Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA.
Neuromuscul Disord. 2012 Mar;22(3):277-85. doi: 10.1016/j.nmd.2011.10.012. Epub 2011 Nov 10.
Spinal Muscular Atrophy (SMA) is a devastating neurodegenerative disease and is a leading genetic cause of infantile death. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). The presence of a nearly identical copy gene called SMN2 has led to the development of several strategies that are designed to elevate SMN levels, and it is clear that SMN2 is an important modifier gene. However, the possibility exists that SMN-independent strategies to lessen the severity of the SMA phenotype could provide insight into disease development as well as aid in the identification of potential therapeutic targets. Muscle enhancement has been considered an interesting target for a variety of neurodegenerative diseases, including SMA. Previously we have shown in SMA mice that delivery of recombinant follistatin resulted in an extension in survival and a general lessening of disease severity. Follistatin is known to functionally block myostatin (MSTN), a potent inhibitor of muscle development. However, follistatin is a multifaceted protein involved in a variety of cellular pathways. To determine whether MSTN inhibition was the primary pathway associated with the previously reported follistatin results, we generated an animal model of SMA in which Mstn was genetically inactivated. In this report we characterize the novel SMA/Mstn model and demonstrate that Mstn inactivation does not significantly enhance muscle development in neonatal animals, nor does it result in an amelioration of the SMA phenotype.
脊髓性肌萎缩症（SMA）是一种毁灭性的神经退行性疾病，是婴儿死亡的主要遗传原因。SMA 是由运动神经元存活 1（SMN1）的纯合缺失引起的。存在一个几乎相同的拷贝基因，称为 SMN2，这导致了几种旨在提高 SMN 水平的策略的发展，很明显，SMN2 是一个重要的修饰基因。然而，存在一种可能性，即不依赖于 SMN 的策略可以减轻 SMA 表型的严重程度，这可能为疾病的发展提供了新的思路，并有助于确定潜在的治疗靶点。肌肉增强一直被认为是各种神经退行性疾病的一个有趣的靶点，包括 SMA。我们之前已经在 SMA 小鼠中表明，重组卵泡抑素的递送导致了生存时间的延长和疾病严重程度的普遍减轻。卵泡抑素已知能够功能性地阻断肌肉生长抑制素（MSTN），MSTN 是肌肉发育的一种有效抑制剂。然而，卵泡抑素是一种涉及多种细胞途径的多功能蛋白。为了确定 MSTN 抑制是否是与之前报道的卵泡抑素结果相关的主要途径，我们生成了一种 SMA 的动物模型，其中 Mstn 被基因失活。在本报告中，我们描述了新型 SMA/Mstn 模型，并证明 MSTN 失活不会显著增强新生动物的肌肉发育，也不会改善 SMA 表型。
