Regulación de la actividad biológica dependiente de miostatina por Angiotensina (1-7)
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2016
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es
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Universidad Andrés Bello
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Licencia CC
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Resumen
La atrofia muscular esquelética está caracterizada por la pérdida de la masa
muscular y la fuerza, principalmente debido a un incremento en la degradación de
proteínas miofibrilares, como la cadena pesada de miosina (MHC). Miostatina (MSTN)
es un factor proteico soluble que regula la masa muscular y cuyos niveles están
incrementados en varios tipos de atrofia muscular. Dentro de los efectos de MSTN en
atrofia, se encuentra un aumento de la degradación de proteínas miofibrilares debido a
una mayor actividad del sistema ubiquitina-proteosoma (UPS), especialmente un
incremento de Atrogina-1 y MuRF-1, dos E3 ubiquitina-ligasas. El efecto atrófico
inducido por MSTN es dependiente de la activación de la vía de señalización de Smad.
El sistema renina angiotensina (RAS) es un regulador de la masa muscular.
Angiotensina (1-7) (Ang (1-7)) es un péptido del eje no-clásico de RAS. En nuestro
laboratorio hemos demostrado previamente que Ang (1-7) tiene actividad anti-atrófica
en modelos de atrofia muscular inducidos por angiotensina II y lipopolisacárido, dos
modelos en los cuales hemos determinado además, alta expresión de MSTN muscular,
sugiriendo que podria ser un factor común en la generación y/o mantención de la atrofia
muscular en estos modelos. Además, se demostró recientemente que Ang (1-7) es
capaz de disminuir la activación de la vía de señalización de Smad dependiente de
TGF-β, una proteína perteneciente a la misma familia que MSTN. En conjunto, estos
antecedentes permiten proponer en esta tesis la siguiente hipótesis: “Ang (1-7)
disminuye la activación de la vía Smad y previene la inducción de parámetros de atrofia
inducida por MSTN”.
Para probar esta hipótesis, se utilizo un modelo in vitro de miotubos C2C12 los
que fueron tratados con MSTN en presencia o ausencia de Ang (1-7) y se evaluó: 1) el
efecto de Ang (1-7) sobre la vía de señalización de Smad activada por MSTN,
determinada por la medición de los niveles proteicos de Smad2 y Smad3 fosforiladas;
2) el efecto de Ang (1-7) sobre parámetros de atrofia inducidos por MSTN, determinado
por la medición del diámetro de miotubos, niveles proteicos y de mRNA de MHC,
Atrogina-1 y MuRF-1.
Los resultados indican que Ang (1-7) atenua la activación de la vía Smad
(disminuye los niveles proteicos de fosfo-Smad2 y fosfo-Smad3) y tiene un efecto
preventivo sobre parámetros de atrofia inducidos por MSTN (previene la disminución
del diámetro de miotubos y niveles proteicos de MHC, asi como también el aumento en
los niveles de mRNA y proteicos de Atrogina-1 y MuRF-1).
En resumen, estos resultados sugieren que Ang (1-7) es un péptido capaz de
disminuir la activación de vía de señalización de Smad y prevenir la inducción de
parámetros de atrofia inducida por MSTN.
