Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
Int J Mol Sci. 2024 Feb 26;25(5):2687. doi: 10.3390/ijms25052687.
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 BaCl-induced damage model of muscle injury to study regeneration and effects on skeletal muscle satellite cells (MuSCs) in and knockout mice. Similar experiments have previously shown deleterious effects on these parameters in mouse models of RNA toxicity. Muscle regeneration in and knockout mice progressed normally with no obvious deleterious effects on MuSC numbers or increased expression of markers of fibrosis. Skeletal muscles in 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.
肌肉盲样（MBNL）家族 RNA 结合蛋白功能丧失已被证明在 1 型肌强直性营养不良（DM1）的 RNA 毒性剪接病中发挥关键作用，DM1 是最常见的影响成人和儿童的肌肉疾病。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，导致肌肉萎缩。我们使用 BaCl 诱导的肌肉损伤模型研究了 和 基因敲除小鼠的肌肉再生和对骨骼肌卫星细胞（MuSCs）的影响。先前的类似实验表明，在 RNA 毒性的小鼠模型中，这些参数存在有害影响。 和 基因敲除小鼠的肌肉再生正常进行，MuSC 数量没有明显减少，纤维化标志物表达也没有增加。骨骼肌中 基因敲除小鼠的组织病理学增加，但 MuSC 数量没有减少，胶原沉积仅略有增加。这些结果表明，除了 MBNL1/MBNL2 的丧失和相关的剪接病之外，可能还有其他因素在 RNA 毒性的小鼠模型中导致骨骼肌再生缺陷和 MuSC 损伤中发挥关键作用，这是由于 CUG 重复扩展引起的。
