title: Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle.
abstract: 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.
authors: Faculty of Health, Angiogenesis Research Group, York University, Toronto, Ontario, Canada.
authors: Emilie
authors: E
authors: Roudier
authors: Paul
authors: P
authors: Forn
authors: Mary Ellen
authors: ME
authors: Perry
authors: Olivier
authors: O
authors: Birot
mesh_terms: D000818:Animals; D002196:Capillaries; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D009765:Obesity / Q000503:physiopathology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2