Skeletal muscle atrophy is characterized by the loss of muscle mass and strength mainly due to an increase in the degradation of myofibrillar proteins such as myosin heavy chain (MHC). Myostatin (MSTN) is a soluble peptide that regulates muscle mass. Its levels are augmented in several types of muscle atrophy. Among the effects of MSTN in atrophy is the increment in the degradation of miofibrillar proteins due to an increase of ubiquitin-proteasome system (UPS) activity, specially an increase of two E3 ubiquitin ligases: atrogin-1 and MuRF-1. In addition, MSTN-induced atrophy depends on Smad signaling activation. Renin angiotensin system (RAS) is a regulator of muscle mass. Angiotensin (1-7) (Ang (1-7)) is a peptide from non-classic axis of RAS. We have previously demonstrated that Ang (1-7) has anti-atrophic activity in two models of skeletal muscle atrophy induced by angiotensin II and lipopolysaccharide, in which we have found high expression of muscular MSTN. These antecedents suggest that MSTN could be a common factor in the generation and/or maintenance of skeletal muscle atrophy in these models. Furthermore, recent data proved that Ang (1-7) diminishes the activation of Smad pathway dependent on TGF-β, another factor that belongs to the same family of MSTN. This data allow us to propose the following hypothesis “Ang (1-7) decreases Smad pathway activation and prevents the induction of atrophy parameters induced by MSTN”. To test this hypothesis, an in vitro model of C2C12 myotubes was used, which were treated with MSTN in presence/absence of Ang (1-7) and it was evaluated: 1) the effect of Ang (1-7) upon Smad signaling pathway by MSTN, determined by the protein levels of phosphorylated Smad2 (pSmad2) and Smad3 (pSmad3); 2) the effect of Ang (1-7) upon atrophy parameters induced by MSTN, determined by the measure of myotube diameter, protein and mRNA levels of MHC, Atrogin-1 and MuRF-1. Our results indicate that Ang (1-7) attenuates Smad pathway activation (diminishes proteic levels of phospho-Smad2 and phospho-Smad3) and has a preventive effect upon atrophy parameters induced by MSTN (prevents the decrease of myotube diameter and protein levels of MHC, and also the increase in the mRNA and protein levels of Atrogin-1 and MuRF-1). In summary, these results suggest that Ang (1-7) is a peptide that decrease the Smad signaling pathway and prevents the induction of atrophy parameters induced by MSTN.
Skeletal muscle atrophy is characterized by the loss of muscle mass and strength mainly due to an increase in the degradation of myofibrillar proteins such as myosin heavy chain (MHC). Myostatin (MSTN) is a soluble peptide that regulates muscle mass. Its levels are augmented in several types of muscle atrophy. Among the effects of MSTN in atrophy is the increment in the degradation of miofibrillar proteins due to an increase of ubiquitin-proteasome system (UPS) activity, specially an increase of two E3 ubiquitin ligases: atrogin-1 and MuRF-1. In addition, MSTN-induced atrophy depends on Smad signaling activation. Renin angiotensin system (RAS) is a regulator of muscle mass. Angiotensin (1-7) (Ang (1-7)) is a peptide from non-classic axis of RAS. We have previously demonstrated that Ang (1-7) has anti-atrophic activity in two models of skeletal muscle atrophy induced by angiotensin II and lipopolysaccharide, in which we have found high expression of muscular MSTN. These antecedents suggest that MSTN could be a common factor in the generation and/or maintenance of skeletal muscle atrophy in these models. Furthermore, recent data proved that Ang (1-7) diminishes the activation of Smad pathway dependent on TGF-β, another factor that belongs to the same family of MSTN. This data allow us to propose the following hypothesis “Ang (1-7) decreases Smad pathway activation and prevents the induction of atrophy parameters induced by MSTN”. To test this hypothesis, an in vitro model of C2C12 myotubes was used, which were treated with MSTN in presence/absence of Ang (1-7) and it was evaluated: 1) the effect of Ang (1-7) upon Smad signaling pathway by MSTN, determined by the protein levels of phosphorylated Smad2 (pSmad2) and Smad3 (pSmad3); 2) the effect of Ang (1-7) upon atrophy parameters induced by MSTN, determined by the measure of myotube diameter, protein and mRNA levels of MHC, Atrogin-1 and MuRF-1. Our results indicate that Ang (1-7) attenuates Smad pathway activation (diminishes proteic levels of phospho-Smad2 and phospho-Smad3) and has a preventive effect upon atrophy parameters induced by MSTN (prevents the decrease of myotube diameter and protein levels of MHC, and also the increase in the mRNA and protein levels of Atrogin-1 and MuRF-1). In summary, these results suggest that Ang (1-7) is a peptide that decrease the Smad signaling pathway and prevents the induction of atrophy parameters induced by MSTN.
Notas
Tesis (Magíster en Biotecnología)
Palabras clave
Marcadores Genéticos, Atrofia Muscular