Document Detail

Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle.
MedLine Citation:
PMID:  22835827     Owner:  NLM     Status:  MEDLINE    
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.
Emilie Roudier; Paul Forn; Mary Ellen Perry; Olivier Birot
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2012-07-26
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  26     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-02     Completed Date:  2013-01-29     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4530-9     Citation Subset:  IM    
Faculty of Health, Angiogenesis Research Group, York University, Toronto, Ontario, Canada.
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MeSH Terms
Gene Expression Regulation / physiology*
Muscle, Skeletal / blood supply*,  metabolism
Neovascularization, Physiologic / genetics,  physiology*
Obesity / physiopathology
Physical Conditioning, Animal / physiology*
Proto-Oncogene Proteins c-mdm2 / genetics,  metabolism*
Rats, Sprague-Dawley
Rats, Zucker
Vascular Endothelial Growth Factor A / genetics,  metabolism
Reg. No./Substance:
0/Vascular Endothelial Growth Factor A; 0/vascular endothelial growth factor A, rat; EC protein, mouse; EC Proteins c-mdm2

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