TY - JOUR
T1 - Interactions between p-Akt and Smad3 in injured muscles initiate myogenesis or fibrogenesis
AU - Dong, Yanjun
AU - Lakhia, Ronak
AU - Thomas, Sandhya S.
AU - Dong, Yanlan
AU - Wang, Xiaonan H.
AU - Silva, Kleiton Augusto Santos
AU - Zhang, Liping
PY - 2013/8/1
Y1 - 2013/8/1
N2 - In catabolic conditions such as aging and diabetes, IGF signaling is impaired and fibrosis develops in skeletal muscles. To examine whether impaired IGF signaling initiates muscle fibrosis, we generated IGF-IR+/- heterozygous mice by crossing loxP-floxed IGF-IR (exon 3) mice with MyoD-cre mice. IGF-IR+/- mice were studied because we were unable to obtain homozygous IGF-IR-KO mice. In IGF-IR+/- mice, both growth and expression of myogenic genes (MyoD and myogenin; markers of satellite cell proliferation and differentiation, respectively) were depressed. Likewise, in injured muscles of IGF-IR+/- mice, there was impaired regeneration, depressed expression of MyoD and myogenin, and increased expression of TGF-β1, α-SMA, collagen I, and fibrosis. To uncover mechanisms stimulating fibrosis, we isolated satellite cells from muscles of IGFIR +/- mice and found reduced proliferation and differentiation plus increased TGF-β1 production. In C2C12 myoblasts (a model of satellite cells), IGF-I treatment inhibited TGF-β1-stimulated Smad3 phosphorylation, its nuclear translocation, and expression of fibronectin. Using immunoprecipitation assay, we found an interaction between p-Akt or Akt with Smad3 in wild-type mosuse muscles and in C2C12 myoblasts; importantly, IGF-I increased p-Akt and Smad3 interaction, whereas TGF-β1 decreased it. Therefore, in muscles of IGF-IR+/- mice, the reduction in IGF-IR reduces p-Akt, allowing for dissociation and nuclear translocation of Smad3 to enhance the TGF-β1 signaling pathway, leading to fibrosis. Thus, strategies to improve IGF signaling could prevent fibrosis in catabolic conditions with impaired IGF signaling.
AB - In catabolic conditions such as aging and diabetes, IGF signaling is impaired and fibrosis develops in skeletal muscles. To examine whether impaired IGF signaling initiates muscle fibrosis, we generated IGF-IR+/- heterozygous mice by crossing loxP-floxed IGF-IR (exon 3) mice with MyoD-cre mice. IGF-IR+/- mice were studied because we were unable to obtain homozygous IGF-IR-KO mice. In IGF-IR+/- mice, both growth and expression of myogenic genes (MyoD and myogenin; markers of satellite cell proliferation and differentiation, respectively) were depressed. Likewise, in injured muscles of IGF-IR+/- mice, there was impaired regeneration, depressed expression of MyoD and myogenin, and increased expression of TGF-β1, α-SMA, collagen I, and fibrosis. To uncover mechanisms stimulating fibrosis, we isolated satellite cells from muscles of IGFIR +/- mice and found reduced proliferation and differentiation plus increased TGF-β1 production. In C2C12 myoblasts (a model of satellite cells), IGF-I treatment inhibited TGF-β1-stimulated Smad3 phosphorylation, its nuclear translocation, and expression of fibronectin. Using immunoprecipitation assay, we found an interaction between p-Akt or Akt with Smad3 in wild-type mosuse muscles and in C2C12 myoblasts; importantly, IGF-I increased p-Akt and Smad3 interaction, whereas TGF-β1 decreased it. Therefore, in muscles of IGF-IR+/- mice, the reduction in IGF-IR reduces p-Akt, allowing for dissociation and nuclear translocation of Smad3 to enhance the TGF-β1 signaling pathway, leading to fibrosis. Thus, strategies to improve IGF signaling could prevent fibrosis in catabolic conditions with impaired IGF signaling.
KW - Fibrosis
KW - Insulin-like growth factor i
KW - Myogenesis
KW - Satellite cells
KW - Smad3
KW - Transforming growth factor-β1
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UR - http://www.scopus.com/inward/citedby.url?scp=84880969207&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.00644.2012
DO - 10.1152/ajpendo.00644.2012
M3 - Article
C2 - 23736539
AN - SCOPUS:84880969207
SN - 0193-1849
VL - 305
SP - E367-E375
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 3
ER -