Combined effect of AAV-U7-induced dystrophin exon skipping and soluble activin Type IIB receptor in mdx mice.
Adeno-associated virus (AAV)-U7-mediated skipping of dystrophin-exon-23 restores dystrophin expression and muscle function in the mdx mouse model of Duchenne muscular dystrophy. Soluble activin receptor IIB (sActRIIB-Fc) inhibits signaling of myostatin and homologous molecules and increases muscle mass and function of wild-type and mdx mice. We hypothesized that combined treatment with AAV-U7 and sActRIIB-Fc may synergistically improve mdx muscle function. Bioactivity of sActRIIB-Fc on skeletal muscle was first demonstrated in wild-type mice. In mdx mice we show that AAV-U7-mediated dystrophin restoration improved specific muscle force and resistance to eccentric contractions when applied alone. Treatment of mdx mice with sActRIIB-Fc increased body weight, muscle mass and myofiber size, but had little effect on muscle function. Combined treatment stimulated muscle growth comparable to the effect of sActRIIB-Fc alone and dystrophin rescue was similar to AAV-U7 alone. Moreover, combined treatment improved maximal tetanic force and the resistance to eccentric contraction to similar extent as AAV-U7 alone. In conclusion, combination of dystrophin exon skipping with sActRIIB-Fc brings together benefits of each treatment; however, we failed to evidence a clear synergistic effect on mdx muscle function.
Leiden University Medical Center (LUMC), Department of Human Genetics, 2333 ZC Leiden, The Netherlands.
Willem M H
WM
Hoogaars
Etienne
E
Mouisel
Arja
A
Pasternack
Juha J
JJ
Hulmi
Karima
K
Relizani
Markus
M
Schuelke
Elja
E
Schirwis
Luis
L
Garcia
Olli
O
Ritvos
Arnaud
A
Ferry
Peter A
PA
't Hoen
Helge
H
Amthor
D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D000229:Dependovirus / Q000235:genetics*; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000235:genetics; D018482:Muscle, Skeletal / Q000254:growth & development / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*
D016189:Dystrophin; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B