Paucity of the survival motor neuron (SMN) protein triggers the oft-fatal infantile-onset motor neuron disorder, spinal muscular atrophy (SMA). Augmenting the protein is one means of treating SMA and recently led to FDA approval of an intrathecally delivered SMN-enhancing oligonucleotide currently in use. Notwithstanding the advent of this and other therapies for SMA, it is unclear whether the paralysis associated with the disease derives solely from dysfunctional motor neurons that may be efficiently targeted by restricted delivery of SMN-enhancing agents to the nervous system, or stems from broader defects of the motor unit, arguing for systemic SMN repletion. We investigated the disease-contributing effects of low SMN in one relevant peripheral organ - skeletal muscle - by selectively depleting the protein in only this tissue. We found that muscle deprived of SMN was profoundly damaged. Although a disease phenotype was not immediately obvious, persistent low levels of the protein eventually resulted in muscle fiber defects, neuromuscular junction abnormalities, compromised motor performance, and premature death. Importantly, restoring SMN after the onset of muscle pathology reversed disease. Our results provide the most compelling evidence yet for a direct contributing role of muscle in SMA and argue that an optimal therapy for the disease must be designed to treat this aspect of the dysfunctional motor unit.

中文翻译：

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特定于肌肉的SMN减少揭示了脊髓性肌肉萎缩模型中的运动神经元非依赖性疾病。

生存运动神经元（SMN）蛋白的缺乏会触发婴儿致命性运动神经元频发性死亡，即脊髓性肌萎缩症（SMA）。增强蛋白质是治疗SMA的一种方法，最近导致FDA批准了目前使用的鞘内递送SMN增强寡核苷酸。尽管出现了这种和其他针对SMA的疗法，但尚不清楚与该疾病相关的麻痹是仅由功能异常的运动神经元引起的，该运动神经元可以通过将SMN增强剂向神经系统的限制递送而有效地靶向，还是源于更广泛的缺陷电机单元的位置，要求进行系统SMN补充。我们通过选择性地仅消耗该组织中的蛋白质，研究了一种相关的外周器官-骨骼肌中低SMN的致病作用。我们发现剥夺SMN的肌肉受到了严重损害。尽管疾病表型并不立即明显，但持续低水平的蛋白质最终会导致肌肉纤维缺陷，神经肌肉接头异常，运动能力下降和过早死亡。重要的是，在肌肉病理发作后恢复SMN可逆转疾病。我们的结果提供了迄今为止最令人信服的证据，证明肌肉在SMA中具有直接作用，并认为必须针对该疾病设计最佳疗法，以治疗运动功能障碍的这一方面。和过早死亡。重要的是，在肌肉病理发作后恢复SMN可逆转疾病。我们的结果提供了迄今为止最令人信服的证据，证明肌肉在SMA中具有直接作用，并认为必须针对该疾病设计最佳疗法，以治疗运动功能障碍的这一方面。和过早死亡。重要的是，在肌肉病理发作后恢复SMN可逆转疾病。我们的结果提供了迄今为止最令人信服的证据，证明肌肉在SMA中具有直接作用，并认为必须针对该疾病设计最佳疗法，以治疗运动功能障碍的这一方面。