E2F transcription factor-1 deficiency reduces pathophysiology in the mouse model of Duchenne muscular dystrophy through increased muscle oxidative metabolism.
E2F1 deletion leads to increased mitochondrial number and function, increased body temperature in response to cold and increased resistance to fatigue with exercise. Since E2f1-/- mice show increased muscle performance, we examined the effect of E2f1 genetic inactivation in the mdx background, a mouse model of Duchenne muscular dystrophy (DMD). E2f1-/-;mdx mice demonstrated a strong reduction of physiopathological signs of DMD, including preservation of muscle structure, decreased inflammatory profile, increased utrophin expression, resulting in better endurance and muscle contractile parameters, comparable to normal mdx mice. E2f1 deficiency in the mdx genetic background increased the oxidative metabolic gene program, mitochondrial activity and improved muscle functions. Interestingly, we observed increased E2F1 protein levels in DMD patients, suggesting that E2F1 might represent a promising target for the treatment of DMD.
Institut de Génétique Moléculaire de Montpellier, Montpellier F-34293, France.
Emilie
E
Blanchet
Jean-Sébastien
JS
Annicotte
Ludivine A
LA
Pradelli
Gérald
G
Hugon
Stéfan
S
Matecki
Dominique
D
Mornet
François
F
Rivier
Lluis
L
Fajas
D000293:Adolescent; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009132:Muscles / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D010084:Oxidation-Reduction
D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse