Neonatal Systemic AAV-Mediated Gene Delivery of GDF11 Inhibits Skeletal Muscle Growth
Neonatal Systemic AAV-Mediated Gene Delivery of GDF11 Inhibits Skeletal Muscle Growth
复制标题
DOI：
10.1016/j.ymthe.2018.01.016
复制
发表时间：
2018-04-04
影响因子：
12.4
通讯作者：
Xiao, Xiao
中科院分区：
文献类型：
--
作者：
Jin, Quan;Qiao, Chunping;Xiao, Xiao
生长与分化因子11 （GDF11; BMP11）是转化生长因子β (tgf - β)超家族中的一种循环细胞因子。用重组GDF11 （rGDF11）蛋白治疗已被证明可以逆转老年小鼠的骨骼肌功能障碍。然而，GDF11在骨骼肌中的作用尚不完全清楚。由于GDF11激活了TGF-b-SMAD2/3通路，我们假设GDF11过表达会抑制骨骼肌的生长。为了验证这一假设，我们构建了含有人GDF11 （AAV9-GDF11）或人IgG1 fc融合GDF11前肽（AAV9- gdf11pro - fc -1）基因的重组腺相关病毒血清型9 （AAV9）载体，研究GDF11过表达或阻断对骨骼肌生长和功能的影响。在新生儿C57BL/6J小鼠静脉注射AAV9-GDF11后，我们观察到16周时持续的肢体肌肉生长抑制以及前肢握力和跑步机耐力的降低。相反，AAV9-GDF11Pro-Fc-1治疗导致28周后肢体肌肉质量和前肢握力增加，尽管治疗组和对照组之间没有观察到总体重/肌肉质量比的差异。总之，我们的研究结果表明GDF11过表达对骨骼肌生长有抑制作用。
Growth and differentiation factor 11 (GDF11; BMP11) is a circulating cytokine in the transforming growth factor beta (TGF-beta) superfamily. Treatment with recombinant GDF11 (rGDF11) protein has previously been shown to reverse skeletal muscle dysfunction in aged mice. However, the actions of GDF11 in skeletal muscle are still not fully understood. Because GDF11 activates the TGF-b-SMAD2/3 pathway, we hypothesized that GDF11 overexpression would inhibit skeletal muscle growth. To test this hypothesis, we generated recombinant adeno-associated virus serotype 9 (AAV9) vectors harboring the gene for either human GDF11 (AAV9-GDF11) or human IgG1 Fc-fused GDF11 propeptide (AAV9-GDF11Pro-Fc-1) to study the effects of GDF11 overexpression or blockade on skeletal muscle growth and function in vivo. After intravenous administration of AAV9-GDF11 into neonatal C57BL/6J mice, we observed sustained limb muscle growth inhibition along with reductions in forelimb grip strength and treadmill running endurance at 16 weeks. Conversely, treatment with AAV9-GDF11Pro-Fc-1 led to increased limb muscle mass and forelimb grip strength after 28 weeks, although a difference in the total body mass/muscle mass ratio was not observed between treatment and control groups. In sum, our results suggest GDF11 overexpression has an inhibitory effect on skeletal muscle growth.