Bentzinger C Florian, Barzaghi Patrizia, Lin Shuo, Ruegg Markus A
Biozentrum, University of Basel, Basel, Switzerland.
FASEB J. 2005 Jun;19(8):934-42. doi: 10.1096/fj.04-3376com.
Mutations in the gene encoding the alpha2 subunit of laminins cause the severe "merosin-deficient congenital muscular dystrophy" (MDC1A). We have recently shown that overexpression of a miniaturized form of the molecule agrin (mini-agrin) counteracts the disease in dy(W)/dy(W) mice, a model for MDC1A. However, these mice express some residual truncated laminin-alpha2, suggesting that the observed amelioration might be due to mini-agrin's presenting the residual laminin-alpha2 to its receptors. Here we show that the mini-agrin counteracts the disease in dy(3K)/dy(3K) mice, which are null for laminin-alpha2. As in dy(W)/dy(W) mice, mini-agrin improves both the function and structure of muscle. We show that muscle regeneration after injury is severely impaired in dy(3K)/dy(3K) mice but is restored in the mini-agrin-expressing littermates. In summary, our results 1) show that the direct linkage of muscle basal lamina with the sarcolemma is the basis of mini-agrin-mediated amelioration and 2) provide unprecedented evidence that this linkage is important for proper regeneration of muscle fibers after injury. Our findings thus suggest that treatment with mini-agrin might be beneficial over the entire spectrum of the MDC1A disease, whose severity inversely correlates with expression levels and the size of the truncation in laminin-alpha2.
编码层粘连蛋白α2亚基的基因突变会导致严重的“缺乏merosin的先天性肌营养不良症”（MDC1A）。我们最近发现，一种小型化形式的聚集蛋白聚糖（微型聚集蛋白聚糖）的过表达可对抗dy(W)/dy(W)小鼠（一种MDC1A模型）的疾病。然而，这些小鼠表达一些残留的截短型层粘连蛋白α2，这表明观察到的病情改善可能是由于微型聚集蛋白聚糖将残留的层粘连蛋白α2呈递给其受体。在此我们表明，微型聚集蛋白聚糖可对抗dy(3K)/dy(3K)小鼠（这些小鼠的层粘连蛋白α2基因完全缺失）的疾病。与dy(W)/dy(W)小鼠一样，微型聚集蛋白聚糖可改善肌肉的功能和结构。我们发现，dy(3K)/dy(3K)小鼠损伤后的肌肉再生严重受损，但在表达微型聚集蛋白聚糖的同窝小鼠中得以恢复。总之，我们的结果1）表明肌肉基底膜与肌膜的直接连接是微型聚集蛋白聚糖介导的病情改善的基础，2）提供了前所未有的证据，证明这种连接对于损伤后肌纤维的正常再生很重要。因此，我们的研究结果表明，用微型聚集蛋白聚糖进行治疗可能对整个MDC1A疾病谱有益，该疾病的严重程度与层粘连蛋白α2的表达水平和截短大小呈负相关。
