Combined Effect of AAV-U7-Induced Dystrophin Exon Skipping and Soluble Activin Type IIB Receptor in mdxMice.

AbstractAdeno-associated virus (AAV)-U7–mediated skipping of dystrophin-exon-23 restores dystrophin expression and muscle function in the mdxmouse 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 mdxmice. We hypothesized that combined treatment with AAV-U7 and sActRIIB-Fc may synergistically improve mdxmuscle function. Bioactivity of sActRIIB-Fc on skeletal muscle was first demonstrated in wild-type mice. In mdxmice we show that AAV-U7–mediated dystrophin restoration improved specific muscle force and resistance to eccentric contractions when applied alone. Treatment of mdxmice 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 mdxmuscle function. [ABSTRACT FROM AUTHOR]