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

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/Δ7‐9 ) mice have a 60% reduction in Mdm2 expression compared with that in wild‐type animals. Capillary staining on muscle sections from Mdm2 Puro/Δ7‐9 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/Δ7‐9 mice. Prolonged exercise training resulted in increased Mdm2 protein expression (+49%) and capillarization (+24%) in wild‐type muscles. However, exercise training‐induced angiogenesis was abolished in Mdm2 Puro/Δ7‐9 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