Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice.
Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice.
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DOI：
10.1016/j.nbd.2014.06.023
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发表时间：
2014-10
影响因子：
6.1
通讯作者：
Notterpek L
中科院分区：
文献类型：
--
作者：
Nicks J;Lee S;Harris A;Falk DJ;Todd AG;Arredondo K;Dunn WA Jr;Notterpek L
腓骨肌萎缩症1A型（Charcot-Marie-Tooth disease type 1A，CMT 1A）是一种以进行性脱髓鞘和远端肌无力为特征的遗传性周围神经病。外周髓磷脂蛋白22（PMP 22）的异常表达与CMT 1A有关，并由Trembler J（TrJ）小鼠建模，这些小鼠在PMP 22中携带与受影响谱系相同的亮氨酸至脯氨酸取代。在神经病小鼠的神经元-许旺细胞外植体培养物中，雷帕霉素对自噬的药理学调节减少了PMP 22聚集体的形成并改善了髓鞘形成。在这里，我们询问通过食物补充或腹膜内注射给予雷帕霉素是否可以减轻受影响小鼠的神经病理表型并改善神经肌肉性能。将雄性和雌性野生型（Wt）和TrJ小鼠的组群从2或4月龄开始分配至安慰剂或雷帕霉素治疗，并每月在旋转棒上进行测试。虽然长期喂食（8或10个月）富含雷帕霉素的饮食或短期注射（2个月）雷帕霉素都不能改善神经病小鼠的运动表现，但两种方案都有利于外周神经髓鞘形成。总之，这些结果表明，虽然用雷帕霉素治疗有益于神经病性雪旺细胞的髓鞘形成能力，但这种干预并不能改善神经肌肉功能。观察到的结果可能是神经和骨骼肌组织对雷帕霉素的不同反应的结果。
Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy characterized by progressive demyelination and distal muscle weakness. Abnormal expression of peripheral myelin protein 22 (PMP22) has been linked to CMT1A and is modeled by Trembler J (TrJ) mice, which carry the same leucine to proline substitution in PMP22 as affected pedigrees. Pharmacologic modulation of autophagy by rapamycin in neuron-Schwann cell explant cultures from neuropathic mice reduced PMP22 aggregate formation and improved myelination. Here we asked whether rapamycin administration by food supplementation, or intraperitoneal injection, could alleviate the neuropathic phenotype of affected mice and improve neuromuscular performance. Cohorts of male and female wild type (Wt) and TrJ mice were assigned to placebo or rapamycin treatment starting at 2 or 4 months of age and tested monthly on the rotarod. While neither long-term feeding (8 or 10 months) on rapamycin-enriched diet, or short term injection (2 months) of rapamycin improved locomotor performance of the neuropathic mice, both regimen benefited peripheral nerve myelination. Together, these results indicate that while treatment with rapamycin benefits the myelination capacity of neuropathic Schwann cells, this intervention does not improve neuromuscular function. The observed outcome might be the result of the differential response of nerve and skeletal muscle tissue to rapamycin.