediated by NFAT During Myoblast Differentiation
Author
dc.contributor.author
Valdés, Juan A.
Author
dc.contributor.author
Flores, Sylvia
es_CL
Author
dc.contributor.author
Fuentes, Eduardo N.
es_CL
Author
dc.contributor.author
Osorio Fuentealba, César
es_CL
Author
dc.contributor.author
Jaimovich Pérez, Enrique
es_CL
Author
dc.contributor.author
Molina, Alfredo
es_CL
Admission date
dc.date.accessioned
2014-02-06T19:32:12Z
Available date
dc.date.available
2014-02-06T19:32:12Z
Publication date
dc.date.issued
2013
Cita de ítem
dc.identifier.citation
J. Cell. Physiol. 228: 1452–1463, 2013
en_US
Identifier
dc.identifier.other
DOI: 10.1002/jcp.24298
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/129261
General note
dc.description
Artículo de publicación ISI
en_US
Abstract
dc.description.abstract
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 g)/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 PLCg 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 PI3Kg, PLCg, 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.