PDF(Pubmed)
Abstract：
Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. MBNL1 and MBNL2 are the most abundantly expressed members in skeletal muscle. A key aspect of DM1 is poor muscle regeneration and repair, leading to dystrophy. We used a BaCl2-induced damage model of muscle injury to study regeneration and effects on skeletal muscle satellite cells (MuSCs) in Mbnl1∆E3/∆E3 and Mbnl2∆E2/∆E2 knockout mice. Similar experiments have previously shown deleterious effects on these parameters in mouse models of RNA toxicity. Muscle regeneration in Mbnl1 and Mbnl2 knockout mice progressed normally with no obvious deleterious effects on MuSC numbers or increased expression of markers of fibrosis. Skeletal muscles in Mbnl1∆E3/∆E3/ Mbnl2∆E2/+ mice showed increased histopathology but no deleterious reductions in MuSC numbers and only a slight increase in collagen deposition. These results suggest that factors beyond the loss of MBNL1/MBNL2 and the associated spliceopathy are likely to play a key role in the defects in skeletal muscle regeneration and deleterious effects on MuSCs that are seen in mouse models of RNA toxicity due to expanded CUG repeats.
摘要：
已显示，肌肉盲样（MBNL）RNA结合蛋白家族成员的功能丧失在1型强直性肌营养不良（DM1）的RNA毒性剪接病中起关键作用。影响成人和儿童的最常见的肌营养不良症。MBNL1和MBNL2是骨骼肌中表达最丰富的成员。DM1的一个关键方面是肌肉再生和修复不良，导致营养不良.我们使用BaCl2诱导的肌肉损伤损伤模型来研究Mbnl1ΔE3/ΔE3和Mbnl2ΔE2/ΔE2敲除小鼠的再生和对骨骼肌卫星细胞（MuSC）的影响。类似的实验先前已经显示了在RNA毒性的小鼠模型中对这些参数的有害影响。Mbnl1和Mbnl2敲除小鼠的肌肉再生正常进行，对MuSC数量没有明显的有害影响或纤维化标志物的表达增加。Mbnl1ΔE3/ΔE3/Mbnl2ΔE2/小鼠的骨骼肌显示组织病理学增加，但MuSC数量没有有害减少，胶原蛋白沉积仅略有增加。这些结果表明,MBNL1/MBNL2丢失和相关剪接病之外的因素可能在骨骼肌再生缺陷和对MuSC的有害作用中起关键作用,这在由于扩大的CUG重复的RNA毒性小鼠模型中可见。
