| First Author | Aiken J | Year | 2016 |
| Journal | FASEB J | Volume | 30 |
| Issue | 3 | Pages | 1120-34 |
| PubMed ID | 26578686 | Mgi Jnum | J:230907 |
| Mgi Id | MGI:5766438 | Doi | 10.1096/fj.15-276964 |
| Citation | Aiken J, et al. (2016) Phosphorylation of murine double minute-2 on Ser166 is downstream of VEGF-A in exercised skeletal muscle and regulates primary endothelial cell migration and FoxO gene expression. FASEB J 30(3):1120-34 |
| abstractText | We demonstrated in a previous study that murine double minute (Mdm)-2 is essential for exercise-induced skeletal muscle angiogenesis. In the current study, we investigated the mechanisms that regulate Mdm2 activity in response to acute exercise and identified VEGF-A as a key stimulator of Mdm2 phosphorylation on Ser(166) (p-Ser166-Mdm2). VEGF-A and p-Ser166-Mdm2 protein levels were measured in human and rodent muscle biopsy specimens after 1 bout of exercise. VEGF-A-dependent Mdm2 phosphorylation was demonstrated in vivo in mice harboring myofiber-specific deletion of VEGF-A (mVEGF(-/-)) and in vitro in primary human and rodent endothelial cells (ECs). Exercise increased VEGF-A and p-Ser166-Mdm2 protein levels respectively by 157 and 68% in human muscle vs. pre-exercise levels. Similar results were observed in exercised rodent muscles compared to sedentary controls; however, exercise-induced Mdm2 phosphorylation was significantly attenuated in mVEGF(-/-) mice. Recombinant VEGF-A elevated p-Ser166-Mdm2 by 50-125% and stimulated migration by 33% in ECs when compared to untreated cells, whereas the Mdm2 antagonist Nutlin-3a abrogated VEGF-driven EC migration. Finally, overexpression of a Ser166-Mdm2 phosphorylation mimetic increased EC migration, increased Mdm2 to FoxO1 binding (+55%), and decreased FoxO1-dependent gene expression compared with ECs overexpressing WT-Mdm2. Our results suggest that VEGF-mediated Mdm2 phosphorylation on Ser(166) is a novel proangiogenic pathway within the skeletal muscle.-Aiken, J., Roudier, E., Ciccone, J., Drouin, G., Stromberg, A., Vojnovic, J., Olfert, I. M., Haas, T., Gustafsson, T., Grenier, G., Birot, O. Phosphorylation of murine double minute-2 on Ser(166) is downstream of VEGF-A in exercised skeletal muscle and regulates primary endothelial cell migration and FoxO gene expression. |
