Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle

作者：Roudier Emilie; Forn Paul; Perry Mary Ellen; Birot Olivier^*

来源：The FASEB Journal, 2012, 26(11): 4530-4539.

DOI：10.1096/fj.12-212720

• VEGF-A
• endothelial cell
• p53
• physiology

Exercise-induced angiogenesis is a key determinant of skeletal muscle function. Here, we investigated whether the E3 ubiquitin ligase murine double minute-2 (Mdm2) exerts a proangiogenic function in exercised skeletal muscle. Mdm2 hypomorphic (Mdm2(Puro/Delta 7-9)) mice have a 60% reduction in Mdm2 expression compared with that in wild-type animals. Capillary staining on muscle sections from Mdm2(Puro/Delta 7-9) sedentary mice with a wild-type or knockout background for p53 revealed that deficiency in Mdm2 resulted in 20% capillary regression independently of p53 status. In response to one bout of exercise, protein expression of the proangiogenic vascular endothelial growth factor-A (VEGF-A) was increased by 64% in muscle from wild-type animals, and endothelial cell outgrowth from exercised muscle biopsy samples cultured in a 3-dimensional collagen gel was enhanced by 37%. These proangiogenic responses to exercise were impaired in exercised Mdm2(Puro/Delta 7-9) mice. Prolonged exercise training resulted in increased Mdm2 protein expression (+49%) and capillarization (+24%) in wildtype muscles. However, exercise training-induced angiogenesis was abolished in Mdm2(Puro/Delta 7-9) mice. Finally, exercise training restored Mdm2, VEGF-A, and capillarization levels in skeletal muscles from obese Zucker diabetic fatty rats compared with those in healthy animals. Our results define Mdm2 as a crucial regulator of capillary maintenance and exercise-induced angiogenesis in skeletal muscle.-Roudier, E., Forn, P., Perry, M. E., Birot, O. Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle. FASEB J. 26, 4530-4539 (2012). www.fasebj.org

• 出版日期2012-11